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Cardiovascular Effects of Sodium-Glucose Cotransporter-2 Inhibitors in Adults With Type 2 Diabetes

  • Vincent C. Woo
    Correspondence
    Address for correspondence: Vincent C. Woo MD, FRCPC, Section of Endocrinology and Metabolism, Health Sciences Centre, University of Manitoba, 838-715 McDermot Ave, Winnipeg, Manitoba R3E 3P4, Canada.
    Affiliations
    Section of Endocrinology and Metabolism, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
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Published:September 24, 2019DOI:https://doi.org/10.1016/j.jcjd.2019.09.004

      Abstract

      Adults with type 2 diabetes mellitus can benefit from pharmacotherapies that lower their risk for cardiovascular disease. This review describes the salient findings from sodium-glucose cotransporter-2 (SGLT2) inhibitor cardiovascular outcome trials that serendipitously revealed the cardiorenal benefits of SGLT2 inhibitors in adults with type 2 diabetes mellitus who either have established cardiovascular disease or multiple cardiovascular risk factors. It also summarizes the findings from other phase 3 clinical studies that measured the cardiovascular effects of SGLT2 inhibitors and real-world evidence reports that compared the cardiovascular impact of SGLT2 inhibitors with other antihyperglycemic agents. The collective data indicate that SGLT2 inhibitors are pleiotropic agents that offer important cardiovascular, metabolic and renal benefits beyond glucose lowering with low incidences of hypoglycemia. Specifically, the placebo-controlled SGLT2 inhibitor cardiovascular outcome trials documented either fewer major adverse cardiac events (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) or a reduction in the composite endpoint of cardiovascular death or hospitalization for heart failure in participants with type 2 diabetes mellitus and established cardiovascular disease. Amongst those with type 2 diabetes mellitus who did not have established cardiovascular disease but did present with multiple risk factors, SGLT2 inhibitors lowered the combined endpoint of cardiovascular death or hospitalization for heart failure but had little impact on the occurrence of major adverse cardiac events. Ongoing clinical trials and subanalyses of the trials that have been reported should shed further light on the clinical benefits and utility of SGLT2 inhibitors.

      Résumé

      Adultes atteints du diabète sucré de type 2 peuvent bénéficier des pharmacothérapies qui abaissent leur risque de maladies cardiovasculaires. La présente revue décrit les principaux résultats des essais sur les résultats cardiovasculaires des inhibiteurs du cotransporteur sodium-glucose de type 2 (SGLT2) qui ont fortuitement révélé les bénéfices cardio-rénaux des inhibiteurs du SGLT2 chez les adultes atteints du diabète sucré de type 2 ayant soit une maladie cardiovasculaire établie ou de multiples facteurs de risque cardiovasculaire. De plus, elle récapitule les résultats d’autres études cliniques de phase III qui portaient sur la mesure des effets cardiovasculaires des inhibiteurs du SGLT2 et fait la synthèse des données probantes du monde réel sur la comparaison des répercussions cardiovasculaires des inhibiteurs du SGLT2 aux autres antihyperglycémiants. L’ensemble des données indiquent que les inhibiteurs du SGLT2 sont des agents à effets pléiotropiques qui, outre la réduction de la glycémie, apportent des bénéfices cardiovasculaires, métaboliques et rénaux, et entraînent un faible risque d’hypoglycémie. Particulièrement, les essais sur les résultats cardiovasculaires des inhibiteurs du SGLT2 contre placebo ont démontré soit une moindre survenue d’événements cardiaques indésirables majeurs (infarctus du myocarde non fatal, accident vasculaire cérébral non fatal et décès d’origine cardiovasculaire) soit une diminution de la survenue du critère combiné de décès d’origine cardiovasculaire ou d’hospitalisation pour insuffisance cardiaque chez les participants atteints de diabète sucré de type 2 et d’une maladie cardiovasculaire établie. Parmi les individus atteints du diabète sucré de type 2 qui n’avaient pas de maladie cardiovasculaire établie, mais présentaient de multiples facteurs de risque, les inhibiteurs du SGLT2 ont fait réduire les critères combinés de décès d’origine cardiovasculaire ou d’hospitalisation pour insuffisance cardiaque, mais avaient peu de répercussions sur la survenue d’événements cardiaques indésirables majeurs. Les essais cliniques et les sous-analyses d’essais en cours rapportées devraient davantage élucider les avantages cliniques et l’utilité des inhibiteurs du SGLT2.

      Keywords

      Mots clés

      • Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce major adverse cardiac events mainly in adults with type 2 diabetes and established cardiovascular disease.
      • SGLT2 inhibitors lower the risk of heart failure hospitalizations in adults with type 2 diabetes regardless of existing cardiovascular disease.
      • SGLT2 inhibitors offer benefits beyond glucose lowering and should be a preferred antihyperglycemic therapy for many patients with type 2 diabetes mellitus.

