The burden of type 2 diabetes mellitus (T2DM) has grown significantly over the last several decades, and the problem is anticipated to worsen. In a 2018 study, investigators from the Centers for Disease Control and Prevention projected that the prevalence of adults with diagnosed diabetes would increase from 22.3 million (9.1% of the US population) in 2014, to 39.7 million (13.9% of the US population) in 2030, and then to 60.6 million (17.9% of the US population) by 2060. The number of people 65 years or older with diabetes would increase from 9.2 million in 2014 to 21.0 million in 2030 and 35.2 million in 2060.1 More than 34.2 million Americans are living with diabetes, and 90% to 95% of this population has T2D.2 Due to high-risk factors associated with their disease, there is a high prevalence of atherosclerotic cardiovascular disease (ASCVD) among individuals with T2DM; the risk of death among those who have experienced a prior CVD-related event is 2-fold that of people with T2DM who have not had a previous CVD event.3-5

The associated adverse events of CVD are closely linked to increased mortality risk among individuals with T2DM, and CVD is 1 of the major reasons for hospitalizations (Figure 1).1 Approximately 65% of CVD-related deaths are associated with ischemic heart disease, congestive heart failure (HF), or stroke.3 The high prevalence, early onset, increased severity, and overall health impact of CVD on individuals with T2DM underscore the need for effective management strategies to reduce the risk of CV events in this population.



Reducing Major Adverse Cardiovascular Events Among Patients With Comorbid T2DM and Heart Disease

If not monitored and treated promptly and aggressively, T2DM can trigger dysfunction and damage multiple organs. Microvascular and macrovascular damage can lead to nephropathy, neuropathy, retinopathy, and ultimately CV complications and reduced quality of life.6 Management of T2DM involves a combination of lifestyle modifications and medications to effectively control hyperglycemia, blood pressure, and lipid levels. People with T2DM may experience HF, another major cause of morbidity and mortality from CVD; owing to the high prevalence of major CVD events with poor outcomes in patients with T2DM, treatment of T2DM should focus on medications with CV benefits. Reducing the risk of major adverse cardiovascular events (MACE) — a composite endpoint frequently used in cardiovascular research, includes cardiovascular and all-cause death, myocardial infarction (MI), stroke, and hospitalization from HF (HHF)7 — is included in the American Diabetes Association targets for T2DM management.5

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are antihyperglycemic agents that have emerged as the standard of care for T2DM due to their CV benefits.8 A systematic review and meta-analysis from several clinical trials have provided unequivocal evidence that SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of CV and all-cause mortality in patients with T2DM who are at high risk for MACE.8-11 Based on the compelling evidence of benefit, the American Diabetes Association recommended the use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with T2DM for CVD risk reduction.5

SGLT2 Inhibitors

SGLT2 inhibitors act on SGLT receptors in the kidney proximal tubules to increase urinary excretion of glucose, thereby lowering blood sugar levels. They also cause weight loss and reduce blood pressure.12,13 Several large-scale randomized trials with SGLT2 inhibitors found CV benefits associated with this class of agents. Trials that specifically evaluated the CV benefits of SGLT2 inhibitors in patients with T2DM and are at risk for CVD are summarized in Table 1.12,13-18

A meta-analysis of 10 trials involving 71,553 patients with T2DM who were at high risk for CVD was performed; a total of 39,053 patients received SGLT2 inhibitors and 32,500 received placebo. At a mean follow-up of 2.3 years, the primary outcome of CV death or HHF was significantly lower among patients treated with SGLT2 inhibitors compared with placebo (8.10% vs 11.56%; P <.001). The incidence of MACE was also significantly lower among patients receiving SGLT2 inhibitors compared with placebo (9.82% vs 10.22%; P  =.03).9



The trials outlined in Table 1 included patients with a risk factor for CVD or with established CVD. Overall, these trials found significant reductions in CV death and HHF in patients receiving SGLT2 inhibitors compared with placebo.The degree of treatment benefit as it relates to CV death or HHF varied between the different SGLT2 inhibitors investigated.9,12

