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New Antidiabetes Medications and Their Cardiovascular and Renal Benefits

  • Enrico G. Ferro
    Affiliations
    Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA

    Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
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  • Mohamed B. Elshazly
    Affiliations
    Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, 601 North Caroline Street, Suite 7200, Baltimore, MD 21287, USA

    Division of Cardiology, Department of Medicine, Weill Cornell Medical College–Qatar, Education City, PO Box 24144, Doha, Qatar
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  • Deepak L. Bhatt
    Correspondence
    Corresponding author. Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, 75 Francis Street, Boston, MA 02115.
    Affiliations
    Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA

    Division of Cardiovascular Medicine, Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
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      Keywords

      Key points

      • Since the 2008 US Food and Drug Administration Guidance to Industry, several rigorous cardiovascular outcome trials have been conducted that unequivocally proved the safety of new antidiabetes medications.
      • Among new antidiabetes medications, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) showed a significant reduction in ischemic events in patients with diabetes with atherosclerotic cardiovascular disease, and all major guidelines now recommend them as first-line therapy, concurrently with metformin, for this population.
      • SGLT2i additionally showed broad cardiorenal benefits, namely a significant reduction in both heart failure hospitalizations and mortality for patients with heart failure with reduced ejection fraction, and prevention of progression of chronic kidney disease; notably, these benefits have been found to apply even to patients without diabetes.
      • Despite the uniform adoption of SGLT2i and GLP-1 RAs by all major international guidelines, the real-world uptake of these agents remains limited, especially outside of endocrinology practices; therefore, it is important to empower all physicians with the knowledge to initiate and monitor patients on these agents.

      Introduction

      In the early 2010s, physicians treating patients with diabetes were faced with a variety of noninsulin medications to choose from, all with similar efficacy in lowering hemoglobin A1c (HbA1c) level, but no clear indication to use one rather than another. Starting in 2015, unexpected evidence emerged suggesting that 2 of these noninsulin agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), caused a significant reduction in some of the most important complications among patients with long-standing diabetes, such as myocardial infarction (MI) and, in the case of SGLT2i, heart failure (HF) hospitalizations (HHFs) and progression of chronic kidney disease (CKD). In 2019 and 2020, the second generation of trials of SGLT2i went on to show that these benefits apply to all patients with HF with reduced ejection fraction (HFrEF) and CKD, even among patients without diabetes.
      • Ferro E.G.
      • Michos E.D.
      • Bhatt D.L.
      • et al.
      New decade, new FDA guidance for diabetes drug development.
      How did some of these noninsulin therapies evolve from simple HbA1c reduction to broad renal and cardiovascular (CV) risk reduction, sometimes even regardless of diabetes status? This article reviews the sequence of fundamental CV outcome trials (CVOTs) that eventually discovered the practice-changing benefits of SGT2i and GLP-1 RA; it describes the proposed mechanisms of action of these agents that are thought to be responsible for their broad cardiorenal effects; it explains how professional guidelines have changed to prioritize the use of these agents among patients with diabetes at high risk for microvascular and macrovascular complications; and it offers practical clinical advice to initiate and monitor treatment with these agents.

      Background and history

      The SGLT2i and GLP-1 RA are the culminating product of more than 12 years of rigorous CVOTs conducted on several classes of noninsulin agents. Before describing their specific properties, therefore, it is essential to understand the broader historical context and impetus that led to the systematic accumulation of data on the CV efficacy and safety of these novel antidiabetic medications.
      • Ferro E.G.
      • Michos E.D.
      • Bhatt D.L.
      • et al.
      New decade, new FDA guidance for diabetes drug development.
      Noninsulin medications have been the ideal option for patients with type 2 diabetes mellitus (T2DM): their nondependence on insulin therapy makes them suitable for agents with low risk of hypoglycemia and weight gain, which in turn can increase patient comfort and adherence. Although HbA1c was initially used as a surrogate efficacy end point in clinical trials of these agents, this glucocentric approach was first challenged when trials showed that reduction of HbA1c level could increase mortality.
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      In 2007, safety concerns emerged regarding agents such as rosiglitazone, a peroxisome proliferator activated receptor γ (PPAR-γ) that was linked to potential increase in MI and CV mortality, although these concerns were ultimately not substantiated.
      • Nissen S.E.
      • Wolski K.
      • Topol E.J.
      Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus.
      ,
      • Nissen S.E.
      • Wolski K.
      Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
      As a result, in 2008 the US Food and Drug Administration (FDA) issued a guidance for industry to evaluate the CV risk of new antidiabetes medications, which switched the focus from simple HbA1c reduction to double-blind, placebo-controlled trials to formally evaluate the impact of these medications on major adverse CV events (MACE; a composite outcome that includes CV death, nonfatal MI, or nonfatal stroke).
      • FDA Background Document
      Endocrinologic and metabolic drugs advisory committee meeting.
      Since then, 12 years of CVOTs unequivocally showed the CV safety of these agents and led to the identification of 2 drug classes with broad cardiometabolic benefits: SGLT2i and GLP-1 RA (Fig. 1).
      • Ferro E.G.
      • Michos E.D.
      • Bhatt D.L.
      • et al.
      New decade, new FDA guidance for diabetes drug development.
      ,
      • Menon V.
      • Lincoff A.M.
      Cardiovascular safety evaluation in the development of new drugs for diabetes mellitus.
      Figure thumbnail gr1
      Fig. 1Timeline of landmark events in noninsulin diabetes drug development. ↑, increased; ↓, decreased; ↔, unchanged; ACS, acute coronary syndrome; CI, confidence interval; CKD, chronic kidney disease; CVOT, cardiovascular outcome trial; DPP, dipeptidyl peptidase; FDA, US Food and Drug Administration; GLP, glucagon-like peptide; HDL, high-density lipoprotein; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; MACE, major adverse CV events; MARCE, major adverse renal and CV events; SGLT, sodium-glucose cotransporter. aHospitalization for HF is included as part of the trial primary end point.
      (Adapted from: Ferro EG, Michos ED, Bhatt DL, Lincoff AM, Elshazly MB. New Decade, New FDA Guidance for Diabetes Drug Development. Journal of the American College of Cardiology. 2020;76(21):2522-2526.)