      Introduction

      The prevalence of diabetes is increasing at a staggering pace across the world. It has been projected that by 2045, approximately 629 million adults between the ages of 20 and 79 years will be living with diabetes (
      International Diabetes Federation
      ). Cardiovascular disease is a leading cause of morbidity and mortality in adults with type 2 diabetes mellitus with its onset estimated to occur 12 to 15 years earlier in people with type 2 diabetes mellitus relative to those who do not have the condition (
      • Booth G.L.
      • Kapral M.K.
      • Fung K.
      • Tu J.V.
      Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: A population-based retrospective cohort study.
      ). Notably, the prognosis after a cardiovascular event is considerably worse in the presence of diabetes with higher short- and long-term mortality, more ischemic cardiovascular events and more heart failure events (
      • Donahoe S.M.
      • Stewart G.C.
      • McCabe C.H.
      • et al.
      Diabetes and mortality following acute coronary syndromes.
      ). Indeed, heart failure is increasingly being recognized as an underappreciated cardiovascular complication of diabetes despite the longstanding evidence that heart failure occurs more frequently in adults with type 2 diabetes and that it features commonly in adults who have type 2 diabetes but not atherosclerotic coronary artery disease (
      • Valle R.
      • Bagolin E.
      • Canali C.
      • et al.
      The BNP assay does not identify mild left ventricular diastolic dysfunction in asymptomatic diabetic patients.
      ).
      In 2008, the United States Food and Drug Administration (
      U.S. Food and Drug Administration
      ) published a guidance document mandating cardiovascular safety evaluations of all new antihyperglycemic agents in large outcome trials prior to consideration for market entry. The reported studies that have adhered to the requirements of this advisory have included between 3,000 and 20,000 adults with type 2 diabetes mellitus and high cardiovascular risk and were powered to assess safety for major adverse cardiac events (MACE) (nonfatal myocardial infarction [MI], nonfatal stroke and cardiovascular death). A subsequent superiority assessment could be performed if cardiovascular safety was met.
      The sodium-glucose cotransporter-2 (SGLT2) inhibitors are 1 of the newer classes of antihyperglycemic drugs that have been subjected to the premarketing requirements of the Food and Drug Administration. They are mechanistically unique from other glucose-lowering therapies because they act independent of the pancreas and promote glucosuria by blocking glucose resorption in the renal proximal tubule. SGLT2 inhibitors have notably made short work of the hurdles typically associated with entry into clinical practice guidelines (
      • Lipscombe L.
      • Booth G.
      • et al.
      Diabetes Canada Clinical Practice Guidelines Expert Committee
      Pharmacologic glycemic management of type 2 diabetes in adults.
      ), in part because they concomitantly improve glycemic control, promote weight loss and lower blood pressure without an increased risk of hypoglycemia, and also because they have been associated with a plethora of cardiorenal improvements (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ,
      • Zelniker T.A.
      • Wiviott S.D.
      • 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.
      ,
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ,
      • Mahaffey K.W.
      • Neal B.
      • Perkovic V.
      • et al.
      Canagliflozin for primary and secondary prevention of cardiovascular events: Results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study).
      ,
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      ).
      This article recapitulates the phase 3 clinical trial evidence addressing the cardiovascular advantages of SGLT2 inhibitors in type 2 diabetes mellitus. It also reviews the rationale, study design and current status of the ongoing and upcoming SGLT2 inhibitor trials. To these ends, a focused literature search was performed in PubMed using the following search terms: canagliflozin, cardiovascular disease, cardiovascular outcome, dapagliflozin, empagliflozin, ertugliflozin, heart failure, sotagliflozin and type 2 diabetes mellitus.

      Cardiovascular Impact of SGLT2 Inhibitors

      Impact on blood pressure and heart rate

      In a systematic review and meta-analysis of 22,528 adults from 43 randomized controlled studies, Mazidi et al (
      • Mazidi M.
      • Rezaie P.
      • Gao H.K.
      • Kengne A.P.
      Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: A systematic review and meta-analysis of 43 randomized control trials with 22 528 patients.
      ) determined that SGLT2 inhibitors decreased systolic blood pressure (SBP) with a weighted mean difference of −2.46 mmHg (95% confidence interval [CI], −2.86 to −2.06); this was accompanied by a weighted mean difference of −1.46 mmHg (95% CI, −1.82 to −1.09) for diastolic blood pressure (DBP). SGLT2 inhibitors were not associated with any change in heart rate.
      The 12-week-long Empagliflozin Removal of Excess of Glucose Blood Pressure trial randomized 823 adults with type 2 diabetes mellitus, with hypertension (mean seated office SBP 130 to 159 mmHg and DBP 80 to 99 mmHg) and taking up to 2 antihypertensive medications to placebo, empagliflozin 10 mg or empagliflozin 25 mg, all once daily (
      • Tikkanen I.
      • Narko K.
      • Zeller C.
      • et al.
      Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension.
      ). At study end, the placebo-adjusted, mean 24-h ambulatory blood pressure monitoring SBP changes from baseline were −3.44 mmHg (95% CI, −4.78 to −2.09) with 10 mg empagliflozin and −4.16 mmHg (95% CI, −5.50 to −2.83) with 25 mg empagliflozin (p<0.001 for both). The corresponding DBP values were −1.36 mmHg (95% CI, −2.15 to −0.56) with 10 mg empagliflozin and −1.72 mmHg (95% CI, −2.51 to −0.93) with 25 mg empagliflozin (both p<0.001) (
      • Tikkanen I.
      • Narko K.
      • Zeller C.
      • et al.
      Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension.
      ). Of note, these blood pressure benefits were evident regardless of the number and type of background antihypertensive medication the participants were on at baseline (
      • Mancia G.
      • Cannon C.P.
      • Tikkanen I.
      • et al.
      Impact of empagliflozin on blood pressure in patients with type 2 diabetes mellitus and hypertension by background antihypertensive medication.
      ).

