Primary Prevention of Cardiovascular Disease in Individuals With Type 2 Diabetes: Time for Cardiology to Get Back in the Game
Over the past two decades, the obesity epidemic has led to a dramatic increase in the prevalence of type 2 diabetes (T2D) in the United States. Based on data from the National Health and Nutrition Examination Survey (NHANES), it is estimated that over 35 million US adults have diabetes, of which 90-95% of cases are T2D. Alarmingly, an additional 92 million US adults have prediabetes.1 The prevalence of T2D varies significantly by sex and race/ethnicity, with a higher frequency in females and non-white races.1 Compared to those without disease, T2D is associated with double the risk for death and a 10-fold increase in hospitalizations for coronary heart disease.1,2 Efforts to prevent, diagnose and adequately treat T2D are key to reducing the burden of cardiovascular disease (CVD) in the US. The newly released 2019 guidelines for the primary prevention of CVD from the American College of Cardiology (ACC) and the American Heart Association (AHA) include recommendations for individuals with T2D.3 In addition to statin therapy in appropriate patients, the writing committee determined four key recommendations, highlighting nutrition, physical activity, metformin and the sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs).
The first recommendation in the ACC/AHA guidelines section on T2D is a recommendation for all adults with T2D to adopt a heart healthy dietary pattern to improve glycemic control, achieve weight loss if needed and improve other CVD risk factors. A heart healthy diet can significantly improve glycemic control and potentially result in remission of T2D. Trials evaluating various dietary patterns including the Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) diet and vegetarian diets have all demonstrated the ability to achieve weight loss and improve glycemic control compared to control diets in participants with T2D.4-7 PREDIMED (Prevención con Dieta Mediterránea), a large clinical trial involving over 7,000 participants, evaluated the effect of a Mediterranean diet on a composite endpoint of cardiac death, myocardial infarction or stroke in a population at high CVD risk. Roughly 50% of individuals in the trial had T2D at baseline and those randomized to the Mediterranean diet had a 30% reduction in the primary outcome. Subgroup analysis showed similar risk reductions in those with and without T2D.7
While the different dietary patterns that demonstrate improved glycemic control do have some unique differences, they also have significant overlap and generally recommend increased consumption of vegetables, fruits, nuts, whole grains and healthy fats while limiting intake of refined carbohydrates, processed meats and sugar-sweetened beverages. Dietary counseling should not be a brief process and generally should be performed with the help of a diabetes educator or dietician. Establishing dietary goals with patients is of critical importance and requires close follow-up to monitor for adherence.
To further emphasize the importance of efforts at lifestyle modification for T2D, the committee also provided a target for physical activity, recommending at least 150 minutes of moderate physical activity or 75 minutes of vigorous activity per week. An active lifestyle is a key component to CVD prevention as noted in the recently updated physical activity guidelines.8 For individuals with T2D, the magnitude of blood glucose reduction and weight changes vary in randomized clinical trials. A 2001 meta-analysis included 12 aerobic training and two resistance training studies and found an absolute reduction in hemoglobin A1c (HbA1c) of approximately 0.5% with exercise interventions of 3-6 months duration. Both aerobic and resistance exercises reduced blood glucose, but the combination was more effective, lowering HbA1c by nearly one percentage point.9 Observational data from the Nurses' Health Study illustrated a dose dependent decrease in CV events as exercise duration increased.10
It is challenging to conduct clinical trials with lifestyle interventions that have adequate size and follow up needed to detect a difference in hard CVD endpoints. However, multiple well-designed observational studies have shown that lifestyle behaviors can impact rates of CVD events in individuals with T2D. Data from the Cardiovascular Health Study portray a significantly lower incidence of diabetes in adults with healthy lifestyle factors that include physical activity, diet, smoking status, alcohol use, body mass index and waist circumference. Diabetes risk was lowered by 35% with the presence of each additional healthy lifestyle factor.11 A more recent analysis studied a population of individuals with T2D and found a 50% lower risk of CVD incidence and 70% lower risk of CVD mortality in those with three or more healthy lifestyle factors compared to those with none.12
In its third recommendation, the writing committee stated it was reasonable to use metformin as first line therapy at the time of diagnosis of T2D along with lifestyle changes to improve glycemic control and reduce ASCVD risk. This recommendation is consistent with the American Diabetes Association (ADA) Clinical Practice Recommendations.13 The supportive text does note that efforts at lifestyle modification alone can be considered before initiating metformin, especially in younger adults. Metformin is a well-established therapy for individuals with T2D who have been unable to obtain glycemic control with lifestyle interventions. It has similar reductions in HbA1c as other oral options, without associated weight gain or dangerous hypoglycemia. Compared to sulfonylureas, metformin use is associated with lower CV mortality.14 When added to insulin, metformin reduces the insulin dose required to achieve fasting glucose targets.15 The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated significant reductions in diabetes related complications, including CVD events and all-cause mortality, in individuals randomized to metformin compared to conventional therapy (lifestyle counseling).16 The UKPDS trial was performed at a time when aggressive control of other CVD risk factors in individuals was much less common and randomized data for metformin in modern populations are lacking, leading the ACC/AHA committee to give the recommendation for metformin a class IIa, level of evidence B.
