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Rulla Alsaedi , Kimberly McKeirnan; Literature Review of Type 2 Diabetes Management and Health Literacy. Diabetes Spectr 1 November 2021; 34 (4): 399–406. https://doi.org/10.2337/ds21-0014

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The purpose of this literature review was to identify educational approaches addressing low health literacy for people with type 2 diabetes. Low health literacy can lead to poor management of diabetes, low engagement with health care providers, increased hospitalization rates, and higher health care costs. These challenges can be even more profound among minority populations and non-English speakers in the United States.

A literature search and standard data extraction were performed using PubMed, Medline, and EMBASE databases. A total of 1,914 articles were identified, of which 1,858 were excluded based on the inclusion criteria, and 46 were excluded because of a lack of relevance to both diabetes management and health literacy. The remaining 10 articles were reviewed in detail.

Patients, including ethnic minorities and non-English speakers, who are engaged in diabetes education and health literacy improvement initiatives and ongoing follow-up showed significant improvement in A1C, medication adherence, medication knowledge, and treatment satisfaction. Clinicians considering implementing new interventions to address diabetes care for patients with low health literacy can use culturally tailored approaches, consider ways to create materials for different learning styles and in different languages, engage community health workers and pharmacists to help with patient education, use patient-centered medication labels, and engage instructors who share cultural and linguistic similarities with patients to provide educational sessions.

This literature review identified a variety of interventions that had a positive impact on provider-patient communication, medication adherence, and glycemic control by promoting diabetes self-management through educational efforts to address low health literacy.

Diabetes is the seventh leading cause of death in the United States, and 30.3 million Americans, or 9.4% of the U.S. population, are living with diabetes ( 1 , 2 ). For successful management of a complicated condition such as diabetes, health literacy may play an important role. Low health literacy is a well-documented barrier to diabetes management and can lead to poor management of medical conditions, low engagement with health care providers (HCPs), increased hospitalizations, and, consequently, higher health care costs ( 3 – 5 ).

The Healthy People 2010 report ( 6 ) defined health literacy as the “degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.” Diabetes health literacy also encompasses a wide range of skills, including basic knowledge of the disease state, self-efficacy, glycemic control, and self-care behaviors, which are all important components of diabetes management ( 3 – 5 , 7 ). According to the Institute of Medicine’s Committee on Health Literacy, patients with poor health literacy are twice as likely to have poor glycemic control and were found to be twice as likely to be hospitalized as those with adequate health literacy ( 8 ). Associations between health literacy and health outcomes have been reported in many studies, the first of which was conducted in 1995 in two public hospitals and found that many patients had inadequate health literacy and could not perform the basic reading tasks necessary to understand their treatments and diagnoses ( 9 ).

Evaluation of health literacy is vital to the management and understanding of diabetes. Several tools for assessing health literacy have been evaluated, and the choice of which to use depends on the length of the patient encounter and the desired depth of the assessment. One widely used literacy assessment tool, the Test of Functional Health Literacy in Adults (TOFHLA), consists of 36 comprehension questions and four numeric calculations ( 10 ). Additional tools that assess patients’ reading ability include the Rapid Estimate of Adult Literacy in Medicine (REALM) and the Literacy Assessment for Diabetes. Tests that assess diabetes numeracy skills include the Diabetes Numeracy Test, the Newest Vital Sign (NVS), and the Single-Item Literacy Screener (SILS) ( 11 ).

Rates of both diabetes and low health literacy are higher in populations from low socioeconomic backgrounds ( 5 , 7 , 12 ). People living in disadvantaged communities face many barriers when seeking health care, including inconsistent housing, lack of transportation, financial difficulties, differing cultural beliefs about health care, and mistrust of the medical professions ( 13 , 14 ). People with high rates of medical mistrust tend to be less engaged in their care and to have poor communication with HCPs, which is another factor HCPs need to address when working with their patients with diabetes ( 15 ).

The cost of medical care for people with diabetes was $327 billion in 2017, a 26% increase since 2012 ( 1 , 16 ). Many of these medical expenditures are related to hospitalization and inpatient care, which accounts for 30% of total medical costs for people with diabetes ( 16 ).

People with diabetes also may neglect self-management tasks for various reasons, including low health literacy, lack of diabetes knowledge, and mistrust between patients and HCPs ( 7 , 15 ).

These challenges can be even more pronounced in vulnerable populations because of language barriers and patient-provider mistrust ( 17 – 19 ). Rates of diabetes are higher among racial and ethnic minority groups; 15.1% of American Indians and Alaskan Natives, 12.7% of Non-Hispanic Blacks, 12.1% of Hispanics, and 8% of Asian Americans have diagnosed diabetes, compared with 7.4% of non-Hispanic Whites ( 1 ). Additionally, patient-provider relationship deficits can be attributed to challenges with communication, including HCPs’ lack of attention to speaking slowly and clearly and checking for patients’ understanding when providing education or gathering information from people who speak English as a second language ( 15 ). White et al. ( 15 ) demonstrated that patients with higher provider mistrust felt that their provider’s communication style was less interpersonal and did not feel welcome as part of the decision-making process.

To the authors’ knowledge, there is no current literature review evaluating interventions focused on health literacy and diabetes management. There is a pressing need for such a comprehensive review to provide a framework for future intervention design. The objective of this literature review was to gather and summarize studies of health literacy–based diabetes management interventions and their effects on overall diabetes management. Medication adherence and glycemic control were considered secondary outcomes.

Search Strategy

A literature review was conducted using the PubMed, Medline, and EMBASE databases. Search criteria included articles published between 2015 and 2020 to identify the most recent studies on this topic. The search included the phrases “diabetes” and “health literacy” to specifically focus on health literacy and diabetes management interventions and was limited to original research conducted in humans and published in English within the defined 5-year period. Search results were exported to Microsoft Excel for evaluation.

Study Selection

Initial screening of the articles’ abstracts was conducted using the selection criteria to determine which articles to include or exclude ( Figure 1 ). The initial search results were reviewed for the following inclusion criteria: original research (clinical trials, cohort studies, and cross-sectional studies) conducted in human subjects with type 2 diabetes in the United States, and published in English between 2015 and 2020. Articles were considered to be relevant if diabetes was included as a medical condition in the study and an intervention was made to assess or improve health literacy. Studies involving type 1 diabetes or gestational diabetes and articles that were viewpoints, population surveys, commentaries, case reports, reviews, or reports of interventions conducted outside of the United States were excluded from further review. The criteria requiring articles to be from the past 5 years and from the United States were used because of the unique and quickly evolving nature of the U.S. health care system. Articles published more than 5 years ago or from other health care systems may have contributed information that was not applicable to or no longer relevant for HCPs in the United States. Articles were screened and reviewed independently by both authors. Disagreements were resolved through discussion to create the final list of articles for inclusion.

PRISMA diagram of the article selection process.

Data Extraction

A standard data extraction was performed for each included article to obtain information including author names, year of publication, journal, study design, type of intervention, primary outcome, tools used to assess health literacy or type 2 diabetes knowledge, and effects of intervention on overall diabetes management, glycemic control, and medication adherence.

A total of 1,914 articles were collected from a search of the PubMed, MEDLINE, and EMBASE databases, of which 1,858 were excluded based on the inclusion and exclusion criteria. Of the 56 articles that met criteria for abstract review, 46 were excluded because of a lack of relevance to both diabetes management and health literacy. The remaining 10 studies identified various diabetes management interventions, including diabetes education tools such as electronic medication instructions and text message–based interventions, technology-based education videos, enhanced prescription labels, learner-based education materials, and culturally tailored interventions ( 15 , 20 – 28 ). Figure 1 shows the PRISMA diagram of the article selection process, and Table 1 summarizes the findings of the article reviews ( 15 , 20 – 28 ).

Findings of the Article Reviews (15,20–28)

SAHLSA, Short Assessment of Health Literacy for Spanish Adults.

Medical mistrust and poor communication are challenging variables in diabetes education. White et al. ( 15 ) examined the association between communication quality and medical mistrust in patients with type 2 diabetes. HCPs at five health department clinics received training in effective health communication and use of the PRIDE (Partnership to Improve Diabetes Education) toolkit in both English and Spanish, whereas control sites were only exposed to National Diabetes Education Program materials without training in effective communication. The study evaluated participant communication using several tools, including the Communication Assessment Tool (CAT), Interpersonal Processes of Care (IPC-18), and the Short Test of Functional Health Literacy in Adults (s-TOFHLA). The authors found that higher levels of mistrust were associated with lower CAT and IPC-18 scores.

Patients with type 2 diabetes are also likely to benefit from personalized education delivery tools such as patient-centered labeling (PCL) of prescription drugs, learning style–based education materials, and tailored text messages ( 24 , 25 , 27 ). Wolf et al. ( 27 ) investigated the use of PCL in patients with type 2 diabetes and found that patients with low health literacy who take medication two or more times per day have higher rates of proper medication use when using PCL (85.9 vs. 77.4%, P = 0.03). The objective of the PCL intervention was to make medication instructions and other information on the labels easier to read to improve medication use and adherence rates. The labels incorporated best-practice strategies introduced by the Institute of Medicine for the Universal Medication Schedule. These strategies prioritize medication information, use of larger font sizes, and increased white space. Of note, the benefits of PCL were largely seen with English speakers. Spanish speakers did not have substantial improvement in medication use or adherence, which could be attributed to language barriers ( 27 ).

Nelson et al. ( 25 ) analyzed patients’ engagement with an automated text message approach to supporting diabetes self-care activities in a 12-month randomized controlled trial (RCT) called REACH (Rapid Education/Encouragement and Communications for Health) ( 25 ). Messages were tailored based on patients’ medication adherence, the Information-Motivation-Behavioral Skills model of health behavior change, and self-care behaviors such as diet, exercise, and self-monitoring of blood glucose. Patients in this trial were native English speakers, so further research to evaluate the impact of the text message intervention in patients with limited English language skills is still needed. However, participants in the intervention group reported higher engagement with the text messages over the 12-month period ( 25 ).

Patients who receive educational materials based on their learning style also show significant improvement in their diabetes knowledge and health literacy. Koonce et al. ( 24 ) developed and evaluated educational materials based on patients’ learning style to improve health literacy in both English and Spanish languages. The materials were made available in multiple formats to target four different learning styles, including materials for visual learners, read/write learners, auditory learners, and kinesthetic learners. Spanish-language versions were also available. Researchers were primarily interested in measuring patients’ health literacy and knowledge of diabetes. The intervention group received materials in their preferred learning style and language, whereas the control group received standard of care education materials. The intervention group showed significant improvement in diabetes knowledge and health literacy, as indicated by Diabetes Knowledge Test (DKT) scores. More participants in the intervention group reported looking up information about their condition during week 2 of the intervention and showed an overall improvement in understanding symptoms of nerve damage and types of food used to treat hypoglycemic events. However, the study had limited enrollment of Spanish speakers, making the applicability of the results to Spanish-speaking patients highly variable.

Additionally, findings by Hofer et al. ( 22 ) suggest that patients with high A1C levels may benefit from interventions led by community health workers (CHWs) to bridge gaps in health literacy and equip patients with the tools to make health decisions. In this study, Hispanic and African American patients with low health literacy and diabetes not controlled by oral therapy benefited from education sessions led by CHWs. The CHWs led culturally tailored support groups to compare the effects of educational materials provided in an electronic format (via iDecide) and printed format on medication adherence and self-efficacy. The study found increased adherence with both formats, and women, specifically, had a significant increase in medication adherence and self-efficacy. One of the important aspects of this study was that the CHWs shared cultural and linguistic characteristics with the patients and HCPs, leading to increased trust and satisfaction with the information presented ( 22 ).

Kim et al. ( 23 ) found that Korean-American participants benefited greatly from group education sessions that provided integrated counseling led by a team of nurses and CHW educators. The intervention also had a health literacy component that focused on enhancing skills such as reading food package labels, understanding medical terminology, and accessing health care services. This intervention led to a significant reduction of 1–1.3% in A1C levels in the intervention group. The intervention established the value of collaboration between CHW educators and nurses to improve health information delivery and disease management.

A collaboration between CHW educators and pharmacists was also shown to reinforce diabetes knowledge and improve health literacy. Sharp et al. ( 26 ) conducted a cross-over study in four primary care ambulatory clinics that provided care for low-income patients. The study found that patients with low health literacy had more visits with pharmacists and CHWs than those with high health literacy. The CHWs provided individualized support to reinforce diabetes self-management education and referrals to resources such as food, shelter, and translation services. The translation services in this study were especially important for building trust with non-English speakers and helping patients understand their therapy. Similar to other studies, the CHWs shared cultural and linguistic characteristics with their populations, which helped to overcome communication-related and cultural barriers ( 23 , 26 ).

The use of electronic tools or educational videos yielded inconclusive results with regard to medication adherence. Graumlich et al. ( 20 ) implemented a new medication planning tool called Medtable within an electronic medical record system in several outpatient clinics serving patients with type 2 diabetes. The tool was designed to organize medication review and patient education. Providers can use this tool to search for medication instructions and actionable language that are appropriate for each patient’s health literacy level. The authors found no changes in medication knowledge or adherence, but the intervention group reported higher satisfaction. On the other hand, Yeung et al. ( 28 ) showed that pharmacist-led online education videos accessed using QR codes affixed to the patients’ medication bottles and health literacy flashcards increased patients’ medication adherence in an academic medical hospital.

Goessl et al. ( 21 ) found that patients with low health literacy had significantly higher retention of information when receiving evidence-based diabetes education through a DVD recording than through an in-person group class. This 18-month RCT randomized participants to either the DVD or in-person group education and assessed their information retention through a teach-back strategy. The curriculum consisted of diabetes prevention topics such as physical exercise, food portions, and food choices. Participants in the DVD group had significantly higher retention of information than those in the control (in-person) group. The authors suggested this may have been because participants in the DVD group have multiple opportunities to review the education material.

Management of type 2 diabetes remains a challenge for HCPs and patients, in part because of the challenges discussed in this review, including communication barriers between patients and HCPs and knowledge deficits about medications and disease states ( 29 ). HCPs can have a positive impact on the health outcomes of their patients with diabetes by improving patients’ disease state and medication knowledge.

One of the common themes identified in this literature review was the prevalence of culturally tailored diabetes education interventions. This is an important strategy that could improve diabetes outcomes and provide an alternative approach to diabetes self-management education when working with patients from culturally diverse backgrounds. HCPs might benefit from using culturally tailored educational approaches to improve communication with patients and overcome the medical mistrust many patients feel. Although such mistrust was not directly correlated with diabetes management, it was noted that patients who feel mistrustful tend to have poor communication with HCPs ( 20 ). Additionally, Latino/Hispanic patients who have language barriers tend to have poor glycemic control ( 19 ). Having CHWs work with HCPs might mitigate some patient-provider communication barriers. As noted earlier, CHWs who share cultural and linguistic characteristics with their patient populations have ongoing interactions and more frequent one-on-one encounters ( 12 ).

Medication adherence and glycemic control are important components of diabetes self-management, and we noted that the integration of CHWs into the diabetes health care team and the use of simplified medication label interventions were both successful in improving medication adherence ( 23 , 24 ). The use of culturally tailored education sessions and the integration of pharmacists and CHWs into the management of diabetes appear to be successful in reducing A1C levels ( 12 , 26 ). Electronic education tools and educational videos alone did not have an impact on medication knowledge or information retention in patients with low health literacy, but a combination of education tools and individualized sessions has the potential to improve diabetes medication knowledge and overall self-management ( 20 , 22 , 30 ).