      Glucagon-like peptide-1 receptor agonists: mechanism of action and current evidence

      To date, GLP-1 RA have been reliably associated with a significant reduction in MACE; unlike SGLT2i, however, there is limited or even conflicting evidence regarding their effect on HF and CKD.
      • Khan M.S.
      • Fonarow G.C.
      • McGuire D.K.
      • et al.
      Glucagon-like peptide 1 receptor agonists and heart failure.
      ,
      • Kristensen S.L.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      Since the 2008 FDA guidance, a total of 7 CVOTs have been conducted for GLP-1 RA; this article reviews the CVOTs related to the GLP-1 RA agents that have been formally endorsed for the reduction of ischemic CV events, namely injectable dulaglutide, liraglutide, and semaglutide (Table 1):
      • 2016: The Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes (LEADER) trial randomized 9340 patients with T2DM and established CV disease (CVD) to receive either daily subcutaneous injections of liraglutide or placebo on top of background glucose-lowering therapy. After a median follow-up of 3.8 years, liraglutide caused a 13% relative reduction in MACE (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.78–0.97; P = .01 for superiority).
        • Marso S.P.
        • Daniels G.H.
        • Brown-Frandsen K.
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
      • 2016: The Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6) trial randomized 3297 patients with T2DM and established CVD to receive either weekly subcutaneous injections of semaglutide or placebo on top of background glucose-lowering therapy. After a median follow-up of 2.1 years, semaglutide caused a 26% relative reduction in MACE (HR, 0.74; 95% CI, 0.58–0.95; P = .0001 for noninferiority).
        • Marso S.P.
        • Bain S.C.
        • Consoli A.
        • et al.
        Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      • 2018: The Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease (HARMONY) trial randomized 10,793 patients with established CVD to receive either weekly subcutaneous injections of albiglutide or placebo on top of background glucose-lowering therapy. After a median follow-up of 1.6 years, albiglutide caused a 22% relative reduction in MACE (HR, 0.78; 95% CI, 0.68–0.90; P = .0006 for superiority).
        • Hernandez A.F.
        • Green J.B.
        • 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.
        Despite receiving FDA approval, the trial sponsor pulled the drug from the market because of poor sales from boxed warnings of anaphylactic reactions and thyroid tumors.
      • 2019: The Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND) trial randomized 9901 patients with T2DM and established CV risk factors to receive either weekly subcutaneous injections of dulaglutide or placebo on top of background glucose-lowering therapy. After a median follow-up of 5.4 years, dulaglutide caused a 22% relative reduction in MACE (HR, 0.88; 95% CI, 0.79–0.99; P = .026).
        • Gerstein H.C.
        • Colhoun H.M.
        • Dagenais G.R.
        • et al.
        Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      • 2019: The Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (PIONEER 6) trial randomized 3183 patients with T2DM and established CV or renal disease, or age greater than 60 years with CV risk factors, to receive either daily oral semaglutide or placebo on top of background glucose-lowering therapy. After a median follow-up of 1.3 years, semaglutide did not result in a significant reduction in MACE (HR, 0.79; 95% CI, 0.57–1.11); thus, it did not meet superiority criteria.
        • Husain M.
        • Birkenfeld A.L.
        • Donsmark M.
        • et al.
        Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        Therefore, current guidelines support the use of dulaglutide, liraglutide, and semaglutide (injectable, not oral) for reduction of ischemic events (discussed later).
      Table 1Key cardiovascular outcome trials for glucagon-like peptide-1 receptor agonists
      LEADERSUSTAIN-6HARMONYREWINDPIONEER-6
      Trial MedicationLiraglutide SQSemaglutide SQAlbiglutide SQ
      This medication is not commercially available for use.
      Dulaglutide SQSemaglutide PO
      Year Published20162017201820192019
      Trial Participants (n)9340329710,79399013183
      Median Follow-up (y)3.82.11.65.41.3
      Mean Age (y)6363646464
      Female Sex (%)3639304632
      Mean Duration of T2DM (y)1314141115
      Established ASCVD (%)8183713185
      History of HF (%)182420912
      eGFR<60 mL/min/1.73 m2 (%)2328232227
      MACE, HR (CI)0.87 (0.78–0.97)0.74 (0.58–0.95)0.78 (0.68–0.90)0.88 (0.79–0.99)0.79 (0.57–1.11)
      All-cause Mortality,
      Secondary end points.
      HR (CI)
      0.85 (0.74–0.97)1.05 (0.74–1.50)0.95 (0.79–1.16)0.90 (0.80–1.01)0.51 (0.31–0.84)
      CV Mortality,
      Secondary end points.
      HR (CI)
      0.78 (0.66–0.93)0.98 (0.65–1.48)0.93 (0.73–1.19)0.91 (0.78–1.06)0.49 (0.27–0.92)
      MI,
      Secondary end points.