The goal of glucose reduction is to prevent CVD events, but until recently data demonstrating benefit for additional T2D medications beyond metformin have not shown positive results. While insulin is effective in lowering glucose levels, use in people with T2D is associated with weight gain and increased insulin resistance. The addition of insulin compared with sulfonylurea to patients already on metformin is associated with increased CVD events and all-cause mortality.17 Moreover, studies evaluating more intensive glucose lowering have not demonstrated improved outcomes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial found that strict glucose control did not improve CVD outcomes and in fact, there was an increase in all-cause mortality.18 Additionally, individuals in ACCORD randomized to intensive control were much more likely to gain significant weight. Almost 28% gained >10 kilograms over the 3.5 years of the trial compared to 14% of those in the standard glucose control group.
SGLT-2 Inhibitors and GLP-1 Receptor Agonists
More recently, medications within two classes of diabetes medications whose mechanisms of action do not lead to weight gain have demonstrated improvement in CVD outcomes in individuals with T2D. The SGLT-2 inhibitors decrease the reabsorption of sodium and glucose in the tubules of the kidney resulting in a decrease in serum glucose, diuresis and weight loss. Three medications (empagliflozin, canagliflozin and dapagliflozin) have been studied in cardiovascular outcomes trials and found to improve outcomes for CVD and heart failure endpoints (Table 1).19–21 A meta-analysis evaluating data from these three trials found a reduction in a composite endpoint of CV death, myocardial infarction and stroke by 11% in those given SGLT-2 inhibitors compared to placebo; however, the benefit was only observed in participants with a history of CVD.22 Treatment with SGLT-2 inhibitors reduced heart failure hospitalizations by 31% regardless of prior history of CVD or heart failure. Mycotic genital infections and diabetic ketoacidosis (DKA) were both higher in the treatment arm, although DKA was uncommon (<1 event in 1000 person years). One trial evaluating canagliflozin observed a nearly two-fold increase in lower extremity amputations in the treatment arm,20 but this was not observed in the other trials. The FDA-approved product labeling for canagliflozin now includes a black box warning for the association of lower limb amputations and patients with T2D and established CVD or risk for CVD. Before initiating canagliflozin, the clinician should consider factors that increase risk of amputation, including a history of peripheral artery disease.
GLP-1RAs lower glucose by stimulating insulin secretion and suppressing glucagon when glucose levels are elevated. GLP-1RAs lead to a similar reduction in HbA1c compared with SGLT-2 inhibitors. Four GLP-1RAs have been studied in clinical trials to assess safety and effectiveness for improving CVD outcomes (Table 1).23–26 All four agents safely lowered serum glucose levels. Compared with placebo, treatment with lixisenatide and exenatide, did not significantly alter CVD events, but liraglutide and semaglutide both demonstrated a significant reduction in a composite endpoint of CV death, MI and stroke. In contrast with the SGLT-2 inhibitors, the mechanism of action for GLP-1RAs appears to be centered on an anti-atherosclerotic effect as there was no reduction in heart failure. A meta-analysis including these trials demonstrated a 10% reduction in a composite CVD endpoint with GLP-1RAs compared with placebo without an increased risk of hypoglycemia.27 The GLP-1RAs do slow gastric emptying, which can lead gastrointestinal disturbances, most commonly nausea.
For its final recommendation, the committee recommended that, for individuals with T2D without adequate glycemic control despite efforts at lifestyle modification and metformin, consideration may be given to initiation of an SGLT-2 inhibitor or a GLP-1RA in those who have additional CVD risk factors beyond diabetes. Given the limited data for these medications in primary prevention populations, the committee gave this recommendation a class IIb, level of evidence B. Similarly, the ADA recommendations include SGLT-2 inhibitors and GLP-1RAs as second line therapy after metformin for patients with T2D and established atherosclerotic CVD or those with concern for weight gain on other agents. Of note, the REWIND (Researching Cardiovascular Events With a Weekly Incretin in Diabetes ) trial,28 a cardiovascular outcomes trial studying the GLP-1RA dulaglutide in a largely primary prevention sample, has recently been completed. The trial authors have preliminarily reported a significant reduction in the primary outcome (CVD death, non-fatal myocardial infarction and non-fatal stroke); however, the full results have not yet been published and therefore this trial was not taken into consideration by the committee when making their recommendation. Once published, it may provide further support for use of these medications for primary prevention.
