Type 2 diabetes mellitus (T2DM) poses an inordinate burden on today's society, a problem that is inextricably related to the fact that T2DM is a major independent predictor of future cardiovascular disease (CVD). CVD remains the number one cause of death in patients with diabetes despite treatment of other cardiovascular risk factors. Each condition independently increases one's risk of developing the other, a correlation stemming from the complex interaction of neurohormonal, myocardial, renal, cellular, and inflammatory mechanisms. A similar bidirectional relationship between T2DM and heart failure (HF) has been established, with diabetics being two to four times more likely to develop HF than non-diabetics.¹ T2DM also increases the risk of death and hospitalization for those with established HF. Given the concurrent rising prevalence of both T2DM and CVD, we must optimize diabetes treatment strategies to impact the adverse relationship more effectively between T2DM and CVD.^1,2

The treatment landscape for T2DM and CVD has evolved dramatically in recent years. While the historical focus of T2DM management revolved around improving glycemic control, contemporary research ultimately revealed that reducing serum glucose alone does not lead to substantial macrovascular benefits. The emergence of two newer classes of glucose lowering agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2-i) and the glucagon-like peptide-1 receptor agonists (GLP-1 RAs), represents a paradigm shift in how the cardiology community understands T2DM treatment and its impact on cardiovascular outcomes.

Starting with the landmark EMPA-REG OUTCOME trial of the SGLT2-i empagliflozin, the bar was raised for evaluating new diabetes drugs. This trial demonstrated a significant benefit on cardiovascular outcomes above and beyond the standard of care, particularly cardiovascular mortality, and HF hospitalizations. This finding was substantiated by a reduction in the composite of major adverse cardiovascular events (cardiovascular mortality, nonfatal myocardial infarction [MI] and nonfatal stroke), in addition to empagliflozin slowing progression of kidney disease among diabetics with high cardiovascular risk.³ The ensuing CANVAS and DECLARE-TIMI 58 studies further reinforced the cardiovascular benefit of SGLT2-i canagliflozin and dapagliflozin, respectively, among diabetics with or at high risk for CVD.^4,5 These cardiovascular outcomes trials (CVOTs) highlight the observed class effects of SGLT2-i as cardioprotective agents independent of their glycemic effect or baseline serum glucose levels. Proposed cardioprotective mechanisms of benefit of SGLT2-i include their secondary renal influence on the renin-angiotensin-aldosterone system (RAAS), increased ketone production, afterload reduction and anti-inflammatory effects. The recent HF with reduced ejection fraction (HFrEF) trials (DAPA-HF, EMPEROR-REDUCED) enrolling diabetics and non-diabetics showed significant benefit of SGLT2-i compared to standard of care, with non-diabetics and diabetics retaining similar benefit.^6,7 Given the advantages of SGLT2-i seen for HF and chronic kidney disease progression in diabetics and non-diabetics, there are likely further positive effects beyond their diuretic and natriuretic impact.

Additional research laid the groundwork for cardiovascular risk reduction using GLP-1 RAs. To date, seven CVOTs have demonstrated substantial reductions in composite cardiovascular outcomes with liraglutide, subcutaneous semaglutide, albiglutide for secondary prevention and dulaglutide for primary and secondary prevention.^8-11 These CVOTs inspired a shift in T2DM treatment guidelines, with the American Diabetes Association and European Society of Cardiology highlighting SGLT2-i and GLP-1 RAs as first-line initial or add-on therapy for diabetics with established CVD in 2019.^12,13 The American College of Cardiology also added a recommendation for dapagliflozin and empagliflozin as a component of first-line therapy for HFrEF.¹⁴

The analysis by Dave et al. published in Circulation evaluates cardiovascular outcomes in patients with T2DM treated with baseline GLP-1 RAs after adding either SGLT2-i or sulfonylureas.¹⁵ By comparing add-on SGLT2-i to sulfonylureas, the authors address the important practical question of how best to approach reducing downstream CVD in diabetic patients. This area is of particular interest given the paucity of data on CVD outcomes with combined use of these agents. The authors demonstrate that in a real-world cohort of over 32,000 patients with T2DM from three United States-based insurance claims databases, adding SGLT2-i to GLP-RAs resulted in greater cardiovascular benefit compared to adding sulfonylureas, as assessed by cumulative incidence of the composite cardiovascular end point, defined as MI or stroke hospitalization or all-cause mortality (HR, 0.76, [95% CI, 0.59-0.98]). The magnitude of cardiovascular risk reduction was comparable to CVOTs showing benefits of SGLT2-i added to standard of care in diabetics with minimal baseline GLP-1 RA use. Moreover, there was a reduction in the primary outcome of HF hospitalizations (HR, 0.64, [95% CI, 0.50-0.82]), which occurred early after the addition SGLT2-i treatment (within 6 months). Secondary outcome analyses revealed the composite cardiovascular end point was primarily driven by decreases in MI (pooled adjusted HR, 0.71 [95% CI, 0.51–1.003]) and all-cause mortality (pooled adjusted HR, 0.68 [95% CI, 0.40–1.14]).

