VERTIS CV Trial: Heterogeneity in Clinical Benefits of Sodium-glucose Cotransporter-2 Inhibitors for Patients with Type II Diabetes?
- The VERTIS CV Trial demonstrated efficacy of ertugliflozin in reducing heart failure hospitalizations in patients with type 2 diabetes similar to that seen with other sodium glucose contransporter-2 inhibitors.
- Empagliflozin and Canagliflozin remain the only two sodium-glucose cotransporters-2 inhibitors that have shown reduction in major adverse cardiac events in patients with type 2 diabetes in randomized clinical trials.
Type 2 diabetes mellitus (T2DM) is a global pandemic currently estimated to affect 370 million people globally; it is one of the most prominent risk factors for atherosclerotic disease, with coronary artery disease accounting for 75% of deaths in diabetics.1,2 With the emergence of novel antihyperglycemic agents over the past decade, there has been a new focus on identifying medications that not only improve glycemic control, but also reduce cardiovascular outcomes. One drug class that has been able to do so is the sodium-glucose cotransport-2 inhibitors (SGLT2i), reducing major cardiovascular events including myocardial infarction, stroke, and cardiovascular death.3,4
Meta-analysis data analyzing the EMPA-REG OUTCOME (Empagliflozin), CANVAS Program (Canagliflozin), and DECLARE-TIMI 58 (Dapagliflozin) trials suggest that the favorable effects of SGLT2i in patients with T2DM for reducing atherosclerotic cardiovascular (ASCVD) events were limited to those that already have ASCVD, although reduction in heart failure hospitalizations (HFH) was noted across all patients regardless of ASCVD status.3-7 The CREDENCE trial (Canagliflozin) evaluated renal outcomes in patients with T2DM with baseline nephropathy, among whom approximately 50% had baseline ASCVD; this recent publication led to an additional meta-analysis which suggested benefit of the SGLT2i in both those with and without CVD for the composite outcome of cardiovascular death and HFH, though overall benefit for SGLT2i is predominately noted in those with baseline ASCVD.8,9
These studies have set the stage for the recently presented VERTIS CV Trial at the 2020 American Diabetes Association Virtual Scientific Sessions. The goal of the trial was to evaluate cardiovascular efficacy and safety of the SGLT2i ertugliflozin in T2DM individuals with known ASCVD. Ertugliflozin remains unique as it is a largely selective SGLT2i (as compared to the SGLT1 receptor) similar to empagliflozin. Similar to other SGLT2i, it has been shown to reduce weight, blood pressure, and hemoglobin A1C, both with and without other antihyperglycemic combinations.10-15
In the VERTIS CV Trial, 8,246 individuals with T2DM and ASCVD were randomized in a 1 to 1 to 1 fashion to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo.16 After a median follow-up of 3.5 years, ertugliflozin was found to be non-inferior to placebo for the composite primary outcome of CV death, nonfatal myocardial infarction, or stroke (11.9% vs. 11.9% respectively, Hazard Ratio (HR): 0.97, 95% confidence interval (CI) 0.85-1.11, p<0.001 for non-inferiority). Similar to other SGLT2i, ertugliflozin was found to be superior as compared to placebo for reducing HFH (2.5% vs. 3.6%, HR: 0.70, 95% CI: 0.54-0.90, p=0.006); however no other secondary endpoints were met, including CV death and all-cause mortality.
Interestingly, although other SGLT2i trials for cardiovascular outcomes showed improvement in renal-related composite secondary outcomes, ertugliflozin did not show improvement in the composite endpoint of renal death, dialysis/transplant, or doubling in the serum creatinine from baseline (HR: 0.82, 95% CI: 0.63-1.04, p=0.08). This may be related to the heterogeneity in the composite renal-related secondary outcomes in the SGLT2i trials, given CANVAS and DECLARE-TIMI 58 focused on a sustained ≥40% reduction in eGFR. Ultimately, ertugliflozin was also found to be safe and well tolerated without any significant difference in serious adverse events as compared to placebo, but with an increase in urinary tract infections and genital mycotic infections as compared to placebo. Importantly, there was no difference in dose of ertugliflozin and relation to adverse events.
The VERTIS CV Trial presents ertugliflozin as the fourth and latest SGLT2i to be tested based on CVD outcomes. A SGLT2i class effect in reducing HFH in T2DM patients with ASCVD appears evident. Unsurprisingly, the benefit of SGLT2i (dapagliflozin) in reducing HFH is also evident among patients with heart failure and reduced ejection fraction regardless of diabetes status.17 However, reduction in major adverse cardiac events (MACE) has only been limited to empagliflozin and canagliflozin in clinical trials in T2DM patients with ASCVD (Figure 1).