Reducing the burden of CVD in the US requires an aggressive, multifaceted approach to the care of individuals with T2D. Major efforts should be made to encourage patients to adopt a heart-healthy diet and increase physical activity as much as possible. Metformin remains first line pharmacologic therapy for all individuals with T2D. While evidence in primary prevention populations for the SGLT-2 inhibitors and the GLP-1RAs are limited, they clearly appear to be the best option for additional glycemic control, especially in individuals with increased CVD risk. Publication of further trials on these medications may provide more support for their use in primary prevention populations. With the increasing complexity of diabetes treatment and prior studies showing a lack of cardiovascular benefit, cardiology has distanced itself from the treatment of diabetes over the past decade. However, given the increasing burden of this major CVD risk factor, the universal importance of efforts at adopting a heart healthy diet and adequate physical activity, as well as the novel medications now available with proven CVD benefit, it's quite clear that it is time for cardiology to "get back in the game" and partner with our colleagues in primary care and endocrinology to optimally manage adults with T2D.
- Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke stastics-2019 update: a report from the American Heart Association. Circulation 2019;139:e56-528.
- Emerging Risk Factors Collaboration, Di Angelantonio E, Kaptoge S, et al. Association of cardiometabolic multimorbidity with mortality. JAMA 2015;314:52-60.
- Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019. [Epub ahead of print]
- Huo R, Du T, Xu Y, et al. Effects of Mediterranean-style diet on glycemic control, weight loss and cardiovascular risk factors among type 2 diabetes individuals: a meta-analysis. Eur J Clin Nutr 2015;69:1200-8.
- Azadbakht L, Fard NR, Karimi M, et al. Effects of the Dietary Approaches to Stop Hypertension (DASH) eating plan on cardiovascular risks among type 2 diabetic patients: a randomized crossover clinical trial. Diabetes Care 2011;34:55-7.
- Kahleova H, Matoulek M, Malinska H, et al. Vegetarian diet improves insulin resistance and oxidative stress markers more than conventional diet in subjects with type 2 diabets. Diabet Med 2011;28:549-59.
- Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med 2019;378:e34.
- Piercy KL, Troiano RP, Ballard RM, et al. The physical activity guidelines for Americans. JAMA 2018;320:2020-8.
- Sigal RJ, Kenny GP, Boule NG, et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med 2007;147:357-69.
- Hu FB, Stampfer MJ, Solomon C, et al. Physical activity and risk for cardiovascular events in diabetic women. Ann Intern Med 2001;134:96-105.
- Mozaffarian D, Kamineni A, Carnethon M, Djousse L, Mukamal KJ, Siscovick D. Lifestyle risk factors and new-onset diabetes mellitus in older adults: the cardiovascular health study. Arch Intern Med 2009;169:798-807.
- Liu G, Li Y, Hu Y, et al. Influence of lifestyle on incident cardiovascular disease and mortality in patients with diabetes mellitus. J Am Coll Cardiol 2018;71:2867-76.
- American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care 2019;42:S90-102.
- Maruthur NM, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2016;164:740-51.
- Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009;169:616-25.
- Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89.
- Roumie CL, Greevy RA, Grijalva CG, et al. Association between intensification and metformin treatment with insul vs sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA 2014;311:2288-96.
- Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.
- Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31-9.
- Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;337:2247-57.
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patietns with type 2 diabetes. N Engl J Med 2016;375:1834-44.
- Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-39.
- Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol 2018;5:105-13.
- Gerstein HC, Colhoun HM, Dagenais GR, et al. Design and baseline characteristics of participants in the Researching cardiovascular Events in a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obes Metab 2018;20:42-9.
Keywords: Primary Prevention, Secondary Prevention, American Heart Association, Benzhydryl Compounds, Amputation, Cardiovascular Diseases, Coronary Disease, Diabetes Mellitus, Type 2, Diabetic Ketoacidosis, Diet, Mediterranean, Diet, Vegetarian, Diuresis, Drug Labeling, Follow-Up Studies, Exercise, Glucagon, Glucagon-Like Peptides, Glucagon-Like Peptide 1, Gastric Emptying, Glucose, Glucosides, Heart Failure, Hospitalization, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypoglycemia, Immunoglobulin Fc Fragments, Incretins, Insulins, Lower Extremity, Myocardial Infarction, Metformin, Nutrition Surveys, Nutritionists, Obesity, Peptides, Peripheral Arterial Disease, Prediabetic State, Primary Health Care, Product Labeling, Recombinant Fusion Proteins, Risk Factors, Risk Reduction Behavior, Sodium-Glucose Transport Proteins, Stroke, Weight Gain, Weight Loss
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