Results from 2 of these trials, CANVAS (ClinicalTrials.gov Identifier: NCT01032629) and EMPA-REG OUTCOME (ClinicalTrials.gov Identifier: NCT01131676), illustrate the significant CV benefits of SGLT2 inhibitors. In the CANVAS trial, 10,142 patients with T2DM and a high risk of CVD were randomly assigned to receive canagliflozin or placebo and were followed for a mean duration of 188.2 weeks. Patients who received canagliflozin had a lower risk of CV events (CVD-related deaths, nonfatal MI, and nonfatal stroke) compared with patients who received placebo (CV events, 26.9 vs 31.5 participants per 1000 patient-years, respectively; P <.001 for noninferiority; P =.02 for superiority).12

Empagliflozin has shown similar CV benefits. In the EMPA-REG OUTCOME trial, 7020 patients with T2DM and CVD were randomly assigned to receive empagliflozin or placebo and were observed for a median duration of 3.1 years. The composite primary outcome — death from CV causes, nonfatal MI, or nonfatal stroke — occurred in a significantly lower percentage of patients in the empagliflozin group (10.5%) compared with the placebo group (12.1%; P =.04 for superiority).13 In the EMPEROR-Reduced trial (ClinicalTrials.gov Identifier: NCT03057977), among patients with chronic HF New York Heart Association (NYHA) II to IV,  the percentage of CVD-related death or HHF was lower in the group randomly assigned to receive empagliflozin (19.4%) compared with those assigned to receive placebo (24.7%; P <.001). The superior response with empagliflozin was seen across prespecified subgroups, including patients with T2DM.14

GLP-1 Receptor Agonists

Although several GLP-1 receptor agonists are now available, their CV risk reduction benefits vary among patients with T2DM. For example, lixisenatide is noninferior to placebo but not superior with respect to CV outcome.11 In contrast, albiglutide, dulaglutide, liraglutide, and semaglutide have demonstrated CV protective effects in patients with T2DM.11,19 Several clinical trials have evaluated the CV benefits of GLP-1 receptor agonists (Table 2).19-25



Overall, results from the HARMONY (albiglutide; ClinicalTrials.gov Identifier: NCT02465515), REWIND (dulaglutide; ClinicalTrials.gov Identifier: NCT01394952),and LEADER (liraglutide; ClinicalTrials.gov Identifier: NCT01179048) trials demonstrated that these agents were superior to placebo in reducing the risk of MACE in patients with T2DM and prior CVD. This reduction in the risk of MACE was driven by fewer strokes, MIs, and CVD-related deaths for patients treated with dulaglutide, albiglutide, and liraglutide, respectively.19-21

The CV benefit of semaglutide was evaluated in the SUSTAIN-6 (subcutaneous formulation; ClinicalTrials.gov Identifier: NCT01720446)22 and PIONEER-6 (oral formulation; ClinicalTrials.gov Identifier: NCT02692716)23 clinical trials. In SUSTAIN-6, among patients with T2DM and high CV risk factors, the primary composite MACE outcome of CV death, nonfatal MI, or nonfatal stroke was significantly lower in patients receiving semaglutide (6.6%) compared with placebo (8.9%; P <.001 for noninferiority; P =.02 for superiority). However, nonfatal MI (2.9% vs 3.9%; P =.12) and risk of CV death (2.7% vs 2.8%; P =.92) were not significantly different between patients who received semaglutide vs placebo.22

In the PIONEER-6 trial evaluating oral semaglutide, among patients with T2DM, the CV risk profile was not inferior to that of patients in the placebo group but it did not show superiority of this agent to placebo.23 The SUSTAIN-6 and PIONEER-6 trials used different criteria for established CVD than those used in the REWIND trial. A subsequent reanalysis assessed the effect of semaglutide on MACE in a pooled population of patients who participated in the SUSTAIN-6 and PIONEER-6 trials and recategorized them into CV risk subgroups using the REWIND CVD criteria. The pooled analysis included 6480 patients; after recategorization using the REWIND CVD criteria, the risk of MACE was significantly lower in patients with established CVD receiving semaglutide compared with placebo, suggesting CV benefits of semaglutide in patients with T2DM who have CVD risk factors.26


Semaglutide adverse effects
Flip
Adverse effects most commonly reported with semaglutide include nausea, vomiting, diarrhea, abdominal pain, and constipation.