      Impact on lipid levels

      SGLT2 inhibitors, in general, raise plasma low-density lipoprotein cholesterol and high-density lipoprotein cholesterol by approximately 5% while concomitantly lowering triglyceride levels by about the same magnitude (
      • Inzucchi S.E.
      • Zinman B.
      • Wanner C.
      • et al.
      SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials.
      ). Notably, data from 2 small, open-label, single-site studies with Japanese cohorts have suggested that use of SGLT2 inhibitors is associated with a reduction in atherogenic, small, dense low-density lipoprotein cholesterol levels (
      • Bando Y.
      • Tohyama H.
      • Aoki K.
      • et al.
      Ipragliflozin lowers small, dense low-density lipoprotein cholesterol levels in Japanese patients with type 2 diabetes mellitus.
      ,
      • Hayashi T.
      • Fukui T.
      • Nakanishi N.
      • et al.
      Dapagliflozin decreases small dense low-density lipoprotein-cholesterol and increases high-density lipoprotein 2-cholesterol in patients with type 2 diabetes: Comparison with sitagliptin.
      ). However, it is still unclear whether the small changes in cholesterol and triglyceride levels are clinically relevant, and if they are, if they may negate some of the SGLT2 inhibitor-associated cardiometabolic benefits.

      Cardiovascular Outcome Trials and a Renal Efficacy Trial of SGLT2 Inhibitors

      To date, 3 placebo-controlled SGTL2 inhibitor cardiovascular safety trials and 1 placebo-controlled SGLT2 inhibitor renal efficacy trial with secondary cardiovascular outcomes have been reported. The Empagliflozin Removal of Excess of Glucose Outcome (EMPA-REG OUTCOME) trial assessed, over a median follow-up duration of 3.1 years, empagliflozin 10 or 25 mg against placebo, in addition to usual care, in 7,010 participants who had established cardiovascular disease (
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ). The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program comprised CANVAS, which randomized 4,330 adults to either canagliflozin 300 mg or placebo, and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus), where 5,812 participants who started with canagliflozin 100 mg had their study drug uptitrated to 300 mg at the investigators’ discretion. The CANVAS Program enrolled adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple risk factors for cardiovascular disease and followed them for a median of 2.4 years (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ). The Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial had a median follow-up period of 4.2 years and used dapagliflozin 10 mg in 17,160 patients, with 59% entering the study because of multiple risk factors for cardiovascular disease and 41% entering with established cardiovascular disease (
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ).
      The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study was a dedicated renal efficacy study where the primary endpoint was a composite of end-stage kidney disease, doubling of serum creatinine and renal or cardiovascular death (
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ). Important secondary endpoints included combined hospitalizations for heart failure (HHFs) and cardiovascular death, and a 3-point MACE (nonfatal MI, nonfatal stroke and cardiovascular death) outcome.
      Although the SGLT2 inhibitor cardiovascular outcome trials have provided robust and, in some cases, unexpected results, it must be stressed that despite all of the trials being randomized, double-blind, multinational, placebo-controlled studies, these trials were not conducted in a head-to-head fashion. Accordingly, the efficacy and adverse events reported for each of these trials should not be compared directly with the others without some caution. Real-world data on the clinical impact of SGLT2 inhibitors continue to emerge and even though they provide a lower level of certainty relative to data from the randomized controlled trials, they do serve to provide an alternative perspective.

      Baseline Characteristics of the SGLT2 Inhibitor Trial Cohorts

      The baseline characteristics of the 3 SGLT2 inhibitor cardiovascular outcome trials differed significantly because of the diverse entry criteria. This likely, at least in part, drove the results. EMPA-REG OUTCOME study participants were required, at baseline, to have established cardiovascular disease and an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m2 (mean baseline eGFR, 74 mL/min/1.73 m2) (
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ). The secondary-to-primary prevention makeup of the CANVAS Program was 66%:34%, and all had to have a baseline eGFR that was >30 mL/min/1.73 m2 (mean baseline eGFR, 77 mL/min/1.73 m2) (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ). In contrast, approximately 41% of the DECLARE-TIMI 58 study cohort had established cardiovascular disease, whereas about 59% did not; the renal entry criterion was a creatinine clearance of ≥60 mL/min and the mean baseline eGFR was 86 mL/min/1.73 m2 (
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ).
      Given that the EMPA-REG OUTCOME trial, CANVAS Program and DECLARE-TIMI 58 trial all enrolled individuals at relatively low renal risk, the renal benefits observed could not be used definitively to anchor potential new clinical practice recommendations. In this respect, the CREDENCE trial with a primary composite renal outcome coupled with the renal entry criteria of eGFR ≥30 mL/min/1.73 m2 and macroalbuminuria (urinary albumin-to-creatinine ratio 300 to 5,000 mg/g) served to provide more directed insights on SGLT2 inhibitors and their renal protective abilities (
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ).