There were several limitations to our literature review. We restricted our search criteria to articles published in English and studies conducted within the United States to ensure that the results would be relevant to U.S. HCPs. However, these limitations may have excluded important work on this topic. Additional research expanding this search beyond the United States and including articles published in other languages may demonstrate different outcomes. Additionally, this literature review did not focus on A1C as the primary outcome, although A1C is an important indicator of diabetes self-management. A1C was chosen as the method of evaluating the impact of health literacy interventions in patients with diabetes, but other considerations such as medication adherence, impact on comorbid conditions, and quality of life are also important factors.

The results of this work show that implementing health literacy interventions to help patients manage type 2 diabetes can have beneficial results. However, such interventions can have significant time and monetary costs. The potential financial and time costs of diabetes education interventions were not evaluated in this review and should be taken into account when designing interventions. The American Diabetes Association estimated the cost of medical care for people with diabetes to be $327 billion in 2017, with the majority of the expenditure related to hospitalizations and nursing home facilities ( 16 ). Another substantial cost of diabetes that can be difficult to measure is treatment for comorbid conditions and complications such as cardiovascular and renal diseases.

Interventions designed to address low health literacy and provide education about type 2 diabetes could be a valuable asset in preventing complications and reducing medical expenditures. Results of this work show that clinicians who are considering implementing new interventions may benefit from the following strategies: using culturally tailored approaches, creating materials for different learning styles and in patients’ languages, engaging CHWs and pharmacists to help with patient education, using PCLs for medications, and engaging education session instructors who share patients’ cultural and linguistic characteristics.

Diabetes self-management is crucial to improving health outcomes and reducing medical costs. This literature review identified interventions that had a positive impact on provider-patient communication, medication adherence, and glycemic control by promoting diabetes self-management through educational efforts to address low health literacy. Clinicians seeking to implement diabetes care and education interventions for patients with low health literacy may want to consider drawing on the strategies described in this article. Providing culturally sensitive education that is tailored to patients’ individual learning styles, spoken language, and individual needs can improve patient outcomes and build patients’ trust.

Duality of Interest

No potential conflicts of interest relevant to this article were reported.

Author Contributions

Both authors conceptualized the literature review, developed the methodology, analyzed the data, and wrote, reviewed, and edited the manuscript. R.A. collected the data. K.M. supervised the review. K.M. is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation

Portions of this research were presented at the Washington State University College of Pharmacy and Pharmaceutical Sciences Honors Research Day in April 2019.

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• Published: 23 July 2015

Type 2 diabetes mellitus

• Ralph A. DeFronzo 1 ,
• Ele Ferrannini 2 ,
• Leif Groop 3 ,
• Robert R. Henry 4 ,
• William H. Herman 5 ,
• Jens Juul Holst 6 ,
• Frank B. Hu 7 ,
• C. Ronald Kahn 8 ,
• Itamar Raz 9 ,
• Gerald I. Shulman 10 ,
• Donald C. Simonson 11 ,
• Marcia A. Testa 12 &
• Ram Weiss 13  

Nature Reviews Disease Primers volume  1 , Article number:  15019 ( 2015 ) Cite this article

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• Diabetes complications
• Type 2 diabetes

Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN

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Acknowledgements

The authors acknowledge grants from: the South Texas Veterans Healthcare System to R.A.D.; the National Institutes of Health (grants R01DK24092 to R.A.D.; DK58845 and P30 DK46200 to F.B.H.; R01 DK-040936, R01 DK-049230, R24 DK-085836, UL1 RR-045935, R01 DK-082659 and R24 DK085610 to G.I.S.; P30 DK036836 to C.R.K. Novo Nordisk Foundation for Basic Metabolic Research and the University of Copenhagen to G.I.S. and C.R.K.; DVA-Merit Review grant and VA San Diego Healthcare System to R.H.; National Institute for Diabetes and Digestive and Kidney Disease (grant P30DK092926) to W.H.; the Swedish Research Council (grants 2010–3490 and 2008–6589) and European Council (grants GA269045) to L.G.; Italian Ministry of University & Research (MIUR 2010329EKE) to E.F.; the Patient-Centered Outcomes Research Institute (PCORI) Program Award (CE1304-6756) to D.C.S. and M.A.T.; NovoNordisk Foundation to the NNF Center for Basic Metabolic Research to J.H. W.H. acknowledges the Michigan Center for Diabetes Translational Research and I.R. thanks R. Sprung for editorial assistance.

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Authors and affiliations.

Diabetes Division, Department of Medicine, University of Texas Health Science Center, South Texas Veterans Health Care System and Texas Diabetes Institute, 701 S. Zarzamoro, San Antonio, 78207, Texas, USA

Ralph A. DeFronzo

CNR Institute of Clinical Physiology, Pisa, Italy

Ele Ferrannini

Department of Clinical Science Malmoe, Diabetes & Endocrinology, Lund University Diabetes Centre, Lund, Sweden

University of California, San Diego, Section of Diabetes, Endocrinology & Metabolism, Center for Metabolic Research, VA San Diego Healthcare System, San Diego, California, USA

Robert R. Henry

University of Michigan, Ann Arbor, Michigan, USA

William H. Herman

University of Copenhagen, Kobenhavn, Denmark

Jens Juul Holst

Department of Nutrition, Harvard T.H. Chan School of Public Health and Department of Epidemiology, Harvard T.H. Chan School of Public Health and Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Frank B. Hu

Harvard Medical School and Joslin Diabetes Center, Boston, Massachusetts, USA

C. Ronald Kahn

Division of Internal Medicine, Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel

Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA

Gerald I. Shulman

Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Donald C. Simonson

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

Marcia A. Testa

Department of Human Metabolism and Nutrition, Braun School of Public Health, Hebrew University, Jerusalem, Israel

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Contributions

Introduction (R.R.H.); Epidemiology (F.B.H.); Mechanisms/pathophysiology (L.C.G., C.R.K., E.F., G.I.S. and R.A.D.); Diagnosis, screening and prevention (W.H.H.); Management (R.A.D.); Quality of life (D.C.S. and M.A.T.); Outlook (I.R., J.J.H. and R.W.); overview of Primer (R.A.D.).

Corresponding author

Correspondence to Ralph A. DeFronzo .

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Competing interests.

The authors declare the following potential COI: (1) R.A.D.: Research Grant Support - AstraZeneca, Bristol Myers Squibb, Janssen; Speaker's Bureau - AstraZeneca, Novo Nordisk, Advisory Board/Consultant - AstraZeneca, Janssen, Novo Nordisk, Boehringer Ingelheim, Lexicon, Intarcia; (2) E.F.: Research Grant Support - Boehringer Ingelheim, Eli Lilly; Consultant/Speaker Bureau-Boehringer Ingelheim, Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Takeda, Medtronic, Intarcia; (3) C.R.K. serves as a consultant for Medimmune, Merck, Five Prime Therapeutics, CohBar, Antriabio, and Catabasis; (4) L.G. has no conflict of interest; (5) R.H. has received grant support from Hitachi, Janssen, Eli Lilly, Sanofi-Aventis and Viacyte and is a consultant/advisory board member for Alere, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clin Met, Eisai, Elcelyx, Gilead, Intarcia, Isis, Janssen, Merck, Novo Nordisk, Sanofi-Aventis, and Vivus; (6) W.H.H. has no conflict of interest; (7) J.J.H. has received grant support from Novartis and Merck and is a consultant/advisory board member for Glaxo, Smith, Kline, Novo Nordisk, and Zealand Pharmaceuticals; (8) M.A.T. has no conflict of interest; (9) R.W. serves as a consultant for Medtronics and Kamada and is on the speaker's bureau for Medtronics and Novo Nordisk; (10) F.H. has received research support from California Walnut Commission and Metegenics; (11) G.I.S. serves on scientific advisory boards for Merck and Novartis and he has received research grant support from Gilead Pharmaceuticals; (12) D.C.S. has no conflict of interest; (13) I.R. – Advisory Board: Novo Nordisk, Astra Zeneca/BMS, MSD, Eli Lilly, Sanofi, Medscape Cardiology; Consultant: Astra Zeneca/BMS, Insuline; Speaker's Bureau: Eli Lilly, Novo Nordisk, Astra Zeneca/BMS, J&J, Sanofi, MSD, Novartis, Teva; Shareholder: Insuline, Labstyle.

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DeFronzo, R., Ferrannini, E., Groop, L. et al. Type 2 diabetes mellitus. Nat Rev Dis Primers 1 , 15019 (2015). https://doi.org/10.1038/nrdp.2015.19

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Type 1 and type 2 diabetes mellitus: Clinical outcomes due to COVID-19. Protocol of a systematic literature review

Contributed equally to this work with: Juan Pablo Pérez Bedoya, Alejandro Mejía Muñoz

Roles Conceptualization, Investigation, Methodology, Project administration, Writing – original draft

* E-mail: [email protected]

Current address: National Faculty of Public Health, University of Antioquia, Medellin, Antioquia, Colombia

Affiliation Epidemiology Group, National Faculty of Public Health, University of Antioquia, Medellín, Colombia

Affiliation Biology and Control of Infectious Diseases Group, Faculty of Exact and Natural Sciences, University of Antioquia, Medellín, Colombia

Roles Supervision, Validation, Writing – review & editing

¶ ‡ NCB and PADV also contributed equally to this work.

Affiliation Department of Translational Medicine, Herbert Wertheim College of Medicine & Department of Global Health, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, United States of America

• Juan Pablo Pérez Bedoya, 
• Alejandro Mejía Muñoz, 
• Noël Christopher Barengo, 
• Paula Andrea Diaz Valencia

• Published: September 9, 2022
• https://doi.org/10.1371/journal.pone.0271851
• See the preprint
• Peer Review
• Reader Comments

Introduction

Diabetes has been associated with an increased risk of complications in patients with COVID-19. Most studies do not differentiate between patients with type 1 and type 2 diabetes, which correspond to two pathophysiological distinct diseases that could represent different degrees of clinical compromise.

To identify if there are differences in the clinical outcomes of patients with COVID-19 and diabetes (type 1 and type 2) compared to patients with COVID-19 without diabetes.

Observational studies of patients with COVID-19 and diabetes (both type 1 and type 2) will be included without restriction of geographic region, gender or age, whose outcome is hospitalization, admission to intensive care unit or mortality compared to patients without diabetes. Two authors will independently perform selection, data extraction, and quality assessment, and a third reviewer will resolve discrepancies. The data will be synthesized regarding the sociodemographic and clinical characteristics of patients with diabetes and without diabetes accompanied by the measure of association for the outcomes. The data will be synthesized regarding the sociodemographic and clinical characteristics of patients with diabetes and without diabetes accompanied by the measure of association for the outcomes.

Expected results

Update the evidence regarding the risk of complications in diabetic patients with COVID-19 and in turn synthesize the information available regarding type 1 and type 2 diabetes mellitus, to provide keys to a better understanding of the pathophysiology of diabetics.

Systematic review registry

This study was registered at the International Prospective Registry for Systematic Reviews (PROSPERO)— CRD42021231942 .

Citation: Pérez Bedoya JP, Mejía Muñoz A, Barengo NC, Diaz Valencia PA (2022) Type 1 and type 2 diabetes mellitus: Clinical outcomes due to COVID-19. Protocol of a systematic literature review. PLoS ONE 17(9): e0271851. https://doi.org/10.1371/journal.pone.0271851

Editor: Alok Raghav, GSVM Medical College, INDIA

Received: July 7, 2022; Accepted: August 23, 2022; Published: September 9, 2022

Copyright: © 2022 Pérez Bedoya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.

Funding: This research was developed within the framework of the project "Repository for the surveillance of risk factors for chronic diseases in Colombia, the Caribbean and the Americas" and has the financial support of the Ministry of Science, Technology and Innovation of Colombia—Minciencias 844 (grant number 111584467754). The opinions expressed are those of the authors and not necessarily of Minciencias.

Competing interests: The authors have declared that no competing interests exist.

The Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), the causal viral agent of coronavirus disease 2019 (COVID-19), currently has the world in one of the greatest public health crises of recent times since its appearance at the end of 2019 in the city of Wuhan, China [ 1 ]. The infection has a mild or even asymptomatic course in most cases, but in elderly patients (over 60 years-of-age) and in those with pre-existing chronic comorbidities, it can progress severe complications such as pneumonia, acute respiratory distress (ARDS) with hyperinflammatory involvement and multi-organ failure, leading in some cases to death [ 2 ].

Different studies have reported that patients diagnosed with diabetes who suffer from COVID-19 disease have higher morbidity and mortality compared with people without diabetes [ 3 ]. An analysis by Gude Sampedro et al. using prognostic models found that diabetic patients had greater odds of being hospitalized (OR 1.43; 95% CI: 1.18 to 1.73), admitted to the intensive care unit (OR 1.61; 95% CI: 1.12 to 2.31) and dying from COVID-19 (OR 1.79; 95% CI %: 1.38 to 2.32) compared with patients without diabetes [ 4 ]. However, it is difficult to establish whether diabetes alone directly contributed to the increase likelihood of complications.

Several studies using secondary data have emerged during the course of the pandemic that seek to determine the association of diabetes with mortality and other clinical outcomes in patients with COVID-19, such as, for example, a meta-analysis carried out by Shang et al. of severe infection and mortality from COVID-19 in diabetic patients compared with those without diabetes. They reported that patients with COVID-19 and diabetes had higher odds of serious infection (OR = 2.38, 95% CI: 2.05 to 2.78) and mortality (OR = 2, 21, 95% CI: 1.83 to 2.66) than patients without diabetes [ 5 ]. Despite the fact that there are several primary studies that attempt to explain the association between diabetes and COVID-19, most studies lack epidemiological rigor in the design and methodology used [ 6 ]. In addition, many of them did not distinguish between type 1 and type 2 diabetes, which are two very different conditions with different clinical development and pathophysiological mechanisms [ 7 ]. This may lead to different degrees of clinical complications from COVID-19. Currently, there is a gap in knowledge about the complications in patients with COVID-19 according to the type of diabetes. Moreover, only limited information exist how COVID-19 affects type 1 patients [ 8 , 9 ].

The objective of this systematic literature review will be to identify whether there are differences in the clinical outcomes of both type 1 and type 2 diabetes patients diagnosed with COVID-19 compared with patients with COVID-19 without a diagnosis of diabetes. This study will provide scientific evidence regarding the risk of complications in diabetic patients with COVID-19 and, in turn, synthesize the available information regarding to type 1 and type 2 diabetes.

Study design

This systematic literature review protocol was prepared according to the Preferred Reporting Elements for Systematic Review and Meta-Analysis Protocols (PRISMA-P) [ 10 ] ( S1 Appendix ). The results of the final systematic review will be reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA 2020) [ 11 , 12 ]. In the event of significant deviations from this protocol, they will be reported and published with the results of the review.

Eligibility criteria

Participants (population)..

Patients with a confirmed diagnosis of COVID-19 without restriction of geographic region, sex, or age. For the diagnosis of COVID-19, the operational definition of confirmed case of the World Health Organization in its latest update will be used as a reference. Confirmed case of SARS-CoV-2 infection: a person with a positive Nucleic Acid Amplification Test (NAAT), regardless of clinical criteria OR epidemiological criteria or a person meeting clinical criteria AND/OR epidemiological criteria (suspect case A) with a positive professional- use or self-test SARS-CoV-2 Antigen RDT [ 13 ].