Further, a reduction in CV mortality, as was seen in EMPA-REG OUTCOMES was not seen in the VERTIS CV Trial. These differences do not appear to be explained based on patient populations given similar trial inclusion and exclusion criteria, as well as similar baseline demographics among the EMPA-REG OUTCOMES and VERTIS CV trials. Additionally, the basis of reduction of MACE and CV death seems unlinked to selectiveness of the SGLT2 receptor, but could be related to other unique differences in the mechanism of action of these medications when interfacing with the cardiovascular system at the molecular level. From a trialist perspective, it has been postulated that the lack of incremental benefit of improvement in MACE over recent years in SGLT2i studies as compared to when EMPA-REG OUTCOME and CANVAS were conducted may be related to more recent aggressive blood pressure guidelines and newer lipid lowering medications such as PCSK9 inhibitors. While this may be possible, the evidence still remains that empagliflozin in the EMPA-REG OUTCOME study and canagliflozin in the CANVAS Program study met both noninferiority and superiority endpoints for the primary outcome of reduction in MACE, with empagliflozin showing significant reduction in CV death as well.
Overall, the VERTIS CV Trial provides further reassurance that SGLT2i are safe and potentially provide a class effect on the reduction of HFH in diabetic patients. However, for MACE and CV death, the important differences among the SGLT2i and a class effect are not a given. Given the safety profiles and cardiovascular benefits, SGLT-2 inhibitors are now recommended in combination with metformin in patients with T2DM and ASCVD, regardless of hemoglobin A1C, in the aligned recommendations of the American College of Cardiology Expert Consensus documentation and the most recent consensus report of the American Diabetes Association.18,19 In addition, the most recent expert consensus from the American College of Cardiology 2020 Novel Therapies of CV Risk Reduction in Diabetes Decision Pathway also recommend initiating a patient-clinician discussion about the use of SGLT2i for those diabetic patients who are also at high risk for ASCVD.20
- Zheng Y, Ley SH, Hu FB. Global etiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018;14:88–98.
- Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139–e228.
- 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;393:31–39.
- 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: systematic review and meta-analysis of cardiovascular outcomes trials. Circulation 2019;139:2022–31.
- Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in Type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–2306.
- Arnott C, Li Q, Kang A, et al. Sodium‐glucose cotransporter 2 inhibition for the prevention of cardiovascular events in patients with type 2 diabetes mellitus: a systematic review and meta‐analysis. J Am Heart Assoc 2020;9:e014908.
- Terra SG, Focht K, Davies M, et al. Phase III, efficacy, and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab 2017;19:721–8.
- Rosenstock J, Frias J, Páll D, et al. Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). Diabetes Obes Metab 2018;20:520–9.
- Hollander P, Liu J, Hill J, et al. Ertugliflozin compared with glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin: the VERTIS SU randomized study. Diabetes Ther 2018;9:193–207.
- Dagogo-Jack S, Liu J, Eldor R, et al. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes Metab 2018;20:530–40.
- Pratley RE, Eldor R, Raji A, et al. Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial. Diabetes Obes Metab 2018;20:1111–20.
- Miller S, Krumins T, Zhou H, et al. Ertugliflozin and sitagliptin co-initiation in patients with type 2 diabetes: the VERTIS SITA randomized study. Diabetes Ther 2018;9:253–68.
- Results of the eValuation of ERTugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV). Presented by Cannon CP, McGuire DK, Cherney D, et al. at the American Diabetes Association Virtual 88th Scientific Sessions; June 16, 2020.
- McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;281:1995–2008.
- Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2020;43:487–93.
- Das SR, Everett BM, Birtcher KK, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease. J Am Coll Cardiol 2018;72:3200–23.
- Das SR, Everett BM, Birtcher KK, et al. 2020 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients with Type 2 Diabetes. J Am Coll Cardiol 2020;Aug 05 [Epub ahead of print].
Keywords: Diabetes Mellitus, Metabolic Syndrome X, Hemoglobin A, Sodium-Glucose Transporter 2, Hypoglycemic Agents, Diabetes Mellitus, Type 2, Creatinine, PCSK9 protein, human, Proprotein Convertase 9, Metformin, Coronary Artery Disease
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