      MACE and Components of MACE in SGLT2 Inhibitor Outcome Trials

      The 3-point MACE, which include cardiovascular death, nonfatal MI and nonfatal stroke, were assessed in all cardiovascular outcome trials with SGLT2 inhibitors. These data are summarized in Figure 1.
      Figure thumbnail gr1
      Figure 1Summary of CV endpoints in large outcome trials with SGLT2 inhibitors. Unlike the CANVAS Program, DECLARE-TIMI 58 trial and EMPA-REG OUTCOME trial, which were cardiovascular safety trials, the CREDENCE trial was a renal efficacy study. Inasmuch as these trials had different entry criteria and were not conducted head-to-head, the data from each trial should not be compared directly with the other trials shown. CANVAS, Canagliflozin Cardiovascular Assessment Study; CI, confidence interval; CKD, chronic kidney disease; CREDENCE, Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation; CV, cardiovascular; CVD, cardiovascular disease; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58; EMPA-REG OUTCOME, Empagliflozin Removal of Excess of Glucose Outcome; HHF, heart failure hospitalization; MACE, major adverse cardiac event; MRF, multiple risk factors; SGLT2, sodium-glucose cotransporter-2.
      In the EMPA-REG OUTCOME trial, the 3-point MACE occurred in 10.5% (490 of 4,687) of the participants in the empagliflozin arm and in 12.1% (282 of 2,333) of those in the placebo group (hazard ratio [HR], 0.86; 95.02% CI, 0.74 to 0.99; p=0.04 for superiority) (
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ). In the CANVAS Program, the 3-point MACE occurred in 26.9 per 1,000 patient-years in the canagliflozin arm and 31.5 per 1,000-patient years in the placebo group (HR, 0.86; 95% CI, 0.75 to 0.97; p=0.02 for superiority) (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ). This was primarily driven by a decrease in the 3-point MACE in the subcohort with established cardiovascular disease (HR, 0.82; 95% CI, 0.72 to 0.95) because there was no significant difference in the occurrences of 3-point MACE between the 2 study arms amongst the participants with multiple risk factors (HR, 0.98; 95% CI, 0.74 to 1.30) (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ). In the DECLARE-TIMI 58 trial, the 3-point MACE occurred in 8.8% (756 of 8,582) of the participants in the empagliflozin arm and in 9.4% (803 of 8,578) of those in the placebo group (HR, 0.93; 95% CI, 0.84 to 1.03; p=0.17 for noninferiority) (
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ). Within the group with established cardiovascular disease, the 3-point MACE occurred in 13.9% and 15.3% of those in the dapagliflozin arm and placebo group, respectively (HR, 0.90; 95% CI, 0.79 to 1.02). In the group with multiple risk factors, the 3-point MACE occurred in 5.3% of the participants in the dapagliflozin arm and 5.2% of those in the placebo group (HR, 1.01; 95% CI, 0.86 to 1.20; p=0.25) (
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ).
      Of note, a recent subgroup analysis of the DECLARE-TIMI 58 trial found, in participants who had a previous MI, that dapagliflozin was associated with significantly lower risk for the 3-point MACE (HR, 0.84; 95% CI, 0.72 to 0.99; p=0.04) compared with those who did not have an MI history. The composite of cardiovascular death or HHF with dapagliflozin in the same participants trended towards significance (HR, 0.81; 95% CI, 0.65 to 1.00; p=0.05); however, the absolute risk reduction (ARR) with dapagliflozin was greater in those with a prior MI history (ARR, 1.9%; 95% CI, 0.0% to 3.8%) than in those who had never experienced an MI (ARR, 0.6%; 95% CI, 0.0% to 1.3%; ARR interaction p=0.01) (
      • Furtado R.H.M.
      • Bonaca M.P.
      • Raz I.
      • et al.
      Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes and previous myocardial infarction.
      ).
      It is noteworthy that the 3-point MACE rates for individuals with established cardiovascular disease were similar across the 3 SGLT2 inhibitor cardiovascular outcome trials and ranged from 41.0 to 43.9 per 1,000 patient-years in the placebo groups (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ,
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ). Amongst those in the CANVAS Program and DECLARE-TIMI 58 trial who did not have established cardiovascular disease, the placebo MACE rates were 15.5 and 13.3 per 1,000 patient-years respectively (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ). A subsequent meta-analysis of the aforementioned SGLT2 inhibitor cardiovascular outcome trials reported that although the 3-point MACE were reduced (HR, 0.86; 95% CI, 0.80 to 0.97) with SGLT2 inhibitor use in adults who had type 2 diabetes mellitus and established cardiovascular disease, the participants who did not have established cardiovascular disease despite presenting with multiple risk factors did not have the same benefits (HR, 1.00; 95% CI, 0.87 to 1.16) (
      • Zelniker T.A.
      • Wiviott S.D.
      • 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.
      ).
      In the CREDENCE trial, the 3-point MACE, which was 1 of the secondary outcomes, occurred less frequently in the canagliflozin arm (38.7 per 1,000 patient-years; HR, 0.80; 95% CI, 0.67 to 0.95; p<0.01) (
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ). The analyses stratifying the participants to those with or without established cardiovascular disease have yet to be reported (
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ).