Patients with COVID-19 and concomitant diagnosis of unspecified diabetes mellitus, differentiated into type 1 diabetes mellitus or type 2 diabetes mellitus, without restriction of geographic region, gender, or age of the patients, who present definition of clinical criteria and /or paraclinical tests used by researchers to classify patients according to their diabetes status.

The operational definition of a confirmed case of diabetes mellitus provided by the American Diabetes Association will be used as a guide. The reference diagnostic criteria for diabetes are fasting plasma glucose ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h or 2-h plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during OGTT or hemoglobin A1C ≥6.5% (48 mmol/mol) or in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, at random plasma glucose ≥200 mg/dL [ 14 ].

In selected primary studies, identification of diabetes status may be based on medical history and International Classification of Diseases codes for type 1 or type 2 diabetes, use of antidiabetic medications, or previously defined diagnostic criteria.

Comparator.

Patients with COVID-19 who do not have a concomitant diagnosis of diabetes mellitus.

The main endpoint is all-cause mortality (according to the definitions of each primary study) and the secondary outcomes are hospitalization and admission to the ICU, where the authors specify a clear definition based on clinical practice guidelines and provide a well-defined criteria for patient outcomes.

Type of study.

Primary observational original research studies (prospective or retrospective cohort, case-control design, and cross-sectional studies) will be included in this systematic review.

Exclusion criteria

Clinical trials, editorials, letters to the editor, reviews, case reports, case series, narrative reviews or systematic reviews and meta-analyses, as well as research in the field of basic sciences based on experimental laboratory models, will be excluded. Original research articles that only include other types of diabetes, such as monogenic diabetes, gestational diabetes, latent autoimmune diabetes in adults, ketosis-prone diabetes, among others, or articles with publication status prior to publication will not be considered. In addition, articles whose main hypothesis is not diabetes and do not have the established outcomes will be excluded.

Information sources and search strategy

Electronic bibliographic databases..

For the preparation of the search strategy, the recommendations of the PRISMA-S guide [ 15 ] will be adopted. Relevant articles will be identified by electronic search applying the equation previously developed by the researchers and validated by an expert librarian ( S2 Appendix ). The following electronic bibliographic databases will be used: MEDLINE, EMBASE, LILACS, OVID MEDLINE, WHO (COVID-19 Global literature on coronavirus disease) and SCOPUS with a publication date from December 2019 to August 15, 2022, without language restriction.

The search for potential primary studies published in gray literature will be performed through the World Health Organization database for COVID-19 (WHO COVID-19 Global literature on coronavirus disease). This database contains different electronic bibliographic databases incorporated into its browser, including Web of Science, EuropePMC and Gray literature, among others.

Unlike electronic bibliographic databases.

To identify other potentially eligible studies, the references of relevant publications will be reviewed to perform a snowball manual search. This technique consists of searching for new articles from the primary studies already selected in order to guarantee exhaustiveness in the search.

Study selection process

Two researchers will independently evaluate all the titles and abstracts of the retrieved articles, using the free access Rayyan® software [ 16 ] with previously established selection criteria. Disagreements will be resolved in first instance through discussion and in the second instance through a third reviewer. Subsequently, the full text of the articles selected in the eligibility phase will be read independently by two researchers, both using the same instrument previously validated in Excel according to predefined criteria. Discrepancies will be resolved by discussion or a third reviewer. The process of identification, selection and inclusion of primary studies will be described and presented using the flowchart recommended by the PRISMA statement in its latest version 2020 [ 11 , 12 ].

Data collection and extraction

Standardized and validated forms will be used to collect the data extracted from the primary studies, accompanied by a detailed instruction manual to specify the guiding questions, and avoid the introduction of bias. Data will be extracted from those articles in full text format. If the full text is not available, contact the author or search for the manuscript with the help of the library system. This process will be carried out by two researchers independently. A third investigator will verify the extracted data to ensure the accuracy of the records. The authors of the primary studies will be contacted to resolve any questions that may arise. The reviewers will resolve the disagreements through discussion and one of the two referees will adjudicate the discrepancies presented through discussion and consensus.

In specific terms, the following data will be collected both for the primary studies that report diabetes and COVID-19 and for those that differentiate between DMT1 and DMT2: author, year and country where the study was carried out; study design; general characteristics of the population, sample size, demographic data of the participants (sex, age, ethnicity), percentage of patients with diabetes, percentage of patients with type 1 and/or type 2 diabetes, percentage of patients without diabetes, frequency of comorbidities in diabetics and non-diabetics, percentage of diabetic and non-diabetic patients who presented the outcomes (hospitalization, ICU admission and mortality) and association measures reported for the outcomes. Data extraction will be done using a Microsoft Excel 365 ® spreadsheets.

Quality evaluation

The study quality assessment tool provided by the National Institutes of Health (NIH) [ 17 ] will be used for observational studies such as cohort, case-control, and cross-sectional. Two tools will be sued: one for cohort and cross-sectional studies (14 questions/domains) and one for case-control studies (12 questions/domains). These tools are aimed at detecting elements that allow evaluation of possible methodological problems, including sources of bias (for example, patient selection, performance, attrition and detection), confounding, study power, the strength of causality in the association between interventions and outcomes, among other factors. The different tools that will be used reflect a score of "1" or "0" depending on the answer "yes" or "no", respectively for each question or domain evaluated, or failing that, the indeterminate criterion option. For observational cohort studies, which consist of 14 risk of bias assessment domains, the studies will be classified as having good quality if they obtain ≥10 points, of fair quality if they obtain 8 to 9 points, and of poor quality if they obtain less than 8 points. On the other hand, in the case of case-control studies that consist of 12 bias risk assessment domains, the studies will be classified as good quality if they obtained ≥8 points, regular quality if they obtained 6 to 7 points and of poor quality if they obtained less than 6 points. However, the internal discussion between the research team will always be considered as the primary quality criterion.

Data synthesis

A narrative synthesis with summary tables will be carried out according to the recommendations adapted from the Synthesis Without Meta-analysis (SWiM) guide to describe in a structured way the methods used, and the findings found in the primary studies, as well as the criteria for grouping of the studies [ 18 ]. A narrative synthesis will be presented in two sections, one for patients with COVID-19 and diabetes and another for patients with COVID-19 and type 1 or type 2 diabetes.

Assessment of clinical and methodological heterogeneity will determine the feasibility of the meta-analysis. Possible sources of heterogeneity identified are the clinical characteristics of the study population, the criteria used to define the outcomes in the groups of patients, the time period of the pandemic in which the study was carried out, and the availability of measurement and control for potential confounding factors. For this reason, it is established a priori that this diversity of findings will make it difficult to carry out an adequate meta-analysis [ 19 ]. However, if meta-analysis is considered feasible, the random effects model will be used due to the high probability of heterogeneity between studies. Statistical heterogeneity will be assessed using the X 2 test and the I 2 statistic, and publication bias assessed using funnel plots if there are sufficient (>10) studies [ 20 ].

Exploratory ecological analysis

An exploratory ecological analysis of the association between the frequency of clinical outcomes of diabetic patients with COVID-19 and the indicators related to the health care dimension, reported for the different countries analyzed by means of the correlation coefficient, will be carried out. The open public databases of the World Bank (WB) [ 21 ], the World Health Organization (WHO) [ 22 ] and Our World In Data [ 23 ] will be used to extract population indicators related to health care, among those prioritized, universal health coverage, hospital beds per 1,000 people, doctors per 1,000 people, current health spending as a percentage of gross domestic product (GDP), percentage of complete vaccination coverage for COVID-19.

Since the first epidemiological and clinical reports were released from the city of Wuhan regarding the clinical characteristics of patients with COVID-19, a high incidence of chronic non-communicable diseases has been observed in Covid-19 patients. Current scientific evidence has shown that certain comorbidities increase the risk for hospitalization, severity of illness or death from COVID-19, such as hypertension, cardiovascular disease, chronic kidney disease, chronic respiratory disease, diabetes, among others [ 24 ].

One of the main chronic comorbidities affected by the COVID-19 pandemic is diabetes. Multivariate analysis of several observational epidemiological studies have revealed that COVID-19 patients with diabetes were at increased risk of hospitalization, ICU admission, and mortality compared with patients without diabetes [ 4 ].

For this reason, it is expected that this systematic literature review will provide scientific support regarding the outcomes and complications that patients diagnosed with COVID-19 with type 1 or type 2 diabetes present compared with patients without diabetes. This information will be useful for healthcare personnel, public health professionals and epidemiologists involved in patient care or decision making, generating epidemiological evidence. Thus, highlighting the decisive role of epidemiological research in the context of the pandemic, especially in the field of diabetes epidemiology may improve comprehensive management and care of diabetic patients. This study may also provide important information that can be used to update of clinical practice guidelines.

Limitations

There are some potential limitations to the proposed systematic review. Firstly, both type 1 and type 2 diabetes may have different key search terms and some studies may be missed. To minimize this limitation, different search equations have been designed for each database in an exhaustive and sensitive manner. In addition to reading references and level ball as an additional strategy. Another limitation is that observational studies evaluating the effect of an intervention may be susceptible to significant confounding bias and may present high heterogeneity in the findings. To report these possible biases, an adequate quality assessment will be carried out, with highly sensitive and previously validated tools, exclusive for each type of observational design. The review is intended for publication in a peer-reviewed journal.

The status of the study

The study is in the selection phase of the records by applying the eligibility criteria to the titles and abstracts. Completion of the project is expected in September 2022 with the publication of the results.

Conclusions

This report describes the systematic review protocol that will be utilized to update the evidence regarding the risk of complications in diabetic patients with COVID-19 and in turn synthesize the information available regarding DM1 and DM2, to provide keys to a better understanding of the pathophysiology of diabetics.

Supporting information

S1 appendix. prisma-p (preferred reporting items for systematic review and meta-analysis protocols) 2015 checklist: recommended items to address in a systematic review protocol..

https://doi.org/10.1371/journal.pone.0271851.s001

S2 Appendix. Search string details for each database.

https://doi.org/10.1371/journal.pone.0271851.s002

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• 17. National Institutes of Health (NIH) [Internet]. Study Quality Assessment Tools; 2021. [cited 16 June 2022]. Available at: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
• 19. Cochrane Handbook for Systematic Reviews of Interventions; 2022. [cited 16 June 2022]. Available at: https://training.cochrane.org/handbook/current
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• 22. World Health Organization (WHO) [Internet]. Global Health Observatory Data Repository; 2021. [cited 16 June 2022]. Available at: https://apps.who.int/gho/data/node.home
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Adherence and Persistence to Basal Insulin Among People with Type 2 Diabetes in Europe: A Systematic Literature Review and Meta-analysis

• Open access
• Published: 23 March 2024

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• Esteban J. Gimeno 1 ,
• Mette Bøgelund 2 ,
• Sara Larsen 3 ,
• Anna Okkels 2 ,
• Signe B. Reitzel 2 ,
• Hongye Ren 3 &
• Domingo Orozco-Beltran 4  

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Introduction

Diabetes is associated with a number of complications, particularly if glycaemic targets are not achieved. Glycaemic control is highly linked to treatment persistence and adherence. To understand the burden of poor persistence and adherence, this systematic literature review identified existing evidence regarding basal insulin adherence/non-adherence and persistence/non-persistence among people with diabetes in Western Europe (defined as the UK, France, Spain, Switzerland, the Netherlands, Ireland, Austria, Portugal, Denmark, Norway, Sweden, Finland, Italy, Germany, Iceland and Belgium).

Eligible studies were systematically identified from two databases, Medline and Embase (published between 2012 and June 2022). Conference abstracts from ISPOR and EASD were manually included. Identified studies were screened by two independent reviewers in a two-step blinded process. The eligibility of studies was decided on the basis of pre-established criteria. A proportional meta-analysis and comparative narrative analyses were conducted to analyse the included studies.

Twelve studies were identified. Proportions of adherence/non-adherence and persistence/non-persistence varied across studies. Pooled rates of non-persistence at 6, 12 and 18 months were 20.3% (95% CI 13.8; 27.8), 33.8% (95% CI 24.1; 44.3) and 36.5% (95% CI 33.6; 39.4), respectively. In the literature, the proportion of adherent people ranged from 41% to 64% (using the outcome measure medication possession ratio (MPR) > 80%), with a pooled rate of 55.6% (95% CI 45.3; 65.6), suggesting that approximately 44% of people with type 2 diabetes (T2D) are non-adherent.

The results highlight that almost half of patients with T2D in Western Europe have poor adherence to insulin therapy and, at 18 months, one in three patients do not persist on treatment. These findings call for new basal insulin therapies and diabetes management strategies that can improve treatment persistence and adherence among people with T2D.

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Avoid common mistakes on your manuscript.

The prevalence of diabetes is increasing and the number of adults with diabetes in Europe is expected to increase from 61 million in 2021 to 69 million in 2045 [ 1 ]. Type 2 diabetes (T2D) accounts for around 90% of diabetes cases [ 2 ]. As a result of the gradual onset of T2D, the condition can remain undiagnosed for many years, while health complications might develop and progress [ 3 ].

It is well known that diabetes is associated with a high number of health complications (renal, cardiovascular, neurological and retinal) as well as increased mortality, especially if glycaemic targets are not achieved [ 4 , 5 , 6 , 7 , 8 , 9 ]. According to the World Health Organization (WHO), adults with diabetes have more than a twofold risk of vascular outcomes, including both coronary heart disease and stroke [ 4 ], and cardiovascular disease is the most common cause of death among people with diabetes [ 10 ]. Additionally, a registry study including 32,725 people with diabetes found a statistically significant association between glycaemic burden and micro- and macrovascular complications such as diabetes foot, disease of the arteries and cerebrovascular disease [ 6 ]. Diabetes complications are burdensome for both the individual and society, as they are associated with a reduced health-related quality of life among people with diabetes and increased costs due to healthcare utilisation and absence from work [ 11 , 12 ]. This emphasises the need for correct and sufficient treatment of diabetes.

Several factors impact whether people with T2D achieve glycaemic control [ 13 , 14 ]. Long-acting insulin, also called basal insulin, has a longer duration and a lower peak of action, which allows for more flexible treatment. The mechanism of basal insulins contributes to an improved glycaemic control among people with T2D who cannot maintain adequate glycaemic control by other glucose-lowering drugs alone as well as a reduction in the risk of hypoglycaemia [ 15 , 16 , 17 , 18 ]. Thus, basal insulin is associated with clinical benefits and potentially a reduced fear of hypoglycaemia among people with T2D and clinicians [ 17 ]. However, earlier research has shown that one in three people with T2D are unwilling to start insulin treatment [ 19 , 20 ]. Furthermore, some people have difficulties managing the insulin treatment, which may result in discontinuation of the treatment [ 16 ], and evidence has shown that one cause of poor glycaemic control is the lack of adherence (defined as complying with the prescribed medicine in terms of drug schedules and dosages) and persistence (defined as continuing to take medication throughout the prescribed period) to antidiabetic medication, i.e. basal insulin treatment [ 21 , 22 , 23 ]. A previously published systematic literature review has found that improved adherence to antidiabetic medication in people with T2D is associated with improved glycaemic control and fewer hospitalisations and emergency department visits [ 24 ]. Hence, adherence and persistence are essential determinants of improved diabetes control.