Tirzepatide, approved by the US Food and Drug Administration (FDA) in 2022 for adults with T2DM,27 is being evaluated against dulaglutide for CV benefits in participants with T2DM who have increased cardiovascular risk (SURPASS-CVOT; ClinicalTrials.gov Identifier: NCT04255433).

Candidates for Treatment With SGLT2 Inhibitors or GLP-1 Receptor Agonists 

In general, SGLT2 inhibitors are recommended for patients with established ASCVD or HF who do not reach appropriate glycemic goals through treatment with metformin and lifestyle modifications. This class of agents can be used as a third agent in patients without established cardiac disease who fail to meet glycemic goals with use of 2 oral agents if insulin is contraindicated.28

GLP-1 receptor agonists can be considered in patients with the existing ASCVD when weight loss and/or avoidance of hypoglycemia are part of the treatment goal. However, GLP-1 receptor agonists should not be used in combination with dipeptidyl peptidase-4 inhibitors (due to a relatively minimal additional benefit) or in combination with prandial insulin (due to lack of supporting data for their use).28

Both SGLT2 inhibitors and GLP-1 receptor agonists are contraindicated in patients with T1DM. Although the cutoff estimated glomerular filtration rate (eGFR) is different for each agent, in general, all SGLT2 inhibitors and GLP-1 receptor agonists are contraindicated below an eGFR of 30 mL/minute/1.73 m2.28

Other Approaches to CVD Risk Reduction

Risk reduction for CVD among patients with T2DM is achieved by targeting modifiable risk factors such as high blood pressure, high cholesterol, hyperglycemia, smoking, obesity, chronic kidney disease, and albuminuria (Figure 2).2,3,5

Lifestyle Modifications

Lifestyle modifications are critical to reducing the risk of MACE and other T2DM complications. Modifications often include increased physical activity, moderate alcohol intake, smoking cessation, weight loss for patients who are overweight or obese, and dietary changes (Table 3).2,5



Hypertension

If it can be safely achieved, the recommended target blood pressure (BP) for patients with T2DM and ASCVD is less than 130/80 mm Hg.2,5 In the Hypertension Optimal Treatment trial of a 5-step intensive BP-lowering regimen, there was a 51% reduction in MACE among the T2DM subpopulation assigned to a diastolic BP target of less than 80 mm Hg.29 In contrast, the ACCORD trial (ClinicalTrials.gov Identifier: NCT00000620), which compared intensive BP control to less than 120 mm Hg vs standard BP control to less than 140 mm Hg, did not reduce total MACE but demonstrated a reduced risk of stroke.30

Angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) are recommended as first-line antihypertensive agents for patients with T2DM and coronary artery disease or albuminuria.2

Dyslipidemia

The American Diabetes Association recommends high-intensity statin therapy in combination with lifestyle modifications for all patients with T2DM and ASCVD.5 The Treating to New Targets study compared treatment with atorvastatin 10 mg vs atorvastatin 80 mg in 1501 patients with T2DM, coronary heart disease, and low-density lipoprotein cholesterol (LDLC) levels greater than 130 mg/dL. The investigators reported a 25% reduction in the risk of MACE (coronary heart disease, death, nonfatal MI, resuscitated cardiac arrest, or stroke) in the high-intensity statin group.31

Patients with LDLC levels greater than 70 mg/dL despite a maximally tolerated statin dose should receive ezetimibe or a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor.5 Ezetimibe reduces intestinal cholesterol absorption. One study involving participants hospitalized for acute coronary syndrome evaluated the effect of ezetimibe added to simvastatin; ezetimibe further lowered LDLC and reduced CV events compared with simvastatin alone. This benefit was even more pronounced in the patient subpopulation with T2DM.32