      Cardiovascular Death in SGLT2 Inhibitor Outcome Studies

      Cardiovascular death was typically part of the 3-point MACE and a combined endpoint with HHF. The EMPA-REG OUTCOME study recorded 309 deaths, and empagliflozin was associated with a 38% lowering of cardiovascular death (
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ) that encompassed sudden death (n=91), worsening of heart failure or cardiogenic shock (n=36), acute MI (n=26), stroke (n=27) and other causes (n=129) (
      • Fitchett D.
      • Butler J.
      • van de Borne P.
      • et al.
      Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME(R) trial.
      ). Of note, cardiovascular death and HHF event rates in the EMPA-REG OUTCOME trial occurred independent of glycated hemoglobin levels (
      • Inzucchi S.E.
      • Zinman B.
      • Wanner C.
      • et al.
      SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials.
      ). In the CANVAS Program, the HRs for cardiovascular death, fatal heart failure and fatal stroke were 0.87 (95% CI, 0.72 to 1.06) (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ), 0.89 (95% CI, 0.49 to 1.60) (
      • Radholm K.
      • Figtree G.
      • Perkovic V.
      • et al.
      Canagliflozin and heart failure in type 2 diabetes mellitus.
      ) and 0.84 (95% CI, 0.44 to 1.59) (
      • Zhou Z.
      • Lindley R.I.
      • Radholm K.
      • et al.
      Canagliflozin and stroke in type 2 diabetes mellitus.
      ), respectively. A total of 494 cardiovascular deaths occurred in the DECLARE-TIMI 58 trial, which translated to a HR of 0.98 (95% CI, 0.82 to 1.17) (
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ). The breakdown analysis indicated 284 sudden cardiovascular deaths and 64 acute MI-related, 56 stroke-related, 47 heart failure-related and 40 other cardiovascular event-related deaths (
      • Kato E.T.
      • Silverman M.G.
      • Mosenzon O.
      • et al.
      Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.
      ). The CREDENCE trial reported no significant impact of canagliflozin on cardiovascular death in their cohort (HR, 0.78; 95% CI, 0.61 to 1.00; p=0.04); the categorization of causes of death has not been reported yet (
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ).
      The inconsistent effect of SGLT2 inhibitors on the rates of cardiovascular death in the SGLT2 inhibitor trials has been a major point of discussion and investigation. There remains, however, no consensus because there does not appear to be any overt cause for the disparity. Some of the reasons speculated to account for the phenomenon are the diverse study cohorts (some had more advanced cardiovascular disease and more comorbidities, whereas others included healthier participants), the subtle differences between the individual trial definitions for cardiovascular death, the broad medication backgrounds of the study participants and the varied adjudication processes.

      Nonfatal MI and Nonfatal Stoke in SGLT2 Inhibitor Outcome Studies

      The EMPA-REG OUTCOME trial had an HR of 0.87 (95% CI, 0.70 to 1.09) for nonfatal MI and 1.24 (95% CI, 0.92 to 1.67) for nonfatal stroke (
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ). In the CANVAS Program, there was a 15% lower risk for nonfatal MI (HR, 0.85; 95% CI, 0.69 to 1.05) and a 10% lower risk for nonfatal stroke (HR, 0.90; 95% CI, 0.71 to 1.15) (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ). The 11% risk reduction for a nonfatal MI in the overall DECLARE-TIMI 58 trial population was primarily driven by the benefits in the group with established cardiovascular disease (HR, 0.87; 95% CI, 0.74 to 1.02) rather than the group with multiple risk factors (HR, 0.94; 95% CI, 0.73 to 1.21) (
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ). The nonfatal stroke rate HRs in the entire, primary and secondary prevention cohorts of the DECLARE-TIMI 58 trial were 1.01 (95% CI, 0.84 to 1.21), 0.97 (95% CI, 0.76 to 1.22) and 1.09 (95% CI, 0.82 to 1.45), respectively (
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ).