      HR (CI)
      0.86 (0.73–1.00)0.74 (0.51–1.08)0.75 (0.61–0.90)0.96 (0.79–1.15)1.18 (0.73–1.90)
      Stroke,
      Secondary end points.
      HR (CI)
      0.86 (0.71–1.06)0.61 (0.38–0.99)0.86 (0.66–1.14)0.76 (0.62–0.94)0.74 (0.35–1.57)
      HHF,
      Secondary end points.
      HR (CI)
      0.87 (0.73–1.05)1.11 (0.77–1.61)NA0.93 (0.77–1.12)0.86 (0.48–1.55)
      MARE,
      Secondary end points.
      HR (CI)
      0.78 (0.67–0.92)0.64 (0.46–0.88)0.87 (0.75–1.02)0.85 (0.77–0.93)NA
      Abbreviations: ASCVD, atherosclerotic CV disease; CI, confidence interval; eGFR, estimated glomerular filtration rate; HARMONY, Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease; HF, heart failure; HHF, hospitalizations for heart failure; HR, hazard ratio; LEADER, Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes; MACE, major adverse CV events; MARE, major adverse renal events; NA, not available; PIONEER 6, Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes; PO, per os; REWIND, Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes; SQ, subcutaneous; SUSTAIN-6, Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
      a This medication is not commercially available for use.
      b Secondary end points.
      As mentioned earlier, however, the evidence on the impact of GLP-1 RA on HF outcomes is inconclusive and potentially conflicting. Among the 7 CVOTs of GLP-1 RA, only the HARMONY trial showed a significant reduction in the secondary outcome of HHF.
      • Khan M.S.
      • Fonarow G.C.
      • McGuire D.K.
      • et al.
      Glucagon-like peptide 1 receptor agonists and heart failure.
      ,
      • Kristensen S.L.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      Furthermore, post hoc combined analyses, stratified according to the presence of HF at baseline, found reduction in all-cause mortality in the subgroup without HF, but not in the subgroup with baseline HF.
      • Fudim M.
      • White J.
      • Pagidipati N.J.
      • et al.
      Effect of once-weekly exenatide in patients with type 2 diabetes mellitus with and without heart failure and heart failure-related outcomes: insights from the EXSCEL trial.
      Moreover, preliminary data suggest that GLP-1 RA may worsen outcomes among patients with HFrEF: among the 3 small randomized GLP-1 RA trials in patients with HFrEF, 2 showed higher rates of adverse events (including death) in the experimental arm.
      • Jorsal A.
      • Kistorp C.
      • Holmager P.
      • et al.
      Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial.
      ,
      • Margulies K.B.
      • Hernandez A.F.
      • Redfield M.M.
      • et al.
      Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial.
      Although no trials of GLP-1 RA have been conducted among patients with HF with preserved ejection fraction (HFpEF), mechanistic insight suggests that this class of medications could exert both positive and negative effects in this specific subpopulation, which need to be further explored through randomized clinical trials.
      On the one hand, GLP-1 receptors have been localized in the sinoatrial node, where their excessive activation by GLP-1 RA may result in potential arrythmias or even simple sinus tachycardia, which has an established association with worse outcomes among patients with HFrEF.
      • Pyke C.
      • Heller R.S.
      • Kirk R.K.
      • et al.
      GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody.
      On the other hand, the action of GLP-1 RA in reducing the appetite level in the brain, or their ability to slow gastric emptying, leads to significant weight loss
      • Myat A.
      • Redwood S.R.
      • Arri S.
      • et al.
      Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS): a double-blind randomised placebo-controlled crossover trial.
      ; this, in turn may reduce blood pressure, diastolic filling pressures, and adverse clinical events among patients with HFpEF.
      • Khan M.S.
      • Fonarow G.C.
      • McGuire D.K.
      • et al.
      Glucagon-like peptide 1 receptor agonists and heart failure.
      These preliminary mechanistic insights call for dedicated randomized trials powered to specifically study the efficacy and safety of GLP-1 RAs in patients with T2DM and HFrEF or HFpEF.
      From a renal perspective, the GLP-1 receptor is also expressed in the kidneys, where its activation reduces the production of reactive oxygen species and associated oxidative injury. Although individual GLP-1 RA trials were not powered to directly assess renal outcomes, this may explain why meta-analyses identified a significant reduction in the composite risk of macroalbuminuria, doubling of serum creatinine, end-stage renal disease, and renal deaths among patients with diabetes.
      • Kristensen S.L.
      • Rørth R.
      • Jhund P.S.
      • et al.
      Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      Once again, however, these mechanistic insight and preliminary data call for dedicated randomized trials of GLP-1 RA among patients with diabetes and CKD.

