Type 2 diabetes is an important cardiovascular risk factor and a global epidemic. As compared to early 20th century, when causes of deaths in patients with diabetes were infections and hyperglycemia, in the 21st century cardiovascular diseases, especially ischemic heart disease and peripheral arterial disease, are the major causes of mortality and morbidity.¹ Global estimates have suggested that in the last two decades while cardiovascular morbidity and mortality from diabetes has stabilized or is declining in high income countries, it is increasing in low- and lower-middle-income countries (LLMICs).^2,3 The Prospective Urban Rural Epidemiology (PURE) study has recently reported that cardiovascular events and cardiovascular mortality is significantly greater among individuals with type 2 diabetes in cohorts from the LLMICs compared to middle- and high-income countries.⁴ The investigators reported that in a cohort of 143,567 individuals aged 35-70 years from 21 countries, free from cardiovascular disease at baseline and followed for a mean of 9±3 years, participants with diabetes from LLMICs, compared to middle- and high-income countries, respectively, had cardiovascular event rate of 10.3/1000 versus 9.2/1000 and 8.3/1000 person-years and cardiovascular mortality of 5.7/1000 versus 2.2/1000 and 1.0/1000 person-years.⁴ The study also reported that major cardiovascular events and mortality in individuals with diabetes were double than in those without diabetes. These are important findings with significant implications.

Social Determinants

Multiple reasons for the greater mortality from cardiovascular disease among diabetes patients in LLMICs have been suggested and include social determinants as well as individual level risk factors. Macrolevel social determinants include low-quality urban and rural health infrastructure, inadequate health care financing, unfavorable social organization, social support and work environment, poverty, illiteracy, food policies, facilities for physical activity, and lack of high-quality primary and secondary healthcare.⁵ It has also been highlighted that type 2 diabetes epidemic and its complications are driven by an interwoven set of structural factors including poverty, inequality, ageing, poor nutrition, food insecurity, low educational attainment and environmental pollution.⁶ All these socioeconomic determinants are widely prevalent in LLMICs.⁷ Most of these social determinants have been extensively studied in context of cardiovascular diseases in middle- and high-income countries but have not been well studied in LLMICs.⁸ The PURE study previously reported that in LLMICs cardiovascular mortality is greater despite lower prevalence of cardiovascular risk factors showing that quality of healthcare is important.⁹ There is also a low availability and affordability of cardiovascular and diabetes medicines in LLMICs associated with greater adverse cardiovascular outcomes.¹⁰

Cardiovascular Risk Factors

Anjana et al. have also reported that greater cardiovascular mortality among participants with diabetes in the PURE study is not influenced by adjustments for cardiovascular risk factors and treatments.⁴ However, in the study, adjustments were made only for a limited number of risk factors: low physical activity, smoking, body mass index, hypertension and baseline cardiovascular disease. Adjustments were not performed for metabolic factors such as abdominal obesity, LDL cholesterol, non-HDL cholesterol and triglycerides. Recent epidemiological data indicate that many of these risk factors, especially obesity and abdominal obesity, high LDL- and non-HDL cholesterol, and triglycerides, are more prevalent in LLMICs than in middle- and high-income countries.^11,12 The investigators also reported that outcomes were adjusted for medications (anti-diabetes, anti-hypertensive, lipid lowering and aspirin). Greater cardiovascular mortality in LLMICs in the PURE study could also be related to factors not evaluated in the present study: social determinants, high intake of unhealthy foods, ambient and indoor pollution, psychosocial stress, and depression. Accessibility and affordability of high-quality cardiovascular care is also important.¹⁰ The quality of acute coronary syndrome management is not uniform in most LLMICs studied in the PURE study (Bangladesh, India, Pakistan, Tanzania, and Zimbabwe). Moreover, in these countries cardiac rehabilitation facilities are limited and there are multiple institutional and personal challenges in adherence to long-term secondary prevention therapies.⁷

Implications

The twin epidemic of cardiovascular diseases and diabetes is still evolving in most parts of the world and LLMICs are at the forefront.¹³ The Lancet Commission on diabetes has suggested that implementation of a society-population-community strategy aiming to reduce illiteracy and social disparity and creation of health-enabling environment supported by a community-based health promotion policy is important.³ The World Health Organization has suggested creation of international partnerships to mobilize resources and accelerate structural transformations for scaling-up access to essential diabetes and cardiovascular medicines and technologies.⁷

Primary prevention of cardiovascular diseases in diabetes is possible, though complex and challenging. Guidelines suggest particular focus on sustained and aggressive lifestyle interventions including regular physical activity, tobacco abstinence, intake of healthy diet, control of ambient and household pollution as well as target based control of hypertension (BP <130/80 mmHg) and lipid management with particular focus on LDL cholesterol targets (<100mg/dl).^14,15 A more stringent LDL cholesterol target of <70 mg/dl has been recommended by European guidelines.¹⁶ The poor status of diabetes management has been reported in LLMICs with control in less than 15%.¹⁷ Studies from LLMICs show significant gaps in blood pressure management, and a study in 44 LLMICs reported that hypertension control to older targets of <140/90 mmHg in less than 20%.¹⁸ Inadequate hypertension control has been reported among diabetes patients in LLMICs,¹⁹ and a multisite study among diabetes patients in India reported low rates of blood pressure control.²⁰  Cholesterol management in diabetes patients is also inadequate in LLMICs¹⁹ and a study reported statin use in less than half of patients with diabetes.²¹