      HHF or Cardiovascular Death in SGLT2 Inhibitor Outcome Studies

      The combined outcome of HHF or cardiovascular death in the EMPA-REG OUTCOME trial was lower with empagliflozin (HR, 0.66; 95% CI, 0.55 to 0.79; p<0.001) and reflective of the lower rate of HHF (HR, 0.65; 95% CI, 0.50 to 0.85; p=0.002). Approximately one-tenth of the study cohort had a known history of heart failure at baseline, and this group experienced a higher incidence of HHF-cardiovascular death and HHF-only outcomes relative to the group that had not had a prior heart failure incident (
      • Fitchett D.
      • Zinman B.
      • Wanner C.
      • et al.
      Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME(R) trial.
      ). The cardiovascular benefits of empagliflozin were, however, evident regardless of whether there was a history of heart failure or not, and in fact were more impactful in the absence of a heart failure history (
      • Fitchett D.
      • Zinman B.
      • Wanner C.
      • et al.
      Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME(R) trial.
      ). Specifically, the HR for the composite of HHF or cardiovascular death was 0.72 (95% CI, 0.50 to 1.04) for the group that had a history of heart failure at baseline and 0.63 (95% CI, 0.51 to 0.78) for the group that did not; the HRs for HHF alone were 0.75 (95% CI, 0.48 to 1.19) and 0.59 (95% CI, 0.43 to 0.82) for the groups with and without a prior heart failure event, respectively (
      • Fitchett D.
      • Zinman B.
      • Wanner C.
      • et al.
      Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME(R) trial.
      ).
      In the CANVAS Program, the HHF or cardiovascular deaths composite (HR, 0.78; 95% CI, 0.67 to 0.91) and HHF (HR, 0.67; 95% CI, 0.52 to 0.87) occurred less frequently with canagliflozin (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ). When the data were stratified according to the presence (14.4% of the study population) or absence of a history of heart failure at baseline, the benefit canagliflozin exerted on cardiovascular death or HHF appeared to be bias towards those who had previously endured a heart failure event (HF, 0.61; 95% CI, 0.46 to 0.80 for those with a prior heart failure history; HR, 0.87; 95% CI, 0.72 to 1.06 for those without a previous heart failure history) (
      • Radholm K.
      • Figtree G.
      • Perkovic V.
      • et al.
      Canagliflozin and heart failure in type 2 diabetes mellitus.
      ). There was a similar trend for HHF alone (HF, 0.51; 95% CI, 0.33 to 0.78 and HR, 0.79; 95% CI, 0.57 to 1.09 for those with and without a history of HF at baseline, respectively) (
      • Radholm K.
      • Figtree G.
      • Perkovic V.
      • et al.
      Canagliflozin and heart failure in type 2 diabetes mellitus.
      ).
      Dapagliflozin decreased HHF significantly (HR, 0.73; 95% CI, 0.61 to 0.88; p=0.005) in the DECLARE-TIMI 58 trial (
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ). This in turn drove the lower frequency of HHF or cardiovascular death (HR, 0.83; 95% CI, 0.73 to 0.95; p=0.005).
      In a meta-analysis of the 3 SGLT2 inhibitor cardiovascular outcome trials conducted by Zelniker et al (
      • Zelniker T.A.
      • Wiviott S.D.
      • 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.
      ), the HR for combined HHF or cardiovascular death in those with established cardiovascular disease was 0.76 (95% CI, 0.69 to 0.84), whereas that for those with multiple risk factors was 0.84 (95% CI, 0.69 to 1.01).
      The benefits for HHF or combined HHF or cardiovascular death in the cardiovascular outcome trials occurred very early in the observation window, with the Kaplan-Meier curves diverging within a few weeks or months after initiation of the study intervention. Interestingly, the CREDENCE trial was stopped early because the primary endpoint (a predominantly renal composite that included cardiovascular death) was met ahead of the anticipated time (HR, 0.70; 95% CI, 0.59 to 0.82) (
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ). Despite one-half of the CREDENCE trial cohort presenting with known cardiovascular disease at baseline, the traditional MACE outcome, as previously mentioned, occurred less frequently in the canagliflozin arm. Likewise, there was a lower risk for the composite of cardiovascular death or HHF with canagliflozin (HR, 0.69; 95% CI, 0.57 to 0.83; p<0.001) and HHF alone (HR, 0.61; 95% CI, 0.47 to 0.80; p<0.001).

      Cardiovascular Outcomes According to Other Subgroup Stratifications

      Subgroup analyses of the EMPA-REG OUTCOME trial data did not uncover any significant difference between groups for the 3-point MACE when the cohort was stratified according to age, race, sex, body mass index, glycated hemoglobin levels or eGFR (
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ). A subsequent post hoc analysis reported that while a history of microvascular complications imposed a higher risk for HHF (HR, 1.63; 95% CI, 1.06 to 2.49), empagliflozin consistently lowered HHF risk regardless of the presence or absence of microvascular disease (
      • Verma S.
      • Wanner C.
      • Zwiener I.
      • et al.
      Influence of microvascular disease on cardiovascular events in type 2 diabetes.
      ). In addition to the subgroups previously mentioned, the CANVAS Program evaluated the potential impact of duration of diabetes, baseline medications, presence of peripheral vascular disease or past amputation on the primary outcome, and likewise found comparable primary outcome results between the groups (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ). The DECLARE-TIMI 58 trial had 2 primary co-endpoints (a composite of cardiovascular death and HHF and the 3-point MACE), neither of which demonstrated clinically or statistically significant differences in the subgroups reported (
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ).