In order to support people with diabetes in achieving adherence and persistence to insulin treatment and thus disease control, it is important first to understand the scope of the problem in a real-world setting. Evidence regarding insulin adherence/non-adherence and persistence/non-persistence among people with diabetes is broad. However, hardly any publications compare and pool evidence focusing particularly on adherence/non-adherence and persistence/non-persistence to basal insulin in Western Europe [ 24 , 25 , 26 ]. Newly published reviews by Evans et al. [ 24 ] and Lee et al. [ 26 ] investigated adherence and persistence to major antidiabetic medication classes, including basal insulin, among people with T2D. However, both studies had no eligibility criteria regarding geography, thus including data from all over the world. Another review by Azharuddin et al. [ 27 ] also investigated adherence to antidiabetic medication among all people living with diabetes, but only with evidence from low- and middle-income countries. Inclusion of countries with differences in the organisation and financing of healthcare systems makes direct comparisons across studies and pooled analyses problematic. Therefore, to make more direct comparisons possible, the objective of this systematic literature review was to identify and collate existing evidence on basal insulin adherence/non-adherence and persistence/non-persistence among people with diabetes in Western Europe.

A systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [ 28 ]. The following research question was addressed in the systematic literature review: What is the persistence/non-persistence and adherence/non-adherence among adults with diabetes using basal insulin in Western Europe? The two electronic databases MEDLINE (via the PubMed platform) and Embase were searched in June 2022. The details of the search strings applied in this systematic literature review are presented in Table  1 . In addition to the systematic search, EASD and ISPOR were manually searched for relevant peer-reviewed conference abstracts. These conferences are some of the leading societies for health economics and outcome research as well as diabetes research, and they are known to publish relevant abstracts on adherence or persistence in diabetes care.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Eligibility Criteria

The PICO (population, intervention, comparator and outcomes) reporting system was used to define a relevant review question and to help formulate the search strategy. The eligibility criteria are presented in Table  2 . The systematic literature review included studies in which there was a population of adults from Western Europe (including the UK, France, Spain, Switzerland, Netherlands, Ireland, Austria, Portugal, Denmark, Norway, Sweden, Finland, Italy, Germany, Iceland and Belgium) with diabetes treated with basal insulin. In addition, studies had to present original data and analyses. The predefined outcomes of interest were all findings related to adherence/non-adherence or persistence/non-persistence to basal insulin treatment reported as proportions of patients. Treatment persistence is defined as continuing to take medication throughout the prescribed period, and treatment adherence is defined as complying with the prescribed medicine in terms of drug schedules and dosages [ 21 ]. The included studies were English-language studies published between 2012 and 2022.

Study Selection and Data Collection

All studies were reviewed in a blinded two-step process by two independent reviewers. The first step was screening of title and abstract. In the second step, eligible studies were screened at full-text level. The studies were included in accordance with the predefined eligibility criteria and any case of disagreement about the eligibility of a study was resolved through discussion between the two reviewers or by referral to the project manager. Each study could only be included once, meaning that a publication would be excluded if it presented a study already included through another publication. However, background information such as study characteristics could be combined from both publications if complete information was not available in one of the publications. Silvi was used to ensure a structured review process [ 29 ].

Any measures of adherence/non-adherence and persistence/non-persistence available from the literature were considered relevant regardless of the follow-up period or methodology. Adherence/non-adherence was often measured by medication possession ratio (MPR) which is calculated as the proportion (or percentage) of days covered by the medication dispensed during a specified time period or over a period of refill intervals (using a threshold of 80%). Other measures of adherence/non-adherence included missed doses, mistimed doses and reduced doses. Persistence/non-persistence was measured as uninterrupted treatment administration.

Identified Studies

The systematic literature search of Medline and Embase resulted in 11 eligible studies. Additionally, we identified two relevant poster abstracts from EASD and ISPOR, yielding a total of 13 eligible studies [ 9 , 15 , 16 , 25 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. The flow of studies through the two-step study selection process is presented in a flowchart in Fig.  1 . This manuscript presents results from the studies regarding insulin adherence/non-adherence and persistence/non-persistence among people with T2D. By further excluding studies that do not present any subgroup results stratified by T2D, this manuscript includes 12 eligible studies. From the 12 studies, a total of 30 relevant subgroup results were identified. It should be noted that one subgroup could present results on multiple outcome measures.

Flowchart. † Although the studies were excluded, they contributed with background information about the subpopulations

Of the 12 studies included in this manuscript, four presented results on adherence/non-adherence [ 15 , 30 , 32 , 37 ] and nine presented results on persistence/non-persistence [ 9 , 16 , 25 , 31 , 33 , 34 , 35 , 36 , 37 ], one of which presented results on both adherence/non-adherence and persistence/non-persistence [ 37 ]. This last-mentioned study included people treated with all kinds of insulin, which is why it was not possible to extract results for basal insulin only. Therefore, the insulin type in the study will be categorised as basal-bolus insulin throughout this manuscript.

Data Extraction and Statistical Analyses

A comprehensive data extraction was conducted from all eligible studies following the PRISMA checklist [ 28 ] and using a pre-specified data extraction form in Microsoft Excel. Separate data points were extracted for each population and subpopulation with individual findings, i.e. subgroups by country, insulin type or background therapy. Data extraction included information on study characteristics, i.e. author, year of publication and information about the study population (size, country, mean age, background therapy, diabetes status, insulin status and diabetes-associated complications), methodology, i.e. data source and follow-up time, and findings from all outcomes deemed relevant for the research question.

When appropriate, a proportional meta-analysis calculating pooled rates was performed to assess insulin adherence/non-adherence and persistence/non-persistence among people with T2D in Western Europe. As recommended in the literature, the pooled rates were based on a random-effects model and Freeman–Tukey transformation using the software JBI SUMARI [ 39 , 40 ]. Heterogeneity between the included studies was assessed through tau squared, chi squared and I 2 statistics. As a result of high variance in the outcome definitions applied in the included studies, comparative narrative analyses were performed, when proportional meta-analysis was inappropriate. In studies not reporting non-persistence or non-adherence rates, these were calculated as 1 minus the reported persistence or adherence rate.

To investigate the identified data further, a number of sensitivity analyses were conducted, including an analysis of persistence rates when results on NPH were excluded, and analyses of both persistence and adherence findings when data not differentiating between basal and bolus insulin were excluded.

Identified Outcome Measures

Among the 12 eligible studies, insulin persistence/non-persistence and adherence/non-adherence were evaluated using 19 different outcome measures (persistence, 5; adherence, 14). Table  3 provides an overview of the identified outcome measures for both persistence and adherence, together with the number of subgroup results for the respective outcome measures.

Results on Insulin Persistence

Persistence to basal insulin was measured after either 3, 6, 12, 18 or 24 months in the nine studies reporting results on insulin persistence. The most frequent measure was persistence after 12 months, which was used in five of the nine studies [ 31 , 34 , 35 , 36 , 37 ]. Persistence after 6 months was measured in four of the studies [ 9 , 31 , 36 , 37 ], and persistence after 3 and 18 months was measured in one study each [ 25 , 37 ]. Persistence after 24 months was measured in two studies [ 16 , 33 ]. The majority of the included studies were based on registry data [ 16 , 25 , 31 , 33 , 34 , 35 , 36 , 37 ]; however, one study used self-reported questionnaire data [ 9 ]. The size of study populations varied from 549 included people [ 9 ] to 680,131 included people [ 16 ]. An overview of the studies, study characteristics and respective results regarding persistence to basal insulin among people with T2D is presented in Table  4 .

On the basis of results from the studies reporting 6- and 12-month persistence rates, we calculated non-persistence rates (equal to 1 minus persistence rates). These are shown by different types of basal insulin in Fig.  2 . Within the first 6 months of treatment, non-persistence ranged between 6% and 33% in the included studies. The lowest non-persistence was reported for degludec (6%) [ 31 ], while the highest non-persistence was reported for the group of non-specified basal insulin therapies (33%) [ 9 ]. It should be noted that the majority of the studies reporting results on persistence at 6 months did not specify the insulin type [ 9 , 36 , 37 ]. Non-persistence rates within the first 12 months of treatment ranged from 14% to 52%. The lowest non-persistence rate within the first 12 months of treatment was reported for insulin glargine-300 (14%) and insulin degludec (16%) [ 31 , 35 ]. The highest non-persistence rate was reported for neutral protamine Hagedorn (NPH) insulin (52%) [ 34 ].

Non-persistence within 6 and 12 months of initiation of basal insulin treatment by type of basal insulin, %. The figure present rates of non-persistence from the eligible studies and lists population size and insulin type for each subgroup. Not all included studies reported results for persistence within both 6 and 12 months. Neither did all studies specify the specific type of basal insulin assessed. Estimates of persistence reported by Perez-Nieves et al. [ 9 ] differ across different countries and are reported in the following countries listed from left to right: France, Spain, Germany and the UK

On the basis of the studies, pooled non-persistence rates among people with T2D were calculated for 6, 12 and 18 months. The pooled non-persistence rate within 6 months of initiation of basal insulin was 20.3% (95% CI 13.8; 27.8) (Fig.  S1 ). It should be noted that four of the seven estimates of non-persistence within 6 months were based on self-reported data, whereas the remaining three were based on registry data. The pooled non-persistence rate was 14.6% (95% CI 6.3; 25.5) if only registry-based data were included and 25.9% (95% CI 20.5; 21.8) if only self-reported data were included (Figs.  S2 and S3 ). The pooled rate of non-persistence further increased from 6 to 12 months to 33.8% (95% CI 24.1; 44.3) (Fig.  S4 ). In a sensitivity analysis, data on NPH were excluded from this analysis, which resulted in a pooled non-persistence rate within 12 months of 31.3% (95% CI 21.7; 41.8) (Fig.  S5 ). Finally, the pooled rate of non-persistence within 18 months of initiating basal insulin was 36.5% (95% CI 33.6; 39.4) (Fig.  S6 ). Figures S7 and S8 show the results of sensitivity analyses in which the study by Sicras et al. 2013 was excluded [ 37 ].

Results on Insulin Adherence

Adherence/non-adherence to basal insulin was measured with several methods in the four included studies reporting results on insulin adherence. The most frequently used measure was MPR > 80%, which was used in two of the four studies [ 32 , 37 ]. MPR > 80% was the only measure that was used by more than one of the included studies. Among the included studies, half of them were based on registry data [ 32 , 37 ], whereas the other half were based on self-reported questionnaire data [ 15 , 30 ]. The size of study populations varied from 162 included people [ 15 ] to 2413 included people [ 32 ]. An overview of all included studies reporting results on insulin adherence/non-adherence is presented in Table  5 .

Figure  3 illustrates the proportion of people with T2D who were adherent to basal insulin treatment (defined as MPR > 80%) within the first 12 months of treatment, stratified by different types of basal insulin. The share of people with MPR > 80% ranged from 41% to 64% [ 32 , 37 ]. The pooled rate of people with MPR > 80% across the relevant studies was 55.6% (95% CI 45.3; 65.6). The results reported by Esposti et al. 2019 differed across different types of background therapies (included as separate subgroup results) [ 32 ]. Figure  S10 presents the results of a sensitivity analysis of the pooled rate of people with MPR > 80% when the study by Sicras et al. was excluded [ 37 ].

Share of people with T2D and MPR > 80% by different types of basal insulin, %. The figure presents proportions of MPR > 80% from the eligible studies and lists population size and insulin type for each subgroup. Estimates of adherence reported by Esposti et al. [ 32 ] differed across different types of background therapies, including the following background therapies listed from left to right: No background therapies, other oral glucose-lowering drugs and DPP4 inhibitors

One of the four included studies assessed insulin non-adherence by measuring the share of people with T2D who missed insulin doses during a 30-day period [ 30 ]. The outcome was measured through an online survey sent to people with T2D and healthcare professionals (primary care practitioners, specialists and nurses). The study found that, on average, 16% of people with T2D had one or more missed doses during a 30-day treatment period, while 1.3% had missed five or more doses in that same period. In addition, the study reported that people with T2D on average missed 1.8 doses of basal insulin within a 30-day treatment period.

Wieringa et al. measured adherence using a questionnaire in the Netherlands by asking their study respondents (physicians involved in the management of T2D in primary and secondary care and people with T2D) how many of the last 7 days they took the recommended basal insulin as prescribed. They found that 84% of people with T2D were adherent all 7 days of the last week [ 15 ].

This systematic literature review identified 12 studies that reported findings of persistence/non-persistence or adherence/non-adherence to basal insulin in people with T2D from Western European countries. The findings highlight an important problem with both persistence (defined as continuing to take medication throughout the prescribed period [ 21 ]) and adherence (defined as complying with the prescribed medicine in terms of drug schedules and dosages [ 21 ]) in T2D.

This systematic literature review found pooled non-persistence rates at 6 and 12 months of approximately 20% and 34%, respectively. At 18 months, the pooled non-persistence rate increased to approximately 37%. In the pooled non-persistence rate at 12 months, results for insulin NPH have been included. Insulin NPH might be given more than once per day, and it is therefore likely that a higher non-persistence rate is found among people receiving insulin NPH compared to other types of basal insulin. Information about daily doses of insulin NPH was not available. However, a sensitivity analysis showed that the pooled non-persistence rate within 12 months only changes by three percentage points (from 34% to 31%) when excluding insulin NPH from the analysis. Although direct comparisons across the studies should be made with caution, taking into account different study characteristics, the numbers for persistence over time could suggest that non-persistence among people with T2D is present already within the first 6 months and that it increases over time but at a diminishing rate. Considering that non-persistence could possibly be related to an unpreferable safety profile or dosing scheme, it seems fair to expect that people not experiencing issues with a treatment within the first 6 months do not experience issues after 6 months. Thus, it seems likely that non-persistence will stall over time. Furthermore, this systematic review found that estimates of adherence in the eligible studies were most often measured as MPR > 80%, which is the adherence rate needed for optimal treatment effect [ 41 ]. Using MPR > 80%, this review found a pooled adherence rate to basal insulin treatment over a 12-month period of approximately 56%. This suggests that 44% of people with T2D are non-adherent to basal insulin treatment within 12 months. It should be noted that one study, which was included in both the persistence and adherence analyses, did not differentiate between basal and bolus insulin. However, neither persistence nor adherence findings changed significantly when the study was excluded in a sensitivity analysis.

It is well established that non-persistence with and non-adherence to prescribed diabetes therapy, including basal insulin, can have profound consequences for people with diabetes, including poor glycaemic control [ 21 ]. Medication non-adherence has been shown to be a key reason why antidiabetic medication is less effective in a real-world setting than in clinical studies. For example, a study by Carls et al. from 2017 found significantly smaller reductions in glycaemic level among people with T2D 1 year after initiation of antidiabetic medication than what had been observed in the randomised control trial setting for the same period. The authors concluded that approximately 75% of the gap was due to lack of patient adherence [ 42 ].

The findings in this systematic review indicate that non-persistence and non-adherence have a great impact in Western Europe. It should be noted that there can be several reasons for interrupting insulin therapy. For instance, insulin therapy might be initiated temporarily, or it might be substituted with other medicines. In addition, insulin persistence and adherence might be impacted by diabetes-related complications, which could complicate the treatment regimen. According to the literature identified as part of this review, studies investigating adherence/non-adherence and persistence/non-persistence among people with type 1 diabetes are sparse. This calls for further investigation before any conclusions can be made about adherence/non-adherence and persistence/non-persistence in this population. However, it should be noted that, according to findings by Elek et al. T2D constitutes 90% of the overall population of people with diabetes [ 43 ].