There is a need for widespread implementation of guideline-based primary prevention strategies for diabetes and cardiovascular diseases focusing on healthy lifestyles. In diabetes patients at moderate to high risk of cardiovascular events there is also need for aggressive blood pressure and lipid management. Recent studies have reported the beneficial role of glucagon-like peptide-receptor agonists and sodium-glucose cotransporter-2 inhibitors for prevention of cardiovascular complications in diabetes.²² Cost of such therapies is rapidly decreasing globally, specifically in India and other LLMICs, and may change the diabetes management paradigm. A low-cost polypill has been shown to be effective in reducing adverse cardiovascular outcomes in LLMICs in high risk patients without cardiovascular disease.²³ It is likely that a judicious combination of society-population-community based health promotion approach, structural transformation of health systems, healthy lifestyles and pharmacotherapy, including a polypharmaceutical approach, would be useful to reduce international disparities in cardiovascular disease mortality, so succinctly highlighted in the PURE study.

References

1. Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2015;38:1777-1803.
2. Lin X, Xu Y, Pan X, et al. Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025. Sci Rep 2020;10:14790.
3. Chan JCN, Lim L-L, Wareham NJ, et al. The Lancet Commission on diabetes: using data to transform diabetes care and patient lives. Lancet 2020;396:2019-82.
4. Anjana RM, Mohan V, Rangarajan S, et al. Contrasting associations between diabetes and cardiovascular mortality rates in low-, middle-, and high-income countries: cohort study data from 143,567 individuals in 21 countries in the PURE study. Diabetes Care 2020;43:3094-3101.
5. Gupta R, Wood DA. Primary prevention of ischemic heart disease: populations, individuals, and healthcare professionals. Lancet 2019;394:685-96.
6. Turning evidence into action on diabetes. Lancet 2020;396:1535.
7. Gupta R, Yusuf S. Challenges in ischemic heart disease management and prevention in low socioeconomic status people in LLMICs. BMC Med 2019;17:209.
8. Havranek EP, Mujahid MS, Barr DA, et al. Social determinants of risk and outcomes for cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2015;132:873-98.
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10. Gupta R, Joseph P, Rosengren A, Yusuf S. Location and level of care, education, availability of medicines and cardiovascular mortality. In: Fuster V, Narula J, Vaishnava P, et al. Editors. Hurst's The Heart. 15th Ed. New York. McGraw Hill. 2021. In press.
11. NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 2016;387:1377-96.
12. NCD Risk Factor Collaboration (NCD-RiSC). Repositioning of the global epicentre of non-optimal cholesterol. Nature 2020;582:73-77.
13. Roth GA, Farouzanfar MH, Moran AE, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med 2015;372:1333-41.
14. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary. J Am Coll Cardiol 2019;74:1376-1414.
15. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention and Rehabilitation (EACPR). Eur Heart J 2016;37:2315-81.
16. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2020;41:111-88.
17. Manne-Goehler J, Geldsetzer P, Agoudavi K, et al. Health system performance for people with diabetes in 28 low- and middle-income countries: a cross-sectional study of nationally representative surveys. PLOS Med 2019;16:e1002751.
18. Geldsetzer P, Manne-Goehler J, Marcus ME, et al. The state of hypertension care in 44 low-income and middle-income countries: a cross sectional study of nationally representative individual-level data from 1.1 million adults. Lancet 2019;394:652-62.
19. Shivashankar R, Kirk K, Kim WC, et al. Quality of diabetes care in low- and middle-income Asian and Middle Eastern countries (1993-2012): 20-year systematic review. Diabetes Res Clin Pract 2015;107:203-23.
20. Gupta R, Sharma KK, Lodha S, et al. Quality of hypertension management in type 2 diabetes in India: a multisite prescription audit. J Assoc Physicians India 2018;66:20-25.
21. Gupta R, Lodha S, Sharma KK, et al. Evaluation of statin prescriptions in type-2 diabetes in India: India Heart Watch-2. BMJ Open Diabetes Res Care 2016;4:e000275.
22. Zelniker TA, Wiviott SD, Raz I, et al. Comparison of effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors for prevention of major cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation 2019;139:2022-31.
23. Yusuf S, Joseph P, Dans A, et al. Polypill with or without aspirin in persons without cardiovascular disease. N Engl J Med 2020;Nov 13:[Epub ahead of print].

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Smoking

Keywords: Diabetes Mellitus, Diabetes Mellitus, Type 2, Hyperglycemia, Cardiovascular Diseases, Myocardial Ischemia, Peripheral Arterial Disease, Social Class, Socioeconomic Factors, Poverty, Developing Countries, Developed Countries, Social Determinants of Health, Risk Factors, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, Smoking, Obesity, Primary Prevention, Secondary Prevention, Metabolic Syndrome

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