      Adverse Events

      Consistent with phase 3 trial data, the most common adverse outcome in the SGLT2 inhibitor cardiovascular outcome trials was genital tract infections, most of which responded to standard therapy and rarely manifested a second time or led to discontinuation. There were unexpected elevated risks of fractures (15.40 vs 11.93 per 1,000 participant-years; HR, 1.26; 95% CI, 1.04 to 1.52) and lower extremity amputations (6.30 vs 3.37 per 1,000 participant-years; HR, 1.97; 95% CI, 1.41 to 2.75) reported for canagliflozin in the CANVAS Program (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ). In contrast, trials evaluating the SGLT2 inhibitors dapagliflozin and empagliflozin have not shown an increase in these adverse events. The concerns have somewhat abated given the lack of evidence for increased rates of fractures and lower extremity amputations in analyses from pooled phase 3 trials (
      • Watts N.B.
      • Bilezikian J.P.
      • Usiskin K.
      • et al.
      Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus.
      ), real-world evidence (
      • Yuan Z.
      • DeFalco F.J.
      • Ryan P.B.
      • et al.
      Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study.
      ) and the CREDENCE trial (
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ).

      Real-World Studies

      Although it is well recognized that randomized controlled trials provide the most robust evidence and are, therefore, most pertinent to the development of clinical recommendations, there have been increasing nods to real-world evidence because it can offer a more realistic perspective of everyday medicine that may be complimentary to trial findings.
      The Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL) study is a large meta-analysis that reviewed data from 309,056 individuals in 6 countries who were newly prescribed either an SGLT2 inhibitor or another antihyperglycemic agent (
      • Kosiborod M.
      • Lam C.S.P.
      • Kohsaka S.
      • et al.
      Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL 2 study.
      ). The CVD-REAL authors reported that relative to other antihyperglycemic agents, SGLT2 inhibitors were associated with lower rates of HHF (HR, 0.61; 95% CI, 0.51 to 0.73; p<0.001), all-cause death (HR, 0.49; 95% CI, 0.41 to 0.57; p<0.001) and the composite of HHF or death (HR, 0.54; 95% CI, 0.48 to 0.60; p<0.001) (
      • Kosiborod M.
      • Cavender M.A.
      • Fu A.Z.
      • et al.
      Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors).
      ). The CVD-REAL 2 study, a subsequent and similar meta-analysis that was conducted using data from 6 other countries, yielded comparable results in that SGLT2 inhibitors, compared with other antihyperglycemic medications, were associated with a lower risk of all-cause death (HR, 0.51; 95% CI, 0.37 to 0.70; p<0.001), HHF (HR, 0.64; 95% CI, 0.50 to 0.82; p=0.001), all-cause death or HHF composite (HR, 0.60; 95% CI, 0.47 to 0.76; p<0.001), MI (HR, 0.81; 95% CI, 0.74 to 0.88; p<0.001) and stroke (HR, 0.68; 95% CI, 0.55 to 0.84; p<0.001) (
      • Kosiborod M.
      • Lam C.S.P.
      • Kohsaka S.
      • et al.
      Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL 2 study.
      ). The SGLT2 inhibitor-associated cardiac benefits were consistent across all the countries studied and the different patient subgroups, including those with and without known cardiovascular disease. Around the same time, a smaller-scale retrospective study using data from general practice sites in the United Kingdom demonstrated that all-cause death occurred less frequently with dapagliflozin in both low- and high-risk cardiovascular populations (
      • Toulis K.A.
      • Willis B.H.
      • Marshall T.
      • et al.
      All-cause mortality in patients with diabetes under treatment with dapagliflozin: A population-based, open-cohort study in The Health Improvement Network Database.
      ). More recently, the Empagliflozin Comparative Effectiveness and Safety program, which mined 3 US databases and compared information on new users of empagliflozin and sitagliptin found that HHF rates were significantly lower in the empagliflozin group (HR, 0.56; 95% CI, 0.43 to 0.73; p<0.0001), regardless of whether there was a history of cardiovascular disease (
      • Patorno E.
      • Pawar A.
      • Franklin J.M.
      • et al.
      Empagliflozin and the risk of heart failure hospitalization in routine clinical care: A First Analysis from the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) study.
      ). In short, unlike the cardiovascular outcome trials, the real-world studies congruently indicate a positive relationship between SGLT2 inhibition and cardiovascular and all-cause death, in the presence and absence of known cardiovascular disease. All the studies, however, are aligned in supporting a benefit for HHF with SGLT2 inhibitor exposure.

      Ongoing Studies With SGLT2 Inhibitors

      There are currently 2 ongoing MACE safety studies—the Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk trial (ClinicalTrials.gov Identifier: NCT03315143) and the Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease, The VERTIS CV Study (MK-8835-004) (ClinicalTrials.gov Identifier: NCT01986881). Both are anticipated to report over the next 3 years.
      Several studies dedicated to evaluating the impact of SGLT2 inhibitors on heart failure are currently in various stages of conduct. These include the following: the Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (ClinicalTrials.gov identifier: NCT03036124), the Dapagliflozin Effect on Symptoms and Biomarkers in Patients With Heart Failure study (ClinicalTrials.gov identifier: NCT02653482), the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure study (ClinicalTrials.gov identifier: NCT03619213) and the Dapagliflozin in PRESERVED Ejection Fraction Heart Failure study (ClinicalTrials.gov identifier: NCT03030235) with dapagliflozin; the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction trial (ClinicalTrials.gov identifier: NCT03057951), the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction trial (ClinicalTrials.gov identifier: NCT03057977), the Empagliflozin in Patients With Chronic Heart Failure With Preserved Ejection Fraction trial (ClinicalTrials.gov identifier: NCT03448406) and the Empagliflozin in Patients With Chronic Heart Failure With Reduced Ejection Fraction trial (ClinicalTrials.gov identifier: NCT03448419) with empagliflozin and the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure trial (ClinicalTrials.gov identifier: NCT03521934) with sotaliflozin. Importantly, these heart failure studies will be assessing how SGLT2 inhibitors affect different types of heart failure, if they yield clinical benefits in both type 1 and type 2 diabetes mellitus and if they may be considered for people who have heart failure but not type 2 diabetes mellitus.