While achievement of glycaemic targets is associated with a reduction in diabetes complications, improper diabetes care, e.g. poor glycaemic control, entails a great risk of long-term complications [ 21 , 44 ]. A systematic literature review from 2019 that investigated the lack of treatment persistence and treatment adherence in people with T2D found that an increase in diabetes complications as a result of poor adherence and persistence is linked to poorer health status and an increase in healthcare resource use and costs [ 9 ]. Additionally, a large study from the UK found a strong association between non-adherence and increased all-cause mortality [ 45 ]. Although a vast number of studies have investigated the cost associated with poor adherence or persistence to insulin treatment among people with T2D, many of these studies have been USA-based; hence, patients’ adherence and persistence are likely to be greatly affected by the high out-of-pocket payments known to be part of the US healthcare system. Thus, in order to understand the complete economic consequences of improper insulin treatment in the Western Europe, where healthcare systems are organised differently from the USA, additional evidence is needed.

Strength and Limitations

As is best practice, this systematic literature review includes a search of two databases, namely Medline (via PubMed) and Embase. For a systematic review literature search, Embase and MEDLINE are key databases. MEDLINE contains more than 22 million records from 5600 journals, whereas Embase has over 29 million records from 8500 journals. Additionally, the systematic literature review complies with the PRISMA guidelines. Inclusion and exclusion criteria used in this study were defined prior to the literature search, and the review process was conducted by two independent reviewers.

The number of studies identified in this systematic literature review was small in light of the seriousness of the challenge with poor control in diabetes. Additionally, they were heterogeneous. The methodological differences, particularly the use of differing outcome measures, problematise the direct comparisons of results across the different studies, countries, insulin products and time. As a result of the lack of a unified criterion for defining adherence and persistence in the identified studies, only a few studies could be meaningfully pooled, thus narrowing the data that went into the calculated pooled rates on persistence/non-persistence and adherence/non-adherence. This constitutes a limitation for the final pooled rates. Furthermore, the statistical tests of heterogeneity in the proportional meta-analyses showed high heterogeneity in the included estimates. It should be noted that the results of the heterogeneity tests should be interpreted with caution, since heterogeneity is expected in prevalence estimates. Therefore, high heterogeneity does not necessarily indicate inconsistent data [ 40 ]. To understand the factors that affect persistence and adherence and thus be able to provide people with T2D with treatment strategies that can improve persistence and adherence in the future, it would be relevant to have a standard practice for the measurement of persistence and adherence. Standardisation of the measurement of persistence and adherence in diabetes care will provide scientists with a guideline for what data should be included in future studies and enable the comparison of results across studies, products etc. Differing data sources in the included studies also poses a challenge in the comparisons. Finally, the inclusion of abstracts of conference papers may be a limitation as they do not include the same information as an article published in a scientific journal. However, the number of studies included from this source was small and it was ensured that they were studies of interest for the systematic review.

Given the clinical and economic consequences associated with non-adherence and non-persistence in T2D, an unmet need remains. These findings call for new basal insulin therapies and diabetes management strategies that can improve treatment persistence and adherence among people with T2D and thus positively affect clinical and economic outcomes. It was outside the scope of this study to investigate reasons for non-persistence and non-adherence. However, several approaches to improve persistence and adherence have been recommended in previous literature, including reduced treatment complexity (fixed-dose combinations and decreased dosing schemes), improved safety profiles, increased knowledge through better educational programmes and improved communication [ 21 , 45 ]. Additionally, knowledge about how other factors, e.g. sociodemographic factors or the presence of diabetes-related complications, influence persistence and adherence should be considered in future research.

This systematic literature review described real-world evidence on basal insulin adherence/non-adherence and persistence/non-persistence among people with T2D from Western Europe. The study identified 12 eligible studies in which non-persistence and non-adherence were evaluated using different outcome measures. Data on non-persistence among people with T2D suggest that non-persistence stagnates over time, with non-persistence rates of 21%, 34% and 37% at 6 months, 12 months and 18 months, respectively. By defining non-adherence as MPR < 20%, this systematic literature review found that 44% of people with T2D are non-adherent within 12 months. These numbers highlight a huge unmet need in the care for people with T2D and indicate that there is a clear opportunity to improve adherence and persistence, while also decreasing the risk of diabetes complications and the healthcare resource utilisation, by providing new diabetes management strategies with reduced treatment complexity, reduced dosing frequency, improved safety profile and better patient education and communication.

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Conceptualization: Hongye Ren, Mette Bøgelund, Esteban J Gimeno, Domingo Orozco-Beltran and Sara Larsen; Methodology: Mette Bøgelund, Signe B Reitzel and Anna Okkels; Formal analysis and investigation: Signe B Reitzel and Anna Okkels; Writing—original draft preparation: Signe B Reitzel and Anna Okkels; Writing—review and editing: Hongye Ren, Mette Bøgelund, Esteban J Gimeno, Domingo Orozco-Beltran and Sara Larsen. All authors have read and approved the final manuscript.

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Hongye Ren and Sara Larsen are employees of Novo Nordisk. Mette Bøgelund, Signe Baattrup Reitzel and Anna Okkels are employees of EY, which is a paid vendor of Novo Nordisk. After completion of the manuscript, Signe Baattrup Reitzel has changed affiliation to Medical Science, Novo Nordisk Foundation. Esteban Jodar reports consultancy services and speaker fees from Audium, Amgen, AstraZeneca, Boehringer, FAES, Eli Lilly, MSD, Novo Nordisk, UCB and ZP pharmaceutica. Domingo Orozco-Beltrán has provided consultancy services to MSD and Novartis and has lectured for Novartis, Mundipharma, Novo Nordisk, Sanofi Aventis and Eli Lilly.

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Gimeno, E.J., Bøgelund, M., Larsen, S. et al. Adherence and Persistence to Basal Insulin Among People with Type 2 Diabetes in Europe: A Systematic Literature Review and Meta-analysis. Diabetes Ther (2024). https://doi.org/10.1007/s13300-024-01559-w

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Effectiveness and safety of the combination of sodium–glucose transport protein 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of observational studies

• Aftab Ahmad 1 , 2 &
• Hani Sabbour   ORCID: orcid.org/0000-0001-6960-1056 3 , 4 , 5  

Cardiovascular Diabetology volume  23 , Article number:  99 ( 2024 ) Cite this article

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Randomized controlled trials and real-world studies suggest that combination therapy with sodium–glucose transport protein 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is associated with improvement in fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), systolic blood pressure (SBP), body mass index (BMI), and total cholesterol levels. However, a systematic review of available real-world evidence may facilitate clinical decision-making in the real-world scenario. This meta-analysis assessed the safety and effectiveness of combinations of SGLT2is + GLP-1RAs with a focus on their cardioprotective effects along with glucose-lowering ability in patients with type 2 diabetes mellitus (T2DM) in a real-world setting.

Electronic searches were performed in the PubMed/MEDLINE, PROQuest, Scopus, CINAHL, and Google Scholar databases. Qualitative analyses and meta-analyses were performed using the Joanna Briggs Institute SUMARI software package and Review Manager v5.4, respectively.

The initial database search yielded 1445 articles; of these, 13 were included in this study. The analyses indicated that SGLT2is + GLP-1RAs combinations were associated with significantly lower all-cause mortality when compared with individual therapies (odds ratio [95% confidence interval [CI] 0.49 [0.41, 0.60]; p < 0.00001). Significant reductions in BMI (− 1.71 [− 2.74, − 0.67]; p = 0.001), SBP (− 6.35 [− 10.17, − 2.53]; p = 0.001), HbA1c levels (− 1.48 [− 1.75, − 1.21]; p < 0.00001), and FPG (− 2.27 [− 2.78, − 1.76]; p < 0.00001) were associated with the simultaneous administration of the combination. Changes in total cholesterol levels and differences between simultaneous and sequential combination therapies for this outcome were not significant.

This systematic review and meta-analysis based on real-world data suggests that the combination of SGLT2is + GLP-1RAs is associated with lower all-cause mortality and favorable improvements in cardiovascular, renal, and glycemic measurements. The findings drive a call-to–action to incorporate this combination early and simultaneously in managing T2DM patients and achieve potential cardiovascular benefits and renal protection.

Graphical Abstract

Introduction

Diabetes is a significant predisposing factor for microvascular and macrovascular complications with cardiovascular events 2–3 times more likely to occur in patients with diabetes than in those without diabetes [ 1 ]. Conventionally, the management of type 2 diabetes mellitus (T2DM) has been glucocentric rather than focusing on reducing cardiovascular events [ 2 ]. However, over the last few years, sodium–glucose transport protein 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to reduce the risk of all-cause mortality, cardiovascular mortality, and kidney failure [ 3 ]. Recent meta-analyses of the major SGLT2i cardiovascular outcome trials (CVOTs) reported a reduced risk of all-cause mortality and major adverse cardiovascular events (MACE) in T2DM patients using SGLT2i [ 4 , 5 ]. Similarly, recent meta-analyses of GLP-1 CVOTs reported a reduction in MACE, relative risk of CV deaths, and all-cause mortality [ 6 , 7 ]. Like SGLT2is [ 8 , 9 ], the CV effects of GLP-1RAs are reported to be independent of glucose reduction as shown in the multicenter, double-blind, placebo-controlled SELECT study (N = 17,604), in which the GLP-1RA semaglutide significantly reduced the incidence of cardiovascular mortality and that of non-fatal myocardial infarction as well as non-fatal stroke when compared to the placebo (6.5% vs. 8.0%, p < 0.001) in non-diabetes patients with preexisting cardiovascular disease and obesity [ 10 ]. While the exact mechanism of action of these two classes of drugs on reducing mortality is still being investigated, several meta-analyses have shown significantly reduced glycated hemoglobin (HbA1c), body weight, body mass index (BMI), systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) when either of these drugs was used individually. However, the reduction in these parameters was more significant when the two classes were used in combination with minimal safety concerns resulting in clinical guidelines recommending their use in T2DM patients with established atherosclerotic cardiovascular disease (ASCVD) or with multiple CV risk factors without ASCVD irrespective of the HbA1c level or use of other glucose-lowering medications [ 7 , 11 , 12 , 13 , 14 , 15 , 16 ]. There has been no direct evidence regarding the effects of the combination of SGLT2is and GLP-1RAs on mortality and other cardiovascular outcomes because of a lack of randomized controlled trials (RCTs) comparing combination versus individual therapies. However, a retrospective study and a subsequent meta-analysis reported significantly reduced risks of MACE, cardiovascular mortality, hypertensive heart failure, and all-cause mortality compared with SGLT2i/GLP1RA monotherapy [ 17 , 18 ].

To date, there has been no meta-analysis conducted to assess the effect of SGLT2i and GLP-1 combination therapy in the real-world context where results can differ significantly from results from randomized controlled trials (RCTs). Our meta-analysis of real-world data is focused on the impact of such a combination on all-cause mortality and the management of T2DM patients.

Review question

What is the effectiveness and safety of combinations of SGLT2is + GLP-1RAs in the management of T2DM among adults?

This systematic literature review (SLR) was conducted as per the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) reporting guidelines. The protocol was registered with the International Prospective Register of Systematic Reviews PROSPERO (registration number: CRD42023434707).

Inclusion criteria

This SLR considered observational real-world studies (prospective cohort, retrospective cohort, and case–control studies published in English) that evaluated the effectiveness and safety of combination therapies of SGLT2is and GLP-1RAs in the management of T2DM in adults (≥ 18 years), irrespective of sex, race, ethnicity, or nationality. Systematic reviews, clinical trials, conference abstracts, case series, and case reports were excluded from the analysis. The classification of patients as having T2DM and selection for treatment were determined by the authors of each study included in this SLR. All included studies either followed patients receiving the combination treatment and compared baseline values with those at the end of the follow-up (at least 6 months) or compared the combination treatment against individual treatments at the 6-month follow-up.

Search strategy

A broad search of MEDLINE (PubMed) was initially undertaken to identify related articles. The index terms derived were then used to develop the search strategy for the PubMed, PROQuest, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Google Scholar (first 100 articles) databases (Additional file 1 : Table S1). The search was performed from inception until May 2023. Citation screening using backward and forward citations of included studies was additionally performed. Only those studies published in English were included; no restrictions on publication dates were set on any search.

Selection of studies

All the citations identified after the search were collated on SR-Accelerator [ 19 ], and duplicates were removed. The screening of titles along with abstracts was carried out by two independent authors (AA and HS) as per the review inclusion criteria. Subsequently, when the full texts were screened, articles were closely analyzed for compliance with the inclusion and exclusion criteria in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram. Additionally, a literature mapping was performed using Litmaps® to indicate the relationship among included articles using their citations.

The included studies were assessed for quality using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Cohort Studies [ 20 ]. Each study was critically appraised by two independent reviewers (AA and HS) based on criteria such as the similarity of study groups, reliability and validity of exposure measurement, identification and handling of confounding factors, freedom from the outcome (at the start of the study), outcome measurement, follow-up time, completeness of follow-up, and appropriateness of statistical analyses. All disagreements regarding appraisals were resolved through discussions. Details are provided in Additional file 2 .

All the studies included in this SLR underwent data extraction by two independent authors (AA and HS) with piloted data extraction sheets. Details of the data extraction process are presented in Additional file 2 .

Study outcomes

The outcomes of interest were all-cause mortality, cardiovascular risk factors (BMI, SBP, and total cholesterol), renal outcomes (eGFR and albuminuria), and glycemic outcomes (HbA1c and FPG). Adverse events were also analyzed qualitatively. The term ‘baseline” represented the time when the patients initiated treatment with either the combination or individual treatments, and this definition was consistent across the included studies.

Subgroup analysis

A subgroup analysis was performed based on whether the patients received the combination simultaneously and had not received either SGLT2is or GLP-1RAs prior to baseline and whether the patients received the combination sequentially, i.e., they were already receiving either SGLT2i or GLP-1RA and the other drug was introduced. The two sequential combination therapy subgroups included patients who were receiving SGLT2i with GLP-1RA added on and patients who were receiving GLP-1RA with SGLT2i added on.

Synthesis of data

All the extracted data were pooled with the help of a statistical meta-analysis model in the Review Manager v5.4 software (RevMan, Cochrane Collaboration software). For continuous data, effect sizes were presented as weighted (or standardized) final mean differences and their 95% confidence intervals (CIs); for dichotomous data, these were presented as odds ratios and 95% CIs. The I 2 statistic for heterogeneity among the included studies was calculated, wherein I 2 values of < 30%, 30%–59%, 60%–90%, and > 90% corresponded to low, moderate, substantial, and high heterogeneity, respectively. All analyses were carried out using a random-effects model.

If statistical pooling was not possible, the findings were presented as a narrative, considering the population characteristics, study design, data source, and assessment of the outcome measure.

Assessing certainty in the findings

Certainties in the quality of the evidence and the estimated effects of the results in this SLR were assessed as per the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) [ 21 ]. The findings were summarized using the GRADEPro GDT v.4 software (McMaster University, ON, Canada), and include all the results on all-cause mortality and changes in HbA1c, FPG, BMI, SBP, GFR, and total cholesterol levels.

Search results

Of the 1445 articles obtained in the initial database search, 976 were identified based on their titles and abstracts. Manual screening of grey literature resulted in an addition of 18 articles. The full texts of 90 articles were retrieved, 77 studies were excluded (Additional file 1 : Table S2), and 13 were included in the study [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Figure  1 shows the PRISMA flowchart.

PRISMA flowchart

Thirteen studies were critically appraised; following this, data were extracted from these studies and analyzed. The literature mapping of the studies included in this SLR is shown in Fig.  2 . Quantitative meta-analysis was performed using 8 studies [ 23 , 26 , 27 , 28 , 29 , 30 , 31 , 33 ]. The remaining 5 studies were considered to be ineligible for inclusion in this meta-analysis as mean values were not available (n = 1), follow-up duration was less than 6 months (n = 2), and only differences in outcomes were provided instead of absolute values (n = 2) (Additional file 1 : Table S3).