Evolocumab is a monoclonal antibody that inhibits PCSK9 and lowers LDL. In a randomized controlled study that included 27,654 patients with atherosclerotic disease, the addition of evolocumab to statin therapy lowered LDL levels by 59% (median, 30 mg/dL) from baseline compared with placebo and it conferred a 15% relative risk reduction in the primary outcome of CVD death, MI, or stroke. A similar benefit was seen in the subgroup of patients with T2DM.33 Alirocumab, another PCSK9 inhibitor, showed similar superior benefits for LDL levels and CVD-related death when it was added to intensive statin therapy in the ODYSSEY trial (ClinicalTrials.gov Identifier: NCT01663402).34

Platelet Dysfunction

Platelet dysfunction plays a critical role in the high prevalence of ASCVD in patients with T2DM. Factors contributing to increased thrombosis include hyperreactive platelets with intensified adhesion, activation, and aggregation.35 Other important factors include increased fibrinogen, decreased antithrombin III activity, and impaired fibrinolysis.2 The role of antiplatelet therapy in the secondary prevention of CVD is well documented in patients with and without T2DM. Aspirin (at a dosage of 75-162 mg/day) is recommended for all patients with T2DM and a history of ASCVD.5

Dual antiplatelet therapy should be considered in selected clinical situations, such as after acute coronary syndrome or a coronary intervention, to lower the risk of MACE.5 Use of clopidogrel, prasugrel, or ticagrelor with aspirin has been demonstrated to reduce rates of CV events but is associated with an increased risk of bleeding.36 Rivaroxaban added to aspirin should be considered in patients with stable coronary artery disease. The benefit of a rivaroxaban plus aspirin was demonstrated in the COMPASS trial (ClinicalTrials.gov Identifier: NCT01776424). Rivaroxaban 2.5 mg added to low-dose aspirin reduced CV events with a more clinically meaningful absolute risk reduction for patients with T2DM.37



References

1. Lin J, Thompson TJ, Cheng YJ, et al. Prediction of the future diabetes burden in the United States through 2060. Popul Health Metr. 2018;16(1)9. doi:10.1186/s12963-018-0166-4.

2. Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022;145(9):e722-e759. doi:10.1161/CIR.0000000000001040

3. Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus – mechanisms, management, and clinical considerationsCirculation. 2016;133(24):2459-2502. doi:10.1161/CIRCULATIONAHA.116.022194

4. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol. 2018;17(1):83. doi:10.1186/s12933-018-0728-6

5. American Diabetes Association Professional Practice Committee. 10. Cardiovascular disease and risk management: standards of medical care in diabetes—2022Diabetes Care. 2022;45(suppl 1):S144-S174. doi:10.2337/dc22-S010

6. Patel R, McComb D, Rehman A, Soos MP. Appropriate use of SGLT2s and GLP-1RAs with insulin to reduce CVD risk in patients with diabetes. In: StatPearls. Treasure Island (FL): StatPearls Publishing. Updated June 30, 2022.

7. Bosco E, Hsueh L, McConeghy KW, Gravenstein S, Saade E. Major adverse cardiovascular event definitions used in observational analysis of administrative databases: a systematic review. BMC Med Res Methodol. 2021;21(1):241. doi:10.1186/s12874-021-01440-5

8. Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Systemic review and meta-analysis of cardiovascular outcomes trialsCirculation. 2019;139(17):2022-2031. doi:10.1161/CIRCULATIONAHA.118.038868

9. Bhattarai M, Salih M, Regmi M, et al. Association of sodium-glucose cotransporter 2 inhibitors with cardiovascular outcomes in patients with type 2 diabetes and other risk factors for cardiovascular disease: a meta-analysis. JAMA Netw Open. 2022;5(1):e2142078. doi:10.1001/jamanetworkopen.2021.42078

10. Kanie T, Mizuno A, Takaoka Y, et al. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021;10(10):CD013650. doi:10.1002/14651858.CD013650.pub2

11. Iorga RA, Bacalbasa N, Carsote M, et al. Metabolic and cardiovascular benefits of GLP-1 agonists, besides the hypoglycemic effect (review). Exp Ther Med. 2020;20(3):2396-2400. doi:10.3892/etm.2020.8714

12. Neal B, Perkovic V, Mahaffey KW, et al; for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925

13. Zinman B, Wanner C, Lachin JM, et al; for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720

14. Packer M, Anker SD, Butler J, et al; for the EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-1424. doi:10.1056/NEJMoa2022190