      Discussion

      Although the original and primary intention of the cardiovascular outcome trials was to demonstrate cardiovascular safety of the novel antihyperglycemic agents, they have uncovered somewhat unexpected efficacy regarding important cardiovascular outcomes. The varying trial entry criteria translated to study cohorts that included only those with established cardiovascular disease and those which had a mix of people with established cardiovascular disease (secondary prevention) or without cardiovascular disease but with multiple cardiovascular risk factors (primary prevention). These baseline differences likely, at least in part, drove the contrasting cardiovascular outcomes assessed. The EMPA-REG OUTCOME trial, the CANVAS Program and the DECLARE-TIMI 58 trial collectively demonstrated that although the SGLT2 inhibitors are associated with fewer 3-point MACE in individuals with established cardiovascular disease, they are neutral on the 3-point MACE in those with multiple cardiovascular risk factors. Notably, the SGLT2 inhibitors offered benefits all around for the composite outcome of HHF or cardiovascular death. About one-quarter of the more renal-centric CREDENCE study cohort were secondary prevention participants and although only the high-level cardiovascular measures are available to date, they do support a cardioprotective role for canagliflozin in type 2 diabetes.
      The robust clinical trial evidence, albeit unexpected, demonstrating cardiovascular benefits triggered rapid recommendation updates across the world. The 2018 Diabetes Canada Clinical Practice Guidelines (
      • Lipscombe L.
      • Booth G.
      • et al.
      Diabetes Canada Clinical Practice Guidelines Expert Committee
      Pharmacologic glycemic management of type 2 diabetes in adults.
      ,
      • Stone J.A.
      • Houlden R.L.
      • Lin P.
      • Udell J.A.
      • Verma S.
      Diabetes Canada Clinical Practice Guidelines Expert Committee
      Cardiovascular protection in people with diabetes.
      ) include recommendations for using SGLT2 inhibitors (empagliflozin and canagliflozin) in those with clinical cardiovascular disease to derive 3-point MACE and heart failure advantages. The recent American Diabetes Association and European Association for the Study of Diabetes Consensus Report (
      • Davies M.J.
      • D'Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ) makes similar recommendations for SGLT2 inhibitor use with known atherosclerotic cardiovascular disease, heart failure and chronic kidney disease.
      Cumulative long-term evidence supports a multifaceted approach for vascular protection in type 2 diabetes. This would specifically include maintenance of healthy lifestyle habits, smoking cessation and improved glycemic, blood pressure and lipid levels with the appropriate pharmacotherapies (i.e. antihyperglycemic agents, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, lipid-lowering medications and antithrombotic agents, as necessary). Despite a growing toolbox of vascular protective medications, many adults with type 2 diabetes are still unable to meet and sustain their recommended therapeutic targets and, therefore, remain at high risk for cardiovascular disease. Clearly, newer and more effective strategies need to be developed and implemented to assist in optimizing therapeutic goal achievements and in turn cardiovascular risk reduction.
      Since the original submission of this manuscript, we have gained further insights on the cardiovascular impact of SGLT2 inhibitors. First, Mahaffey et al (
      • Mahaffey K.W.
      • Jardine M.J.
      • Bompoint S.
      • et al.
      Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups.
      ) reported that canagliflozin was associated with robust reductions in the risk of kidney failure and cardiovascular events in the primary and secondary cardiovascular prevention groups of the CREDENCE cohort. Notably, these benefits occurred in the absence of any excess amputation or fracture with canagliflozin relative to placebo. Second, the Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF), which enrolled individuals who had established heart failure with reduced ejection fraction, with and without diabetes, and on excellent standard-of-care therapy, revealed that dapagliflozin reduced cardiovascular death and HHF events significantly and consistently across all of the prespecified subgroups (
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ). These outcomes were accompanied by marked improvements in quality of life as well as low and comparable rates of adverse events between the dapagliflozin and placebo groups. Clearly, the full clinical impact of the SGLT2 inhibitors has yet to be defined.

      Acknowledgments

      I thank Hwee Teoh, PhD, HTaq Biomedical Editorial and Education Services Inc., for editorial support in the preparation of this manuscript.

      Author Disclosures

      V.C.W. has received clinical trial support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen and Merck and has served on advisory panels of and received speaker honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen and Merck.

      Author Contributions

      V.C.W. conceived the work, prepared the literature search, drafted the original version and critically revised the manuscript prior to submission. V.C.W. agrees to act as the guarantor of the work.

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