Literature mapping of the included studies (Litmaps®)

Each point on the map represents one included study in the systematic literature review. The size of each point is a function of the “momentum” of the study, which is calculated based on the “cited by” count and weighted by recency. The most recent articles appear on the right-hand side of the map and the most cited articles appear at the top, so recent popular studies appear in the top right-hand corner.

Ten studies were assessed to be of moderate-to–low quality (score 6–8), and three studies were of low quality (score ≤5) (Table  1 ). Low-quality studies typically had issues in their methodology, such as unclear or inadequate management of confounding factors, unreliable or invalid outcome measurements, incomplete follow-up without adequate exploration of reasons, and inappropriate or unclear use of statistical analysis. These deficiencies suggest potential biases in the studies, which could affect the trustworthiness of their findings and limit their contributions to evidence-based practice.

Given that meta-analysis and subgroup analyses included a relatively small number of studies, inadequate data were available to provide a statistical estimate of publication bias.

Qualitative analysis (systematic review)

All the studies included in this SLR are real-world observational studies published during 2015–2023, had sample sizes ranging from 15 to 2.2 million, and a follow-up ranging from 3 months to 20 years (Table  2 ). Patients in the included studies were 49.5–70.4 years old, and 43.6%–65.5% were males (Table  3 ). Prior comorbidities included cardiovascular disease, hypertension, hyperlipidemia, and obesity. Patients in the included studies reported the concomitant use of other antidiabetic drugs such as metformin, sulfonylureas, and insulin, among others (Table  4 ).

Genital infections, urinary tract infections, abdominal pain, nausea, bloated abdomen, diarrhea, polyuria, asthenia, yeast infections, dry mouth, and hypotension were among the commonly reported adverse events in the included studies. In the study by Carretero-Gomez et al. [ 27 ], symptomatic hypoglycemia was reported in < 10% of the patients and one death due to subarachnoid hemorrhage was reported. Treatment with SGLT2i was discontinued due to genital mycotic infection, worsening of renal function, leg amputation, and bariatric surgery. Treatment with GLP-1RA was discontinued due to gastrointestinal effects, insulin intensification, and worsening of renal function. In the study by Kim et al. [ 31 ], gastrointestinal adverse effects were commonly reported after 3 months, but their incidence was reduced at later time points. Mild hypoglycemia was also reported in < 5% of the patients. Major adverse effects such as ketoacidosis, pancreatitis, fractures, or acute renal failure were not reported.

Quantitative analysis (meta-analysis)

All-cause mortality.

The number of all-cause mortality events was significantly lower with the combination therapy than with SGLT2i (p = 0.0003) or GLP-1RA (p = 0.03), with an overall decrease in the odds for all-cause mortality with the combination therapy (n = 2 studies; odds ratio [95% CI] 0.49 [0.41, 0.60]; I 2  = 93.0%; p < 0.00001) (Fig.  3 A).

Findings from the main analysis. A Odds of all-cause mortality with SGLT2i + GLP-1RA combination therapy versus SGLT2i or GLP-1RA therapy. B Changes in BMI with combination therapy at the baseline versus the 6-month follow-up. C Changes in SBP with combination therapy at the baseline versus the 6-month follow-up. D Changes in total cholesterol with combination therapy at the baseline versus the 6-month follow-up. E Changes in eGFR with simultaneous combination therapy at the baseline versus the 6-month follow-up. F Changes in HbA1c with combination therapy at the baseline versus the 6-month follow-up. G Changes in FPG with combination therapy at the baseline versus the 6-month follow-up. BMI Body mass index, CI confidence interval, eGFR estimated glomerular filtration rate, FPG fasting plasma glucose, M–H Mantel–Haenszel, GLP-1RA glucagon-like peptide-1 receptor agonist, HbA1c glycated hemoglobin, IV importance value, SBP systolic blood pressure, SD standard deviation, SGLT2i Sodium–glucose transport protein 2 inhibitor

Cardiovascular risk factors

The combination significantly reduced BMI and SBP at follow-up (BMI: n = 4 studies; mean difference [95% CI] − 1.71 [− 2.74, − 0.67]; I 2  = 32%; p = 0.001, Fig.  3 B; SBP: n = 5 studies; mean difference [95% CI] − 6.35 [− 10.17, − 2.53]; I 2  = 61%; p = 0.001, Fig.  3 C). Although there was a decrease in the mean total cholesterol levels at follow-up from baseline with the combination therapy, the difference was not significant (n = 3 studies; mean difference [95% CI] − 0.11 [− 0.25, 0.02]; I 2  = 0%; p = 0.09) (Fig.  3 D).

Renal outcomes

The combination therapy was not associated with significant decreases in eGFR levels at follow-up from baseline (n = 2 studies; mean difference [95% CI]  − 1.04 [− 4.56, 2.49]; I 2  = 0%; p = 0.56) (Fig.  3 E). Two studies (Carretero-Gomez et al. [ 28 ] and Diaz-Trastoy et al. [ 26 ]) reported results related to albuminuria. In the study by Carretero-Gomez et al. [ 28 ], there was a significant reduction in total urinary albumin-to–creatinine ratio (UACR; − 15.14 mg/g; p < 0.0001) and macroalbuminuria (UACR > 30 mg/g; − 63.18 mg/g; p < 0.0001) at 26 weeks. In the study by Diaz-Trastoy et al. [ 26 ], albuminuria data were available for 127 of 212 patients, 10 patients progressed from normoalbuminuria to micro- and macroalbuminuria, and 13 patients showed regression.

Glycemic outcomes

Treatment with the SGLT2i + GLP-1RA combination was also associated with improved glycemic control, expressed as a significant decrease in HbA1c and FPG levels at the 6-month follow-up from baseline (HbA1c: n = 7 studies; mean difference [95% CI] − 1.48 [− 1.75, − 1.21]; I 2  = 66.0%; p < 0.00001, Fig.  3 F; FPG: n = 5 studies; mean difference [95% CI] − 2.27 [− 2.78, − 1.76]; I 2  = 65.0%; p < 0.00001, Fig.  3 G).

Findings from the subgroup analyses

The pattern of administration of the combination therapy did not significantly affect BMI at follow-up (n = 2 studies; mean [95% CI] 1.00 [− 0.15, 2.16]; I 2  = 20%; p = 0.09, Fig.  4 A). However, the reduction in BMI was significant when patients were already on GLP-1RA and received add-on SGLT2i (n = 2 studies; mean [95% CI] 1.52 [0.28, 2.75]; I 2  = 0%; p = 0.02). Although there was a reduction in the SBP levels in those on sequential combination therapy compared with those on simultaneous combination therapy at 6 months follow-up, this change was not significant (n = 5 studies; mean [95% CI] 2.62 [− 0.48, 5.71]; I 2  = 0%; p = 0.10, Fig.  4 B).

Findings from the subgroup analyses. A Changes in BMI with simultaneous versus sequential combination therapy at the 6-month follow-up. B Changes in SBP with simultaneous versus sequential combination therapy at the 6-month follow-up. C Changes in HbA1c levels with simultaneous versus sequential combination therapy at the 6-month follow-up. D Changes in FPG levels with simultaneous versus sequential combination therapy at the 6-month follow-up. BMI body mass index, CI confidence interval, FPG fasting plasma glucose, GLP-1RA glucagon-like peptide-1 receptor agonist, HbA1c glycated hemoglobin, IV importance value, SBP systolic blood pressure, SD standard deviation, SGLT2i sodium–glucose transport protein 2 inhibitor, Seq. Combn. Tx sequential combination therapy, Simult. Combn. Tx simultaneous combination therapy

In the study by Carretero-Gomez et al. [ 28 ], the extent of reduction in the total UACR was significant and similar when the combination was started simultaneously or when a GLP-1RA was added to ongoing SGLT2i therapy (− 17.19 mg/g and − 16.4 mg/g, respectively; p < 0.0001). A greater reduction in macroalbuminuria was observed when an SGLT2i was added to a GLP-1RA than when a GLP-1RA was added to an SGLT2i (− 116.7 mg/g [n = 24] and − 55.5 mg/g [n = 21]; p < 0.005).

For the subgroup analyses, outcomes at the 6-month follow-up were compared between patients treated with the combination of SGLT2i + GLP-1RA administered simultaneously versus sequentially. Pooled estimates for changes in HbA1c levels and FPG levels showed no significant differences between the simultaneous combination therapy and sequential combination therapy at follow-up (HbA1c: n = 4 studies; mean [95% CI] − 0.06 [− 0.24, 0.13]; I 2  = 31.0%; p = 0.55, Fig.  4 C; FPG: n = 2 studies; mean [95% CI] − 0.10 [− 0.32, 0.13]; I 2  = 0%; p = 0.41, Fig.  4 D).

Due to the lack of studies comparing simultaneous combination and sequential combination therapies at follow-up, meta-analysis could not be performed for all-cause mortality outcomes, and changes in eGFR and total cholesterol levels.

GRADE analysis

According to the GRADE analysis (Table  5 ), the certainty of evidence for the outcomes of all-cause mortality and changes in BMI, SBP, HbA1c, eGFR, and total cholesterol levels was “low.” The certainty of evidence for the outcome of changes in FPG was “very low.”

Our meta-analysis of real world data showed a significant reduction in all-cause mortality as well as significant reductions in HbA1c, SBP, and body weight in T2DM patients treated with SGLT2i + GLP-1RA combination compared to either 2 drug class used alone.

Individual use of SGLT2is and GLP-1RAs can significantly improve cardiovascular outcomes and reduce mortality. This association has been reported in several landmark RCTs and meta-analyses [ 7 , 11 , 12 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Empagliflozin was associated with a reduction in CV mortality, nonfatal MI, or nonfatal stroke, as well as a reduction in all-cause mortality [ 35 , 36 , 37 ], whereas DECLARE showed dapagliflozin reduced all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF) but not in those without HFrEF [ 39 ] The CANVAS and CANVAS-R studies on canagliflozin have reported similar benefits [ 38 ]. Death from CV causes and all-cause mortality were reduced in participants receiving liraglutide in the LEADER study [ 42 , 43 ], while the SUSTAIN-6 study demonstrated lower CV deaths in patients receiving subcutaneous semaglutide [ 44 ]. Oral semaglutide significantly reduced CV risk factors such as HbA1c, body weight, and SBP with nearly 50% reduction in CV and all-cause mortality in the PIONEER-6 trial [ 45 ]. The SOUL study demonstrated the non-inferiority of semaglutide to placebo in terms of CV mortality outcomes [ 46 ]. The REWIND study reported a lower incidence of MACE-3 and other CV outcomes [ 41 ], whereas, albiglutide reduced CV events driven by a reduction in myocardial infarction with similar CV deaths [ 40 ].

In the absence of studies directly comparing SGLT2i/GLP-1RA combination versus either of these being used alone, meta-analyses of CVOTs and observational studies have assessed whether the concurrent use of SGLT2is + GLP-1RAs provides an additional advantage in reducing the incidence of MACE, cardiorenal endpoints, and cardiovascular mortality. A retrospective cohort study evaluating the added benefits of administering GLP-1RAs + SGLT2is in patients with T2DM (N = 5576) showed that the addition of GLP-1RA reduced the risk of composite all-cause mortality, myocardial infarction, and stroke by 67% [ 17 ]. However, an analysis of three US claims datasets from 2013 to 2018 for all-cause mortality among patients (N = 12,584) who received add-on SGLT2i while already receiving GLP-1RA therapy showed that although the SGLT2i addition reduced the risk of MACE and hospitalizations related to heart failure, it did not reduce all-cause mortality [ 47 ]. In a study by Jensen et al. [ 30 ], treatment with metformin + SGLT2is and metformin + GLP-1RAs was associated with a reduced risk of MACE, all-cause mortality, and severe hypoglycemia; however, patients who received triple therapy with SGLT2i + GLP-1RAs + metformin had the lowest risk of all three outcomes.

Although initial metanalyses on SGLT21/GLP-1 combination reporting greater reductions in HbA1c, SBP, and body weight were not powered or did not assess MACE or all-cause mortality, a later meta-analysis of CVOTs using SGLT2i or GLP-1 reported significant reductions in MACE (30%), cardiovascular mortality/hospitalization due to heart failure (31%), and all-cause mortality (57%) compared with monotherapy with either SGLT2i or GLP-1RA [ 18 , 48 ]. Our real-world meta-analysis supports further the reduction in all-cause mortality, suggesting better cardiovascular protection when these two drug classes with different mechanisms of action are used together.

Although the exact mechanisms by which SGLT2is and GLP-1RAs reduce CV and all-cause mortality are not yet fully understood, endothelial dysfunction is a common pathogenetic feature underlying HF, especially with preserved ejection fraction, T2DM, and frailty, and empagliflozin has recently been demonstrated to act via regulation of microRNAs and reduction of mitochondrial oxidative stress [ 49 , 50 ]. The cardiovascular benefits of empagliflozin were evident through the significant improvement in the 5-m gait speed test within 3 months of treatment in older and frail individuals with T2DM and hypertension [ 50 ]. The combination of empagliflozin and liraglutide reduced central systolic blood pressure, perfused boundary region, and arterial stiffness in patients with T2DM to a greater extent than insulin in addition to similar glycemic effects, suggesting that the combination should be preferred over traditional insulin plus metformin in patients with T2DM and high cardiovascular risk [ 51 ]. Vascular remodeling is a pathological process in cardiovascular diseases, and GLP-1RAs, including semaglutide, have been shown to reduce vessel remodeling through their anti-inflammatory and anti-proliferative effects independent of their interaction with GLP-1R [ 52 ].

The present analysis indicates that simultaneous treatment with the combination of SGLT2is + GLP-1RAs is effective in significantly reducing baseline HbA1c and FPG levels in patients with T2DM at follow-up. Accumulated data underscore the advantages of combining SGLT2is and GLP-1RAs for cardiovascular, renal, and metabolic health in T2DM patients at a low risk of developing hypoglycemia [ 53 ]. Individuals newly diagnosed with T2DM frequently present with multiple comorbid conditions that increase their susceptibility to CVD, such as hypertension, dyslipidemia, and obesity [ 54 ]. The severity of these comorbidities is especially high in patients after 1 year of being diagnosed with T2DM and presenting with HbA1c levels of > 6.5% [ 55 ]. Hence, it is crucial to attain early and sustained glycemic control to prevent diabetes-related complications.

GLP1-RAs promote pancreatic insulin secretion to regulate the levels of glucose in the blood. Apart from their role in insulin secretion, GLP-1RAs delay gastric emptying, stimulate the appetite centers in the brain to induce early satiety, and consequently reduce food consumption [ 13 , 26 , 56 ]. SGLT2is also contribute to weight loss as a result of caloric loss through glycosuria; however, the weight loss may be less than expected due to increased food intake, especially if adequately intensive lifestyle changes are not implemented [ 57 ]. A retrospective search of the electronic prescriptions of patients with T2DM (N = 446,798) for SGLT2i + GLP-1RA treatment in Spain (2018) showed that the combination resulted in faster weight loss and greater HbA1c reduction when administered simultaneously than when the drugs were administered sequentially [ 26 ]. This real-world data analysis also shows a significant decrease in BMI with the combination therapy. Notably, there was a higher reduction in BMI when an SGLT2i was added to the GLP-1RA therapy rather than vice versa.