      Sodium-glucose cotransporter-2 inhibitors

      Mechanism of Action

      The broad cardiorenal benefits identified in SGLT2i trials (discussed later) have prompted researchers to carefully characterize their direct mechanisms of action, as well as the indirect effect they may exert on hemodynamics and metabolism, in order to understand the full spectrum of potential therapeutic applications.
      Their most intuitive effect is the direct inhibition of the sodium-glucose cotransporter (SGLT), which exists in 6 isoforms in the human body. Of these, the most important are SGLT1 and SGLT2. SGLT1 is predominantly found in the small intestines, where its inhibition results in delay in glucose absorption and reduction in postprandial glycemia; it is additionally found in the terminal part of the proximal tubule of the kidney, where it mediates about 10% of renal glucose reabsorption. SGLT2, instead, is found in the initial part of the proximal tubule of the kidney, where it mediates about 90% of renal glucose reabsorption. SGLT is a cotransporter, because it allows glucose to enter the renal tubular cell against its concentration gradient by coupling it with sodium entry according to its concentration gradient, which is actively maintained by the well-known sodium-potassium pump. Glucose can then exit the renal tubular cell to enter the blood stream down its concentration gradient.
      • Zelniker T.A.
      • Braunwald E.
      Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review.
      Patients with T2DM are known to express a significantly higher number of SGLT2s in the proximal tubule, which greatly increases glucose reabsorption and hyperglycemia in their blood. As a result, SGLT inhibitors were developed to selectively target SGLT2 in the kidney. To date, 4 SGLT2i have been approved by the FDA for the treatment of T2DM. In order of decreasing selectivity for SGLT2, these are empagliflozin, ertugliflozin, dapagliflozin, and canagliflozin. An SGLT2/1 inhibitor, sotagliflozin, is also being studied (discussed later).
      The reduction in glucose reabsorption in the kidneys is the most intuitive and beneficial mechanism of action of SGLT2i. As explained earlier, however, they also inhibit sodium reabsorption in the kidneys, which generates a cascade of indirect and supposedly beneficial changes in hemodynamics. Less sodium reabsorption leads to less water reabsorption, which effectively generates a diuretic effect and decreases plasma volume. This process explains how SGLT2i decrease both preload and afterload, and lead to a reduction in both systolic and diastolic blood pressure,
      • Verma S.
      • Mazer C.D.
      • Yan A.T.
      • et al.
      Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial.
      ,
      • Kario K.
      • Okada K.
      • Kato M.
      • et al.
      24-hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: results from the randomized, placebo-controlled SACRA study.
      which is achieved without a concurrent increase in heart rate. Perhaps, this happens because the decrease in plasma volume increases the hematocrit and does not compromise the oxygen-carrying capacity of the blood; it is also possible that SGLT2i are able to increase the hematocrit by directly promoting renal erythropoietin release.
      • Bhatt D.L.
      • Verma S.
      • Braunwald E.
      The DAPA-HF trial: a momentous victory in the war against heart failure.
      The combination of these effects may explain the benefits of SGLT2i in reducing HHF among patients with HFrEF, regardless of diabetes status.
      In addition to CV hemodynamics, studies have shown that SGLT2i may exert a beneficial effect on the heart through broader cardiometabolic activity. For example, the constant glycosuria leads not just to weight loss but also to a metabolic shift in favor of free fatty acid oxidation; in turn, this increases beta-hydroxybutyrate consumption by the heart, which optimizes mitochondrial function in the cardiac myocytes and ultimately improves myocardial function. This metabolic switch may contribute to reducing epicardial fat; thus, decreasing noxious stimuli that can promote the inflammation and fibrosis associated with HF. Ongoing research is trying to elucidate how these processes at the cellular level alter the overall cardiac structure and function: recent randomized trials among patients with T2DM found that, compared with placebo, both empagliflozin and dapagliflozin significantly reduced left ventricular mass index (measured with cardiac MRI), which is a known predictor of MACE, a benefit that was noted as early as 6 to 12 months after treatment initiation, and independently of the concurrent reduction in blood pressure.
      • Verma S.
      • Mazer C.D.
      • Yan A.T.
      • et al.
      Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial.
      ,
      • Brown A.J.M.
      • Gandy S.
      • McCrimmon R.
      • et al.
      A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH trial.
      In a more recent randomized trial among patients with HFrEF without diabetes, empagliflozin showed significant reduction in left ventricular mass and volume as well as increased systolic function, compared with control.

      Santos-Gallego CG, Vargas-Delgado AP, Requena JA, et al. Randomized trial of empagliflozin in non-diabetic patients with heart failure and reduced ejection fraction. J Am Coll Cardiol 2021;77(3):243-55.

      In addition, some of the SGLT2i have also been found to cross-react with the cardiac sodium-hydrogen exchanger, which has been linked to decreased arrythmia burden.
      • Zelniker T.A.
      • Bonaca M.P.
      • Furtado R.H.M.
      • et al.
      Effect of dapagliflozin on atrial fibrillation in patients with type 2 diabetes mellitus.
      Given the well-established connection between cardiac and renal hemodynamics (such as the cardiorenal syndrome in patients with HF), it is possible that the beneficial effects of SGLT2i on cardiac performance translate indirectly to improved renal performance and slow the progression of CKD. In addition, it is thought that SGLT2i exert a direct effect on intrarenal hemodynamics. Surprisingly, the decrease in preload associated with their diuretic effect has not been found to promote the activation of the renin-angiotensin-aldosterone system, which prevents the increase in intraglomerular pressure. The increase in sodium contained in the tubular fluid (which is not reabsorbed by the inhibited SGLT2 transporter) may promote a tubuloglomerular feedback that leads to vasodilation of the efferent glomerular arteriole and further reduces intraglomerular pressure. Taken together, these nephroprotective effects may explain the beneficial effect of SGLT2i in reducing renal mortality among patients with CKD, regardless of diabetes status.
      • Zelniker T.A.
      • Braunwald E.
      Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review.