15. Wiviott SD, Raz I, Bonaca MP, et al; for the DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389

16. Cannon CP, Pratley R, Dagogo-Jack S, et al; for the VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetesN Engl J Med. 2020;383(15):1425-1435. doi:10.1056/NEJMoa2004967

17. Bhatt DL, Szarek M, Pitt B, et al; for the SCORED Investigators. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129-139. doi:10.1056/NEJMoa2030186

18. Bhatt DL, Szarek M, Steg PG, et al; for the SOLOIST-WHF Trial Investigators. Sotagliflozin in patients with diabetes and recent worsening heart failureN Engl J Med. 2021;384(2):117-128. doi:10.1056/NEJMoa2030183

19. Hernandez AF, Green JB, Janmohamed S, et al; for the Harmony Outcomes Committees and Investigators. 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(10157):P1519-P1529. doi:10.1016/S0140-6736(18)32261-X

20. Gerstein HC, Colhoun HM, Dagenais GR, et al; for the REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double‐blind, randomised placebo‐controlled trialLancet. 2019;394(10193):121‐130. doi:10.1016/S0140-6736(19)31149-3

21. Marso SP, Daniels GH, Brown‐Frandsen K, et al; for the LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311‐322. doi:10.1056/NEJMoa1603827

22. Marso SP, Bain SC, Consoli A, et al; for the SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetesN Engl J Med. 2016;375(19):1834‐1844. doi:10.1056/NEJMoa1607141

23. Husain M, Birkenfeld AL, Donsmark M, et al; for the PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841‐851. doi:10.1056/NEJMoa1901118

24. Pfeffer MA, Claggett B, Diaz R, et al; for the ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247‐2257. doi:10.1056/NEJMoa1509225

25. Holman RR, Bethel MA, Mentz RJ, et al; for the EXSCEL Study Group. Effects of once‐weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228‐1239. doi:10.1056/NEJMoa1612917

26. Verma S, Fainberg U, Husain M, et al. Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: an exploratory analysis of cardiovascular outcomes with semaglutide. Diabetes Obes Metab. 2021;23(7):1677-1680. doi:10.1111/dom.14360

27. Mounjaro. Prescribing information. Eli Lilly and Company; 2022. Accessed July 19, 2022. https://pi.lilly.com/us/mounjaro-uspi.pdf

28. Patel R, McComb D, Rehman A, Soos MP. Appropriate use of SGLT2s and GLP-1RAs with insulin to reduce CVD risk in patients with diabetes. 2022 Mar 31. In: StatPearls. Treasure Island (FL): StatPearls. Updated June 30, 2022.

29. Hansson L, Zanchetti A, Carruthers SG, et al; for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension; principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet. 1998;351(9118):P1755-P1762. doi:10.1016/S0140-6736(98)04311-6

30. Cushman WC, Evans GW, Byington RP, et al; on behalf of the ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585. doi:10.1056/NEJMoa1001286

31. Shepherd J, Barter P, Carmena R, et al; for the Treating to New Targets Investigators. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care. 2006;29(6):1220-1226. doi:10.2337/dc05-2465

32. Giugliano RP, Cannon CP, Blazing MA, et al; on behalf of the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)Circulation. 2018;137(15):1571-1582. doi:10.1161/CIRCULATIONAHA.117.030950

33. Sabatine MS, Giugliano RP, Keech AC, et al; for the FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular diseaseN Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664

34. Schwartz GG, Steg PG, Szarek M, et al; for the ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174

35. Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation. 2011;123(7):798-813. doi:10.1161/CIRCULATIONAHA.109.913376

36. Wilson SJ, Newby DE, Dawson D, Irving J, Berry C. Duration of dual antiplatelet therapy in acute coronary syndrome. Heart. 2017;103(8):573-580. doi:10.1136/heartjnl-2016-309871

37. Eikelboom JW, Connolly SJ, Bosch J, et al; for the COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular diseaseN Engl J Med. 2017;377(14):1319-1330. doi:10.1056/NEJMoa1709118

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Endocrinology Advisor had no role in this content’s preparation.

Updated July 2021