A significant decrease in SBP was seen at 6 months follow-up compared to baseline among patients who received simultaneous SGLT2i + GLP-1RA therapy. While no significant difference in the SBP between patients who received the simultaneous versus sequential combination therapy was apparent, the reduction in SBP was greater in patients who first received SGLT2is and then received GLP-1RAs. This is consistent with a previous review that focused on data from placebo-controlled trials regarding the antihypertensive effects of GLP-1RAs, SGLT2is, and DPP-4 inhibitors; this review reported that SGLT2is are more potent than the other two drug classes in reducing SBP and diastolic blood pressure among patients with T2DM [ 58 ]. The decrease in SBP can be attributed to the natriuresis induced by SGLT2is [ 59 ]. GLP-1RAs exhibit a nephroprotective effect by directly interacting with renal cells; they prevent glomerular hyperfiltration by promoting diuresis and natriuresis [ 60 ].

In the present analysis, the difference between the baseline and the follow-up eGFR was statistically non-significant in patients with T2DM who received the combination; however, the duration of follow-up in these real-world studies was not long enough to observe any improvement in kidney function that was demonstrated in larger SGLT2i trials, e.g., the DECLARE TIMI58 trial (median follow-up: 4.2 years [ 39 ]) and CANVAS trial (mean follow-up: 3.6 years [ 38 ]). More recently, the FLOW study, which focused on evaluating the nephroprotective and cardioprotective efficacy of semaglutide, a GLP-1RA, in patients with T2DM and CKD (N = 3534), was stopped prematurely as it met certain pre-specified efficacy criteria, with a very high likelihood of study success on reducing the progression of renal disease [ 61 ]. Microalbuminuria is an independent risk factor for progressive CKD and cardiovascular events, especially in patients with T2DM [ 62 ]. Post hoc analyses of the double-blind, placebo-controlled Semaglutide Treatment Effect in People with obesity (STEP) 2 trial, which involved overweight/obese patients with T2DM (N = 1210), showed that those on semaglutide had an improved UACR status. Additionally, treatment with semaglutide led to a reduction in the proportion of patients with microalbuminuria (UACR 30–300 mg/g) compared to treatment with placebo at the end of week 68 (11.5% vs. 22.4%) [ 63 ]. SGLT2is are recommended for the treatment of patients with T2DM and CKD (eGFR ≥ 30 mL/min/1.73 m 2 and UACR > 30 mg/g), given their nephroprotective effects via the renin–angiotensin–aldosterone system [ 64 ]. However, for those with impaired renal function (eGFR < 30 mL/min/1.73 m 2 ), the lowering of HbA1c levels by SGLT2is is negligible [ 65 ]. This again supports the rationale for combining SGLT2is with GLP-1RAs, which exert their glucose-lowering effect independent of kidney function. GLP-1RAs are reported to inhibit the development and/or progression of kidney disease in patients with T2DM while reducing the risk of kidney damage [ 66 ].

Estimates for CV mortality could not be derived in this meta-analysis, given the lack of real-world studies reporting CV mortality outcomes and meeting the study eligibility criteria. The Journal of the American College of Cardiology 2020 expert consensus report on the combined use of these drugs suggested the need for more evidence-based studies supporting the use of this combination for its CV benefits but concluded that the concurrent use of both SGLT2is and GLP-1RAs is permissible when indicated, considering the patient benefits established in numerous trials [ 67 ]. Guidelines and recommendations from various medical bodies, including the American Diabetes Association (ADA), European Society of Cardiology, and Diabetes Canada, have advocated for adding an SGLT2i following the use of a GLP-1RA, or vice versa, for T2DM patients with a high risk of developing ASCVD and those with CKD [ 68 , 69 , 70 ].

Despite the substantial amount of literature proposing the advantages of using SGLT2is + GLP-1RAs, a retrospective cross-sectional two-center study conducted in Riyadh, Saudi Arabia (January–December 2020), showed that physicians were under-prescribing these drugs; the study showed that endocrinologists most frequently prescribed SGLT2is or GLP-1RAs (60.6%), followed by internal medicine physicians (11.4%), cardiologists (9.8%), and nephrologists (2.0%) [ 71 ]. While RCT meta-analyses and findings from the present real-world analysis demonstrate the added benefit of combination therapy among patients with T2DM [ 13 , 14 , 16 , 51 , 72 , 73 , 74 ], very little has truly been translated into practice. Despite recommendations to include the combination in patients with T2DM, cardiologists view diabetes care independently of cardiovascular care, and consequently, are reluctant to prescribe SGLT2is + GLP-1RAs for their cardiovascular benefits in the management of patients with T2DM [ 75 , 76 ]. Recognizing this reluctance, it is important to analyze the barriers associated with integrating these treatments into routine clinical practice to enhance cardiovascular outcomes [ 71 ]. Combination therapy with SGLT2is + GLP-1RAs can address multiple components of the ominous octet (insulin and glucagon secretion, hepatic glucose production, gastrointestinal incretin defect, appetite and weight loss, and muscle and hepatic insulin sensitivity), improve cardiovascular risk, and prevent diabetic nephropathy and should therefore be considered as an option during the early treatment stages of patients with T2DM. Combination therapy should perhaps be considered for first-line treatment in patients with T2DM who are at high risk of cardiovascular and renal disease as it is not associated with any notable safety issues or adverse event outcomes [ 77 ]. Treatment goals for patients with T2DM should be focused on the timely control of HbA1c levels along with the prevention of microvascular and macrovascular complications [ 78 ].

This systematic review has some limitations. First, publication bias assessment was not possible as relatively few studies were identified for each of the outcomes presented in this SLR. Second, there was considerable heterogeneity in patient demographics (e.g., age), duration of diabetes, medical history (e.g., baseline HbA1c), treatment history, and concomitant medications for T2DM (e.g., insulin, metformin, or other glucose-lowering agents) among the included studies. Most of the studies did not report the duration for which the patients received treatment with SGLT2i or GLP-1RA until add-on was initiated, which would have provided insights into the extent of heterogeneity in the timing of therapy titration. Accordingly, for all the outcomes, the certainty of evidence was deemed low-to–very low in the GRADE analysis. Third, unadjusted mortality values have been presented in the current meta-analysis. Given that both SGLT2is and GLP-1RAs strongly influence BMI and microalbuminuria, it will be interesting to note how mortality varies as a function of these parameters. Such adjustment analyses could not be conducted due to lack of number of studies reporting mortality outcomes. Fourth, a meta-analysis for cardiovascular mortality could not be performed due to the lack of sufficient data. This calls for more and larger-sized real-world studies to strengthen the evidence that supports the early use of these combinations to improve cardiovascular outcomes and glycemic control in patients with T2DM.

This SLR and meta-analysis of real-world studies suggests that the combination of SGLT2is + GLP-1RAs is associated with significantly lower all-cause mortality than individual therapies, with an improvement in cardiovascular, renal, and glycemic measurements. Providing evidence that supports the advantages of introducing the combination early can significantly strengthen the foundation for making confident clinical decisions. Moreover, the simultaneous use of these drugs could prove more beneficial than sequential combination therapy in patients with T2DM, and if similar results are reported with the use of oral GLP-1RAs, it may be easier to initiate the combination earlier in the disease course.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed.

Abbreviations

American Diabetes Association

Body Mass Index

Chronic kidney disease

Estimated glomerular filtration rate

Fasting plasma glucose

Glucagon-like peptide-1 receptor agonists

Grading of Recommendations, Assessment, Development and Evaluation

Joanna Briggs Institute

Lipoprotein cholesterol

Major Adverse Cardiovascular Events

Randomized controlled trials

Sodium–glucose transport protein 2 inhibitors

Systolic blood pressure

Type 2 diabetes mellitus

Mean difference

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Department of Endocrinology, Imperial College London Diabetes Centre, Abu Dhabi, United Arab Emirates

Aftab Ahmad

Department of Endocrinology, Khalifa Medical University, Abu Dhabi, United Arab Emirates

Department of Cardiology, Mediclinic Hospital, Abu Dhabi, United Arab Emirates

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Additional file 1: table s1..

Search strategy for the systematic literature review. Table S2. List of studies excluded at the full-text screening stage with reasons for exclusion. Table S3. List of studies excluded from the meta-analysis and reasons for exclusion.

Additional file 2.

Assessment of study quality and data extraction.

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Ahmad, A., Sabbour, H. Effectiveness and safety of the combination of sodium–glucose transport protein 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of observational studies. Cardiovasc Diabetol 23 , 99 (2024). https://doi.org/10.1186/s12933-024-02192-4

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• Diabetes mellitus
• Sodium–glucose transport protein 2 inhibitor
• Glucagon-like peptide-1 receptor agonist
• Cardiovascular
• Meta-analysis
• Observational studies

Cardiovascular Diabetology

ISSN: 1475-2840

• Submission enquiries: [email protected]

Prevalence of new-onset diabetes mellitus after kidney transplantation: a systematic review and meta-analysis

Affiliations.

• 1 College of Nursing, Chengdu University of Traditional Chinese Medicine, No.37 Shi-er-qiao Road, Chengdu City, 610075, Sichuan Province, China.
• 2 Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, No.39 Shi-er-qiao Road, Chengdu City, 610072, Sichuan Province, China. [email protected].
• PMID: 38507083
• DOI: 10.1007/s00592-024-02253-w

Aims: Post-transplant diabetes is a prevalent and consequential complication following kidney transplantation, which significantly augments the risk of cardiovascular disease, graft loss, infection, and mortality, thereby profoundly impacting both graft and patient survival. However, the early stages of post-transplant diabetes often go unnoticed or receive inadequate management. Consequently, this study systematically assesses the incidence of new-onset diabetes after kidney transplantation with the aim to enhance medical staff awareness regarding post-transplantation diabetes and provide clinical management guidance.

Methods: We conducted a comprehensive search across multiple databases including PubMed, Web of Science, Embase, The Cochrane Library, CNKI, Wanfang, VIP, and SinoMed until September 21, 2023. Data extraction was performed using standardized tables and meta-analysis was conducted using Stata 16.0 software. A random effects model was employed to estimate the combined prevalence along with its corresponding 95% confidence interval. The source of heterogeneity was explored using subgroup analysis and sensitivity analysis, while publication bias was assessed through funnel plot and Egger's test. This study has been registered with PROSPERO under the registration number CRD42023465768.

Results: This meta-analysis comprised 39 studies with a total sample size of 16,584 patients. The prevalence of new-onset diabetes after transplantation was found to be 20% [95% CI (18.0, 22.0)]. Subgroup analyses were conducted based on age, gender, body mass index, family history of diabetes, type of kidney donor, immunosuppressive regimen, acute rejection episodes, hepatitis C infection status and cytomegalovirus infection.

Conclusions: The incidence of post-kidney transplantation diabetes is substantial, necessitating early implementation of preventive and control measures to mitigate its occurrence, enhance prognosis, and optimize patients' quality of life.

Clinical trial registration: PROSPERO: CRD42023465768.

Keywords: Diabetes mellitus; Kidney transplantation; Meta-analysis; Prevalence; Systematic review.

© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.

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Effectiveness of diabetes education and awareness of diabetes mellitus in combating diabetes in the United Kigdom; a literature review

Chaudhary muhammad junaid nazar.

1 Department of Nephrology, Shifa International Hospital, Islamabad, Pakistan

Micheal Mauton Bojerenu

2 Department of Internal Medicine, Sickle Cell Unit, Harvard University Hospital, Washington DC, USA

Muhammad Safdar

Jibran marwat.

Diabetes mellitus is a metabolic disorder that is characterized by high blood glucose level, and body cannot produce enough insulin, or does not respond to the produced insulin. In spite of the diabetes education campaigns and programmes, a large number of people in the United Kingdom are living with diabetes. The main objective of the study is to evaluate the role of knowledge and awareness of diabetes in fighting against diabetes and to interpret to which extent is diabetes education successful. The systematic review to be carried out will include literature from 2001 to 2011 in the United Kingdom regarding awareness of diabetes among UK population and effectiveness of diabetes education. Literature will be accessed using search database, British medical journals, and library. Good quality papers will be used for the systematic review. Previous studies about diabetes education will consulted and assessed. This study is going to summarize the efficacy of diabetes education campaigns and programmes which are promising to enhance the awareness The outcome of the review will be the guideline for the government, education centres, researchers, and campaigns to implement more diabetic education programmes and easily accessible diabetes services and education interventions to increase the awareness of risk factors and complications of diabetes to overcome the increasing epidemic of diabetes in the United Kingdom.

Implication for health policy/practice/research/medical education:

Diabetes mellitus is a metabolic disorder, in which there is high blood glucose level, and body cannot produce enough insulin, or the body does not respond to the insulin produced. In spite of the diabetes education campaigns and programmes, a large number of people in the United Kingdom are living with diabetes. The main objective of the study is to evaluate the role of knowledge and awareness of diabetes in fighting against diabetes and to interpret to which extent is diabetes education successful. The outcome of the review will be the guideline for the government, education centres, researchers, and campaigns to implement more diabetic education programmes and easily accessible diabetes services and education interventions to increase the awareness of risk factors and complications of diabetes to overcome the increasing epidemic of diabetes in in the United Kingdom.

Introduction

Diabetes is a serious and life-threatening disease, however it can be managed very well through proper treatment and controlling. Diabetes self-management training and education plays a vital role in the management of diabetes ( 1 ). It is crucial for diabetic patients to be aware of nature, treatment, risk factors and complication of disease due to providing suitable modality to attenuate following complications. In a study to detect the relation between health literacy, complication awareness and diabetic control among patients with type 2 diabetes mellitus, it was concluded that patient awareness scores and health literacy was negatively related to diabetes control ( 2 ). This study was 6 months study, carried out from September 2005 to February 2006 with about 150 Chinese patients.

Materials and Methods

For this review, we used a variety of sources by searching through PubMed, EMBASE, Scopus and directory of open access journals (DOAJ). The search was performed by using combinations of the following key words and or their equivalents; Prevalence of diabetes mellitus, awareness and knowledge about diabetes and its management, diabetes education programmes, effectiveness of diabetes education.

Looking at the study carried out to explore the total prevalence of diabetes mellitus in 2001 in England to support delivery of healthcare services it was estimated that in 2001 the prevalence of diabetes (diagnosed as well as undiagnosed) in England was about 4.5%, affecting more than 2 million persons ( 3 ). It was found that the prevalence of type 2 diabetes was 92% affecting 2000000 persons and the prevalence of type 1 diabetes was nearly 8% affecting 160000 persons. The prevalence of diabetes was estimated to be more in women (5.2%) than men (3.6%). It was also estimated that the prevalence of diabetes was higher in the people from ethnic minority groups than the white people. The estimated prevalence rates are 4.3 for white people, 5.7 for black African/Caribbean, and 6.6 for South Asians and 2.1% for other groups. The prevalence of diabetes was found to be increased rapidly with age as the prevalence was found to be 0.3 in people aged 0–29, 3.3 in those 30–59 and 14% in people over 60 years age.

According to Diabetes UK (2010) in 2009, the prevalence of diabetes in adults over 17 years old is estimated to be 5.1% in England affecting 2213138, 4.5% in Northern Ireland affecting 65066, 4.6% in Wales affecting 146173 and 3.9% in Scotland affecting 209886 people. The total average prevalence of diabetes in 2009 in the United Kingdom is estimated to be 4.26%.