      Sodium-Glucose Cotransporter-2 Inhibitors: Current Evidence for MACE Outcomes

      Since 2015, all 4 SGLT2i have been evaluated in the context of double-blinded, placebo-controlled clinical trials: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. The first generation of SGLT2i trials were traditional CVOTs designed to show the CV safety of these medications; therefore, they compared SGLT2i with placebo (Table 2):
      • 2015: The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial randomized 7020 patients with T2DM and established CVD to receive either empagliflozin or placebo on top of background glucose-lowering therapy. After a median follow-up of 3.1 years, empagliflozin caused a 14% relative reduction in MACE (HR, 0.86; 95% CI, 0.74–0.99; P = .04 for superiority).
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      • 2017: The Canagliflozin Cardiovascular Assessment Study (CANVAS) trial randomized 10,142 patients with T2DM, who were required to have established CVD or at least 2 CV risk factors, to receive either canagliflozin or placebo on top of background glucose-lowering therapy. After a median follow-up of 2.4 years, canagliflozin also caused a 14% relative reduction in MACE (HR, 0.86; 95% CI, 0.75–0.97; P<.001 for noninferiority; P = .02 for superiority).
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      • 2018: The Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) trial randomized 17,160 patients with T2DM and either established CVD or multiple CV risk factors to receive either dapagliflozin or placebo on top of background glucose-lowering therapy. After a median follow-up of 4.2 years, dapagliflozin did not cause a significant reduction in MACE (HR, 0.93; 95% CI, 0.84–1.03), although it met criteria for noninferiority. However, unlike prior trials, DECLARE-TIMI 58 evaluated an additional primary composite outcome of CV mortality or HHF. Notably, this coprimary outcome was added over the course of the trial in response to external data that suggested the prevention of HHF was a major unexpected benefit of SGLT2i (discussed later). As a result, dapagliflozin caused a 17% relative reduction in CV mortality or HHF (HR, 0.83; 95% CI, 0.73–0.95; P = .005 for superiority), which was primarily driven by a 27% relative reduction in HHF (HR, 0.73; 95% CI, 0.60–0.88), with no significant between-group difference in CV mortality.
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      • 2020: The Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS CV) trial randomized 8246 patients with T2DM and established CVD to receive either ertugliflozin or placebo on top of background glucose-lowering therapy. After a median follow-up of 3.5 years, ertugliflozin did not cause a significant reduction in MACE (HR, 0.97; 95% CI, 0.85–1.11), although it met criteria for noninferiority.
        • Cannon C.P.
        • Pratley R.
        • Dagogo-Jack S.
        • et al.
        Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      Table 2First generation of cardiovascular outcome trials for sodium-glucose cotransporter-2 inhibitors
      EMPA-REG OUTCOMECANVASDECLARE-TIMI-58VERTIS CV
      Trial MedicationEmpagliflozinCanagliflozinDapagliflozinErtugliflozin
      Year Published2015201720182020
      Trial Participants (n)702010,14217,1608246
      Median Follow-up (y)3.12.44.23.5
      Mean Age (y)63636464
      Female Sex (%)29363730
      Mean Duration of T2DM (y)>10141113
      Established ASCVD (%)100664176
      History of HF (%)10141024
      eGFR <60 mL/min/1.73 m2 (%)2620722
      MACE, HR (CI)0.86 (0.74–0.99)0.86 (0.75–0.97)0.93 (0.84–1.03)0.97 (0.85–1.11)
      All-cause Mortality,
      Secondary end points.
      HR (CI)
      0.68 (0.57–0.82)0.87 (0.74–1.01)0.93 (0.82–1.04)0.93 (0.80–1.08)
      CV Mortality,
      Secondary end points.
      HR (CI)
      0.62 (0.49–0.77)0.87 (0.72–1.06)0.98 (0.82–1.17)0.92 (0.77–1.11)
      MI,
      Secondary end points.
      HR (CI)
      0.87 (0.70–1.09)0.85 (0.69–1.05)0.89 (0.77–1.01)1.00 (0.86–1.27)
      Stroke,
      Secondary end points.
      HR (CI)
      1.24 (0.92–1.67)0.90 (0.71–1.15)1.01 (0.84–1.21)1.00 (0.76–1.32)
      CV Mortality + HHF, HR (CI)NANA0.83 (0.73–0.95)NA
      HHF,
      Secondary end points.
      HR (CI)
      0.65 (0.50–0.85)0.67 (0.52–0.87)0.73 (0.60–0.88)0.70 (0.54–0.90)
      MARE,
      Secondary end points.
      HR (CI)
      0.54 (0.40–0.75)0.60 (0.47–0.77)0.53 (0.43–0.66)0.81 (0.63–1.04)
      Abbreviations: CANVAS, Canagliflozin Cardiovascular Assessment Study; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events; EMPA-REG OUTCOME, Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes; T2DM, type 2 diabetes mellitus; VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes.
      a Secondary end points.