These findings are comparable to those seen in the EMPA-REG OUTCOME, CANVAS, and DECLARE trials. This analysis evaluated a predominantly primary prevention diabetic population (only 20% of patients in either group had known CVD) similar to DECLARE, as opposed to the secondary prevention cohorts in EMPA-REG and CANVAS. This suggests that the cardiovascular benefits of SGLT2-i can likely be generalizable to both primary and secondary CVD prevention in T2DM populations.

This data calls for a reconsideration of where sulfonylureas fit in to our treatment algorithm of T2DM. Widespread utilization of sulfonylureas persists in practice today despite no confirmed beneficial impact on CVD. Recent data from the National Health and Nutrition Examination shows that the use of sulfonylureas is over three times that of the SGLT2-i and GLP-1 RA classes combined.¹⁶ A strong case should be made to relegate sulfonylureas to a lower status in the T2DM management tree given the superiority of GLP-1 RAs and SGLT2-i on CVD outcomes. Furthermore, when evaluating the hierarchy of diabetes medications for CVD, we are left with the question of whether similar positive results would be observed if GLP-1 RAs were added to baseline SGLT2-i instead of the opposite sequence assessed in this study. The AMPLITUDE trial showed that the cardiovascular protective effects of the exendin-based GLP-1 RA in a higher risk T2DM population was independent of baseline SGLT2-i use.¹⁷ The different proposed modes of action of the SGLT2-i and GLP-1 RA classes make it seem likely that their effects would be additive independent of which class was added to the other.

Overall, current evidence supports a shift in the perception of SGLT2-i from being solely regarded as diabetes drugs to being considered a fundamental pillar of cardiovascular treatment and prevention. Perhaps the approach to glycemic treatment of diabetics with CVD or at high risk for developing CVD should be modified such that drugs that reduce A1c and CVD events be used as first line, considering cost and access, with downstream addition of other medications to optimize A1c levels. These considerations warrant further research to bridge the gap between clinical knowledge, practice patterns and optimization of CVD outcomes in our diabetic patients. In the meantime, cardiologists need to accelerate appropriate utilization of these agents in diabetics and non-diabetics to mitigate cardiovascular risk, just as they would for adding statins or RAAS inhibitors.

References

1. Dunlay SM, Givertz MM, Aguilar D, et al. Type 2 diabetes mellitus and heart failure, a scientific statement from the American Heart Association and Heart Failure Society of America. J Card Fail 2019;25:584-619.
2. Benjamin EJ, Virani SS, Callaway CW, et al. Heart Disease and Stroke Statistics-2018 Update: a report from the American Heart Association. Circulation 2018;137:e67-e492.
3. 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.
4. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:2099.
5. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.
6. Jackson AM, Dewan P, Anand IS, et al. Dapagliflozin and diuretic use in patients with heart failure and reduced ejection fraction in DAPA-HF. Circulation 2020;142:1040-54.
7. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-24.
8. 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.
9. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.
10. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519-29.
11. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121-30.
12. American Diabetes A. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care 2019;42:S90-S102.
13. Grant PJ, Cosentino F. The 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: new features and the 'Ten Commandments' of the 2019 Guidelines are discussed by Professor Peter J. Grant and Professor Francesco Cosentino, the Task Force chairmen. Eur Heart J 2019;40:3215-17.
14. Maddox TM, Januzzi JL Jr., Allen LA, et al. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:772-810.
15. Dave CV, Kim SC, Goldfine AB, Glynn RJ, Tong A, Patorno E. Risk of cardiovascular outcomes in patients with type 2 diabetes after addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-1RA therapy. Circulation 2021;143:770-79.
16. Le P, Chaitoff A, Misra-Hebert AD, Ye W, Herman WH, Rothberg MB. Use of antihyperglycemic medications in U.S. adults: an analysis of the National Health and Nutrition Examination Survey. Diabetes Care 2020;43:1227-33.
17. Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med 2021;Jun 28:[Epub ahead of print].

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Diabetes and Cardiometabolic Disease

Keywords: Diabetes Mellitus, Type 2, Cardiovascular Diseases, Cardiotonic Agents, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Renin-Angiotensin System, Hemoglobin A, Sodium-Glucose Transporter 2, Heart Failure, Diuretics, Glucagon-Like Peptide 1, Secondary Prevention, Glucose, Prevalence, Ketones, Cause of Death, Standard of Care, Stroke Volume, Risk Factors, Renal Insufficiency, Chronic, Myocardial Infarction, Pharmaceutical Preparations, Primary Prevention, Stroke, Hospitalization, Insurance, Algorithms, Anti-Inflammatory Agents, Perception

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