A systematic review was conducted to estimate the age- and sex-specific diabetes prevalence worldwide for years 2010 and 2030 ( 4 ). Studies from 91 countries were selected and it was found from the review findings that the incidence of diabetes among people aged 20–80 years will be 6.5% in 2010 and 286 million adults will be affected in 2010. The prevalence of diabetes will increase to 7.8%, and nearly 440 million adults will be affected by 2030. It was suggested that there will be a 70% increase in the prevalence of diabetes in adults of developing countries and about 21% rise in developed countries. By looking at CHASE study, a cross-sectional survey carried out involving nearly 4800 children aged 9-10 years old recruited from London, Birmingham and Leicester, it is found that South Asians adults, residents of UK are 3 times more prone to develop type 2 diabetes than white Europeans ( 5 , 6 ). These people have higher blood levels of glycated haemoglobin (HbA1c), higher level of C-reactive proteins in the blood, lower level of High-density lipoprotein -cholesterol (HDL-C) and high triglyceride levels than white people. Black African-Caribbean adults residing in the United Kingdom have also most of these diabetic risk factors but these people have high HDL-C levels and low triglyceride levels.

Better diabetic education and knowledge to control and treat diabetes at right time can minimize the chances to develop complications of diabetes and thus reduce morbidity and mortality in diabetics ( 7 , 8 ). It suggests that as the rising figures of people diagnosed with diabetes is becoming a challenge in the United Kingdom so a randomised clinical trial will be run by independent research teams to interpret effective delivery and cost effectiveness of CASCADE (Child and Adolescent Structured Competencies Approach to Diabetes Education) for children and young people involved in this trial. As we know that if diabetes is diagnosed in childhood and bitterly controlled, the chances to develop long-term complications become less. The CASCADE is a multi-centre randomised control trial involving 26 clinics randomly selected as control/intervention groups, including 572 children and young people ( 7 ). Despite of the advanced medications and their delivery systems there is less improvement in control of diabetes in children and young people in the United Kingdom in last decade ( 8 ). So new health delivery systems are needed for children and young people to improve and control the diabetes.

With regards to this, in 2010, fifth national survey was carried out to assess the delivery of UK diabetes services to children and young people and identified changes in service delivery systems since 2002 ( 9 ). One hundred twenty-nine services took part in the survey involving 220 clinics. Ninety-eight percent of paediatric consultants were found having special interest in diabetes whereas in 2002 about 89% of consultants were interested in diabetes. In 88% of services, the diabetes specialist nurse worked alone in paediatric diabetes compared to 53% of the services in 2002. So overall it was concluded that there is much improvement in diabetes services for children providing high quality care, but serious deficiencies still remains.

According to Diabetes UK (2010) most of the people with diabetes type 2 in the United Kingdom are over 60; their level of diabetes knowledge tends to be poorer. According to Diabetes UK (2010) report, the residents of care homes fail to receive diabetes education and screening. A care home resident gets admitted to the hospital for screening and diagnosis of diabetes due to the lack of screening facilities and lack of diabetes education. There are diabetic residents in 6 out of 10 care homes that cannot provide special education ( 10 ).

UK prospective diabetes study has shown that adapting the effective therapy to reduce high blood pressure and high blood glucose level will result in reducing the diabetes complications ( 11 ). Diabetes UK invested more than 2 million on this study ( 11 ). The UK Prospective Diabetes Study, the 20-year study involving 5000 patients with diabetes in the United Kingdom, has revealed that intensive blood glucose level control and adopting better treatment methods can reduce the risk of diabetic retinopathy by a quarter and early renal damage by a third ( 11 ). Intensive management and control of blood pressure in hypertensive patients can reduce the risk of death resulting from life threatening long-term complications of diabetes by a third, vision loss by more than a third and cardiovascular disease by more than a third ( 10 ).

By looking at the data collected between 1st April 2008 and 31st March 2010 from 1421 weight reducing operations carried out, it is found that before surgery 379 of these 1421 patients were having type 2 diabetes ( 11 ). After 1 year of surgery it was found that this number of diabetic patients was decreased to 188 from 379 ( 11 ). Therefore by providing knowledge of advance treatment methods to people helps in controlling the diabetes as educating people about the weight loss surgeries (gastric bypass and gastric bands) can tackle type 2 diabetes as seen in this study.

Diabetes education can improve the quality of life of diabetic patients and can also prevent the costs of long-term complications of diabetes in the patients ( 10 ). As amputation of lower limb in a diabetic patient, a long-term complication of diabetes is a costly intervention, the diabetes education can help in reducing the amputation rate that can lead to large cost savings ( 10 ). Diabetic foot ulcers can develop in patients having diabetes both in type 1 and type 2 diabetes ( 11 ). It has been found, 10% of diabetic individuals may suffer from foot ulcer during their lifetime. Foot ulcer often occurs in the people who develop peripheral diabetic neuropathy and also by wearing tight shoes, by walking on tread mill, having cuts, blisters and also having narrowed arteries; atherosclerotic peripheral arterial disease. The diabetic foot ulcers should not be avoided and diabetic foot needs a special care, otherwise the diabetic foot ulcer can result in the amputation of the foot even the whole lower limb ( 11 ). The risk of lower limb amputation in diabetic patients is 15 to 45 times more than in people with no diabetes ( 10 ). About 25% of hospital admissions of diabetic people in United States and Great Britain are due to diabetic foot complications ( 10 ). The annual incidence of diabetic foot ulcers and amputation are 2.5% to 10.7% and 0.25% to 1.8%, respectively ( 12 ).

In the United States an estimated more than 130 billion dollars in 2002 is the cost of diabetes ( 13 ). Because of these devastating numbers, the cost-efficacy of preventing and treating diabetes, and the cost-effectiveness of diabetes self-management training and medical nutrition therapy to treat diabetes are receiving much attention ( 13 ). While in the United Kingdom, the cost of diabetes to the National Health Service (NHS) stands at approximately £1 million per hour, and is increasing rapidly. Diabetes accounts for approximately a tenth of NHS budget each year, a total exceeding £9 billion ( 11 ). With regards to this a systematic review was carried out involving 26 articles including randomized controlled trials, retrospective database analyses, meta-analysis, prospective, quasi-experimental and, to evaluate the cost-effectiveness of diabetes education. The results of more than half of the studies reviewed were indicated positive association between diabetes education and decreased cost. The findings of these studies indicate that diabetes self-management education (DSME) has more benefits in reducing the costs associated with diabetes intervention. Study agreed with this finding by conducting a 12-month study involving primary care trusts in the United Kingdom to assess the long-term clinical and cost-effectiveness of the diabetes education and self-management for ongoing and newly diagnosed (DESMOND) intervention ( 14 ). The cost-utility analysis was undertaken using data from a 12-month, multicentre, cluster randomised controlled trial and the study resulted that the DESMOND intervention is considered to be cost effective compared with usual care, especially with respect to the real world cost of the intervention to primary care trusts, with reductions in Cardiovascular disease (CVD) risk especially reduction in weight and smoking ( 14 ).

According to a cohort study, conducted in 2005 by Diabetes UK, The cancer risk and mortality is progressively elevating in insulin treated diabetic individuals ( 15 ). This study involved 28900 UK resident patients with insulin-treated diabetes who were less than 50 years old at the diagnosis of diabetes. However, the results showed, risks of some cancers such as liver, pancreatic, endometrial, renal and colorectal cancer slightly are raising in patients with prime type 2 diabetes but some cancer incidence including gall bladder, breast cancers and non-Hodgkin lymphoma (NHL) have not changed or prostate cancer risk has been reduced ( 15 ).

Celiac disease, as a chronic immune mediated disorder, is triggered by gluten intake in predisposed patients ( 16 ). Type 1 diabetes is one of the diseases associated with celiac disease ( 18 ). Both diseases have a common genetic predisposition. In one Turkish study involving 100 diabetic patients (51 female, 49 male, mean age 26 ±9 years, and 80 control subjects - 40 female, 40 male, mean age 27 ± 8 years), it was estimated that the prevalence of celiac disease is more in diabetic patients than the general people and celiac disease in diabetic patients can only be diagnosed by screening tests for celiac disease as CD is mostly seen as asymptomatic in these patients. The most sensitive and specific test for the diagnosis of CD is the anti-endomysial IgA antibody (IgA-EMA) test with a sensitivity of more than 90% and a specificity about 100%. This is a screening method in patients at high risk for CD. Anti-endomysium IgA was tested by indirect immunofluorescence using sections of human umbilical cord for screening. Some investigators predicted that the complications of diabetes are increased in the presence of celiac disease and worsens the metabolic control in these diabetic patients ( 17 ).

High blood glucose level can lead to microvascular and macrovascular complications ( 18 ). For examining this, a prospective observational study (UKPDS 35) was conducted by Stratton et al ( 18 ). To report positive correlation between hyperglycaemia and macro/micro-vascular insults in type 2 diabetic patients. This study involved 23 hospital-based clinics in England, Scotland and Northern Ireland. About 4600 patients including white, Asian Indian and African-Caribbean patients were participated in incidence rates analysis. Risk factors related macro-vascular complication were noticed in about 3600 of the total patient. The results of the study indicated that there is a direct relation between hyperglycemia, micro-vascular and macro-vascular complications ( 18 ). This is also clear by examining a cohort study, conducted by Fuller et al to assess cardiovascular disease associated risk in type 1 diabetic patients in the United Kingdom ( 19 ). This study consisted of group of 7500 patients with type 1 diabetes and 5 age- and gender-matched controls per non-diabetic individuals comparison group (nearly 38200) selected from the General Practice Research Database (GPRD). The cardiovascular events in these two groups were apprehended between1992-1999. These high CVD risks were seen for strokes, acute coronary disorders, and for coronary revascularizations. Results showed that women having type 1 diabetes continue to experience greater relative risks of cardiovascular disease than men compared with those without diabetes ( 19 ). Hence, there is increased absolute and relative risk of mortality due to CVD in patients with type 1diabetes compared with those without diabetes in the United Kingdom ( 19 ).

Blood glucose awareness training and cognitive behavioural therapy have been able to balance blood glucose level in type 1 diabetic patients ( 20 ). To support this evidence, a systematic review was completed ( 20 ) in Oxford to assess fear of hypoglycaemia in the patients having diabetes. About 36 papers were reviewed. And it was implicated from the review that fear of hypoglycaemia can have negative impact on diabetes management and awareness training is needed to reduce this fear of hypoglycaemia. This was further supported by a randomised control trial, carried out ( 21 ) on 650 randomly selected diabetic patients from Bournemouth Diabetes and Endocrine Centre’s diabetes register to determine the relationship between numeracy skills and glycaemic control in type 1 diabetes. Out of 650 patients 112 patients completed the study. Forty-seven percent were the male patients and it was found that low numeracy skills were badly associated with glycaemic control in diabetes and literacy was also badly associated with glycaemic control in diabetes and also relationship between literacy and glycaemic control was found to be independent of the duration of diabetes and socio-economic status of the patients.

Diabetic patients can develop hyperglycaemia and hypoglycaemia in the critical care setting while hospitalized due to various factors including infection, poor diet, and drugs ( 22 ). Hospitalized patients can develop hyperglycaemia even in the absence of family history of diabetes ( 22 ). The blood glucose level range of 100–200 mg/dl is the target of glycaemic control in the hospitalized patients. Insulin infusion is done in hospitalized patients having type 1 diabetes and in type 2 diabetic patients, oral drugs are stopped and insulin is started for glycaemic control ( 22 ).

Educational and psychosocial interventions are able to approximately improve diabetes management. ( 23 , 24 ). A systematic review was completed by Hampson et al ( 23 ) to investigate the educational and psychosocial intervention efficacy on improvement of diabetes management in adolescents type 1 diabetes patients. About 60 articles were reviewed. This systematic review gave the result that educational and psychosocial interventions have beneficial impacts on various diabetes management consequences. Similarly a systematic review was conducted by Norris et al ( 24 ) to assess the effectiveness of self-management education on glycosylated hemoglobin in adults having type 2 diabetes. Total 31 articles on randomized control trials were reviewed and it was found that DSME improves glycated hemoglobin levels at immediate follow-up by 0.76%, that long-lasting interventions may be needed to maintain the improved glycaemic control brought about by DSME programs as the more contact time between patient and educator enhances the efficacy of the result and that the improvement in glycosylated hemoglobin level drops 1–3 months after the intervention ceases ( 24 ). Further supporting this, another systematic review was conducted by Hawthorne et al ( 25 ) to determine the efficacy of various diabetic diet advice on balancing blood glucose level and weight in type 2 diabetic individuals. Only randomized controlled trials of 6 months or longer, were selected for the review and total 36 articles were reviewed. In this review study, some parameters such as weight, mortality, maximal exercise capacity and compliance various lipoproteins levels and blood pressure were measured. The review indicated that dietary advice is effective in the glycaemic control in type 2 diabetes mellitus ( 25 ) further supported all these reviews by conducting a systematic review to assess the effectiveness of culturally appropriate diabetes health education on type 2 diabetes mellitus as prevalence of type 2 diabetes mellitus is higher in ethnic minorities in the developed countries like the United Kingdom ( 25 ). Eleven randomised control trials of culturally appropriate diabetes health education on people having type 2 diabetes over 15 years from defined ethnic minority groups of developed countries were reviewed. The trials indicated both glycaemic control as well as improvement in knowledge after culturally appropriate diabetes education interventions. It was suggested from the review that culturally appropriate diabetes health education is effective in glycaemic control in type 2 diabetes and improving the knowledge score and changing the lifestyles and attitudes of the people.

Various diabetes education courses are being carried out in the United Kingdom, including DAFNE, DESMOND and X-PERT in order to increase awareness and knowledge of diabetes among people. These diabetes courses are designed to empower diabetic patients to manage their own condition effectively. Various factors like cost, distance, shortage of enough educators or centres, lack of appropriate services affect many people with diabetes to get access to diabetes knowledge. Educating the patients regarding diabetes have a key role in encouraging and supporting them to assume active responsibility for the day to day control of their situation. The review depicts that illiteracy and lack of knowledge poses a great challenge to effective health education. The review demonstrates that south Asian patients face problems regarding diet aspect and show poor level of knowledge about diabetes and also are discouraged to join educational sessions. The review indicates that impaired awareness of the diabetes increases the chances to develop complications of diabetes as the severe hypoglycaemia is becoming more common in insulin treated type 2 diabetes than previously recognized and with increased duration of insulin therapy may increase to meet that observed in type 1 diabetes. The risk of severe hypoglycaemia increases with having impaired awareness of hypoglycaemia. The authors has concluded that diabetes associated complications and psychological insults is usual in diabetic individuals. The study indicates that many providers involved in the study are aware of the diabetes related psychological problems but lack confidence in their ability to evaluate these problems and to support these patients. So, there is a need for manipulating models of care that provide essential psychosocial services. There is also need of integrating mental health professionals into the diabetes care team. This study will help the government to implement the diabetes education programmes that are cost effective and attractive to the public, easy to get access. Any diabetes service should provide highly structured diabetes education programme. In spite of the advanced medications and their delivery systems there is less improvement in control of diabetes in children and young people in UK in last decade. Better diabetic education and knowledge to control and treat diabetes at right time can reduce the risk factors and minimize the chances to develop complications of diabetes and thus reduce morbidity and mortality in diabetics.

Authors’ contribution

CMJN completed the article, MS and MMB reviewed the article, and JM completed the draft.

Conflicts of interest

The authors declared no competing interests.

Ethical considerations

Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

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Please cite this paper as: Nazar CMJ, Bojerenu MM, Safdar M, Marwat J. Effectiveness of diabetes education and awareness of diabetes mellitus in combating diabetes in the United Kigdom; a literature review. J Nephropharmacol. 2016;5(2):110-115.