      Sodium-Glucose Cotransporter-2 Inhibitors: Current Evidence for HF Outcomes

      It is important to understand that the aforementioned 2008 FDA guidance only made a general recommendation to enrich trials with patients at higher risk for CV events and mandated the inclusion of a primary MACE outcome that was focused on the atherosclerotic complications of diabetes.
      • FDA Background Document
      Endocrinologic and metabolic drugs advisory committee meeting.
      The guidance did not provide any formal recommendations with regard to enrollment of patients with HF, nor the evaluation of related outcomes such as HHF. However, trials sponsors proactively began to include HHF as part of secondary outcomes, based on concerning HF signals from prior trials of dipeptidyl peptidase-4 (DPP4) inhibitors.
      • Udell J.A.
      • Cavender M.A.
      • Bhatt D.L.
      • et al.
      Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials.
      Unexpectedly, the cumulative evidence from the first generation of SGLT2i trials showed that these agents had a more consistent and robust effect on the prevention of HF events (and renal outcomes, as discussed later) compared with atherosclerotic CV events (see Table 2):
      • In the EMPA-REG OUTCOME trial, empagliflozin caused a 35% relative reduction (HR, 0.65; 95% CI, 0.50–0.85; P = .002) in the secondary exploratory outcome of HHF.
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      • In the CANVAS trial, canagliflozin caused a 33% relative reduction (HR, 0.67; 95% CI, 0.52–0.87) in the secondary exploratory outcome of HHF, although from the prespecified hypothesis-testing sequence, this finding could not be claimed as statistically significant.
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      • It was because of these favorable exploratory analyses that the protocol of the DECLARE-TIMI 58 trial (discussed earlier) was amended to formally include a coprimary end point of CV mortality or HHF, which was found to be significantly reduced among patients randomized to dapagliflozin, and primarily driven by a 27% relative reduction in HHF (HR, 0.73; 95% CI, 0.60–0.88).
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      Despite these encouraging findings, it is critical to highlight that, in all these trials, the reported prevalence of HF at the time of enrollment was low (10%–14%), and there was minimal characterization of the baseline HF phenotype (ie, ejection fraction [EF], New York Heart Association [NYHA] Functional Classification) and use of concurrent guideline-directed medical therapy (GDMT).
      • Menon V.
      • Lincoff A.M.
      Cardiovascular safety evaluation in the development of new drugs for diabetes mellitus.
      ,
      • Butler J.
      • Packer M.
      • Greene S.J.
      • et al.
      Heart failure end points in cardiovascular outcome trials of sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a critical evaluation of clinical and regulatory issues.
      Therefore, it was assumed that the benefit of SGLT2i was mainly in the prevention of new-onset HF and associated hospitalizations. Nonetheless, these observations called for dedicated trials among patients with HF, which led to the second generation of SGLT2i trials, in which the traditional MACE primary outcome was substituted with a primary outcome of CV mortality or HHF (Table 3):
      • 2019: The Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial randomized 4744 patients with HFrEF (EF ≤ 40%) and NYHA class II, III, or IV to receive either dapagliflozin or placebo on top of background recommended diabetes and HF therapy. After a median follow-up of 1.5 years, dapagliflozin caused a 26% relative reduction (HR, 0.74; 95% CI, 0.65–0.85; P<.001) in CV mortality, HHF, and urgent visits for intravenous diuresis. In a prespecified subgroup analysis, the magnitude of this benefit was similar for patients with HF with (n = 2139) and without (n = 2605) T2DM.
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
      • 2020: The Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR-Reduced) trial randomized 3730 patients with HFrEF (EF ≤ 40%) and NYHA class II, III, or IV to receive either empagliflozin or placebo on top of background recommended diabetes and HF therapy. After a median follow-up of 1.3 years, empagliflozin caused a 25% relative reduction (HR, 0.75; 95% CI, 0.65–0.86; P<.001) in CV mortality and HHF. Importantly, the magnitude of this benefit was once again reproduced both in patients with (n = 1856) and without (n = 1874) T2DM.
        • Packer M.
        • Anker S.D.
        • Butler J.
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
      • 2020: The Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial randomized 1222 patients with diabetes and either HFrEF (EF<50%) or HFpEF (EF ≥ 50%) and increased N-terminal B-type natriuretic peptide (NT pro-BNP), who were recently hospitalized for worsening HF and had been clinically stabilized (ie, no hypotension or need for supplemental oxygen, intravenous inotropic therapy, or intravenous diuretics). These patients were randomized to receive either sotagliflozin (a novel SGLT1/2 inhibitor) or placebo on top of GDMT. The trial was terminated early because of loss of funding from the sponsor at the onset of the coronavirus disease 2019 (COVID-19) pandemic, resulting in a smaller sample size and shorter follow-up duration than anticipated. Nonetheless, after a median follow-up of 0.75 years, sotagliflozin caused a 33% relative reduction (HR, 0.67; 95% CI, 0.52–0.85; P = .0009) in the primary end point of total CV deaths, HHF, and urgent visits for HF. The prespecified subgroup analysis also suggested, for the first time in the history of SGLT2i trials (or with any other drug class for HF), a significant reduction in the primary outcome in both HFrEF and patients with HFpEF (discussed later).
        • Bhatt D.L.
        • Szarek M.
        • Steg P.G.
        • et al.
        Sotagliflozin in patients with diabetes and recent worsening heart failure.
      Table 3Second generation of heart failure–focused trials for sodium-glucose cotransporter-2 inhibitors
      DAPA-HFEMPEROR-ReducedSOLOIST
      Trial MedicationDapagliflozinEmpagliflozinSotagliflozin
      Year Published201920202020
      Trial Participants (n)474437301222
      Median Follow-up (y)1.51.30.75
      Mean Age (y)66.466.969.5
      Female Sex (%)232434
      T2DM (%)4250100
      Ejection Fraction (Mean)312735
      NYHA Classification (%)
      Class II687545
      Class III312446
      Class IV114
      eGFR<60 mL/min/1.73 m2 (%)414870
      CV Mortality + HHF, HR (CI)0.74 (0.65–0.85)
      Also includes urgent visits for HF.
      0.75 (0.65–0.86)0.67 (0.52–0.85)
      Also includes urgent visits for HF.
      All-cause Mortality,
      Secondary end points.
      HR (CI)
      0.83 (0.71–0.97)0.92 (0.77–1.10)0.82 (0.59–1.14)
      HHF,
      Secondary end points.
      HR (CI)
      0.70 (0.59–0.83)0.69 (0.59–0.81)0.64 (0.49–0.83)
      MARE,
      Secondary end points.
      HR (CI)
      0.71 (0.44–1.16)0.50 (0.32–0.77)NA
      Abbreviations: DAPA-HF, Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction; EMPEROR-Reduced, Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure; SOLOIST, Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes.
      a Secondary end points.
      b Also includes urgent visits for HF.
      Taken together, these groundbreaking results support the notion of a class benefit for SGLT2i in the improvement of HF outcomes. In 2020 the FDA approved a label expansion for dapagliflozin for the treatment of HFrEF in adults with and without T2DM, marking the first time that a drug class developed for diabetes was successfully repurposed to treat HF, even when diabetes is not present.
      • FDA News Release
      FDA approves new treatment for a type of heart failure.
      As the FDA prepares to update its recommendation in a proposed 2020 guidance to industry,
      • FDA Guidance Document
      Type 2 diabetes mellitus: evaluating the safety of new drugs for improving glycemic control guidance for industry.
      the authors and others have advocated that future trials of novel antidiabetes medications should be required to enroll a number of patients with HF proportional to the real-world prevalence of HF with diabetes (ie, 20%–30%), with a sufficiently high risk of HF decompensation, detailed characterization of their phenotype (ie, EF, NYHA) at enrollment, mandatory administration of background GDMT (eg, β-blockers, angiotensin-converting enzyme inhibitors [ACEi]/angiotensin receptor blockers [ARBs]) to clearly identify any incremental cardiometabolic benefit of novel drugs, and formal inclusion of HHF among the primary trial end points.
      • Ferro E.G.
      • Michos E.D.
      • Bhatt D.L.
      • et al.
      New decade, new FDA guidance for diabetes drug development.

      Sodium-Glucose Cotransporter-2 Inhibitor: Current Evidence for Chronic Kidney Disease Outcomes

      Even though the SGLT2i primary mechanism of action targets sodium and glucose transporters in the renal tubules (discussed earlier), the 2008 FDA guidance did not mandate the formal inclusion of renal outcomes among the primary end points of CVOTs,
      • FDA Background Document
      Endocrinologic and metabolic drugs advisory committee meeting.
      because the broad cardiometabolic impact of these and other novel antidiabetes drugs was not well understood at that time. However, similarly to HHF, trial sponsors also included renal events as part of secondary outcomes, based on the understanding that diabetes is a fundamental risk factor for CKD/end-stage renal disease (ESRD), and the similar risk of MACE and CKD progression among patients with T2DM.
      • Kluger A.Y.
      • Tecson K.M.
      • Barbin C.M.
      • et al.
      Cardiorenal outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME trials: a systematic review.
      Because SGLT2i act at the level of the renal tubules, it was also important to prespecify the severity of baseline kidney disease in the inclusion and exclusion criteria, given the expectation for reduced pharmacodynamic response in patients with more advanced CKD. Similarly to HHF, the cumulative evidence from the first generation of SGLT2i trials showed that these agents had a more consistent and robust effect on the prevention of major adverse renal events (MAREs) compared with atherosclerotic CV events (see Table 2).
      • In the EMPA-REG OUTCOME trial (discussed earlier), where patients needed an estimated glomerular filtration rate (eGFR, defined in milliliters per minute per 1.73 m2) greater than 30 for enrollment, empagliflozin caused a 46% relative reduction (HR, 0.54; 95% CI, 0.40–0.75; P<.001) in the secondary MARE outcome, defined as doubling of serum creatinine level accompanied by eGFR less than or equal to 45, initiation of renal-replacement therapy (RRT), or renal death.
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      • In the CANVAS trial (discussed earlier), where patients needed eGFR greater than 30 for enrollment, canagliflozin caused a 40% relative reduction (HR, 0.60; 95% CI, 0.47–0.77; P<.001) in the secondary MARE outcome, defined as 40% reduction in eGFR sustained for at least 2 consecutive measures, initiation of RRT, or renal death.
        • 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 (discussed earlier), where patients needed a creatinine clearance greater than 60 mL/min (but no minimum eGFR) for enrollment, dapagliflozin caused a 47% relative reduction (HR, 0.53; 95% CI, 0.43–0.66; P<.001) in the secondary MARE outcome, defined as 40% reduction in eGFR to less than 60, progression to ESRD (including need for RRT), or renal or CV death. Notably, this was an example of a composite outcome that integrated both major adverse cardiac and renal events (MARCEs).
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      Despite these encouraging findings, it is critical to highlight that these trials primarily recruited patients with high CV risk but with overall low risk for kidney failure. As a result, even if they enrolled an average of 1700 patients with CKD, they were still considered underpowered to unequivocally show renal benefit.
      • Kluger A.Y.
      • Tecson K.M.
      • Barbin C.M.
      • et al.
      Cardiorenal outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME trials: a systematic review.
      • Rangaswami J.
      • Soman S.
      • McCullough P.A.
      Key updates in cardio-nephrology from 2018: springboard to a bright future.
      • Kluger A.Y.
      • Tecson K.M.
      • Lee A.Y.
      • et al.
      Class effects of SGLT2 inhibitors on cardiorenal outcomes.
      This finding was further jeopardized by variability both in enrollment criteria (ie, eGFR vs creatinine clearance) and definition of MARE or MARCE. Nonetheless, these observations called for dedicated and structured trials among patients with CKD, which led to the second generation of SGLT2i trials, in which the traditional MACE primary outcome was substituted with a primary MARCE outcome (Table 4):
      • 2019: The Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE) trial randomized patients with T2DM and associated CKD (eGFR 30–90 and albuminuria, namely urine albumin/creatinine ratio 300–5000 mg/g) to receive either canagliflozin or placebo on top of background renin-angiotensin system blockade. The trial was terminated early (with a median follow-up of 2.6 years and 4401 randomized patients), because, in a planned interim analysis, canagliflozin caused a 30% relative reduction (HR, 0.70; 95% CI, 0.59–0.82; P = .00001) in the primary MARCE outcome, defined as ESRD (RRT, renal transplant, or sustained eGFR <15), doubling of serum creatinine level, or renal or CV death.
        • Perkovic V.
        • Jardine M.J.
        • Neal B.
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      • 2020: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) trial randomized 4304 patients with CKD (eGFR 25–75 and albuminuria, namely urine albumin/creatinine ratio ≥200 mg/g) to receive either dapagliflozin or placebo on top of background renin-angiotensin system blockade. With a median follow-up of 2.4 years, dapagliflozin caused a 39% relative reduction (HR, 0.61; 95% CI, 0.51–0.72; P = .000000028) in the primary MARCE outcome, defined as sustained greater than or equal to 50% eGFR decline, ESRD, and renal or CV death. In a prespecified subgroup analysis, the magnitude of this benefit was similar for patients with CKD with or without T2DM.
        • Heerspink H.J.L.
        • Stefánsson B.V.
        • Correa-Rotter R.
        • et al.
        Dapagliflozin in patients with chronic kidney disease.
      • 2020: The Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial randomized 10,584 patients with T2DM and CKD (eGFR 25–60), notably with or without albuminuria, to receive either sotagliflozin (a novel SGLT2/1 inhibitor) or placebo on top of background renin-angiotensin system blockade. The trial was terminated early because of loss of funding from the sponsor at the onset of the COVID-19 pandemic; nonetheless, after a median follow-up of 1.3 years, sotagliflozin caused a 26% relative reduction (HR, 0.74; 95% CI, 0.63–0.88; P = .0004) in the modified primary end point of total CV deaths, HHF, and urgent visits for HF. Despite early termination, the trial remained adequately powered to show a 16% relative reduction in the original coprimary MACE safety end point (HR, 0.84; 95% CI, 0.72–0.99) and a 23% relative reduction in the original coprimary efficacy end point of CV deaths and HHF (HR, 0.77; 95% CI, 0.66–0.91). However, early stopping did result in an insufficient number of events to formally evaluate the prespecified MARE outcomes, where no significant improvement was found compared with placebo.
        • Bhatt D.L.
        • Szarek M.
        • Pitt B.
        • et al.
        Sotagliflozin in patients with diabetes and chronic kidney disease.
      • 2022: The Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) trial will complete enrollment of patients with CKD (eGFR 20–45 or 45–90 with urine albumin/creatinine ratio ≥200 mg/g), randomized to receive either empagliflozin or placebo on top of background renin-angiotensin system blockade. It will assess a primary MARCE outcome, defined as ESRD, sustained greater than or equal to 40% eGFR decline, and renal or CV death.
        EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin).
      Table 4Second generation of chronic kidney disease–focused trials for sodium-glucose cotransporter-2 inhibitors
      CREDENCEDAPA-CKDSCORED
      Trial MedicationCanagliflozinEmpagliflozinSotagliflozin
      Year Published201920202020
      Trial Participants (n)4401430410,584
      Median Follow-up (y)2.62.41.3
      Mean Age (y)636269
      Female Sex (%)343344
      T2DM (%)10067100
      Established ASCVD (%)504788
      History of HF (%)151131
      Mean eGFR (mL/min/1.73 m2)564344
      eGFR <60 mL/min/1.73 m2 (%)4090100
      Albumin/Creatinine Ratio (Median, IQR)927 (463–1833)950 (477–1886)74 (17–482)
      CV Mortality + HHF, HR (CI)NANA0.77 (0.66–0.91)
      MARCE, HR (CI)0.70 (0.59–0.82)0.61 (0.51–0.72)NA
      All-cause Mortality,
      Indicates secondary end points.
      HR (CI)
      0.83 (0.68–1.02)0.69 (0.53–0.88)0.99 (0.83–1.18)
      CV Mortality,
      Indicates secondary end points.
      HR (CI)
      0.78 (0.61–1.00)0.81 (0.58–1.12)0.90 (0.73–1.12)
      MARE,
      Indicates secondary end points.
      HR (CI)
      0.66 (0.53–0.81)0.56 (0.45–0.68)0.69 (0.38–1.25)
      Abbreviations: CREDENCE, Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy; DAPA-CKD, Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease; MARCE, major adverse renal and CV event; SCORED, Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk.
      a Indicates secondary end points.
      Taken together, these groundbreaking results support the notion that SGLT2i improve renal outcomes in CKD even when diabetes is not present, and have already resulted in a label expansion for dapagliflozin for the treatment of patients with albuminuric CKD, even when diabetes is not present. This approval marks the first time a new agent has been added for renoprotection since renin-angiotensin system blockade was introduced in 2001.
      • Kluger A.Y.
      • Tecson K.M.
      • Lee A.Y.
      • et al.
      Class effects of SGLT2 inhibitors on cardiorenal outcomes.
      As the FDA prepares to update their recommendation in a proposed 2020 guidance to industry,
      • FDA Guidance Document
      Type 2 diabetes mellitus: evaluating the safety of new drugs for improving glycemic control guidance for industry.
      the agency plans to increase the focus on CKD by mandating that at least 500 patients with stage 3or 4 CKD are included in each trial. The authors and others have additionally advocated that the FDA closely and routinely monitors whether this number of patients with CKD is sufficient to assess both the safety and the efficacy of novel antidiabetes medications, and that trials expand the traditional MACE end point to major adverse renal, CV, and HF events (MARCHE), effectively transitioning from traditional CVOTs to a new generation of cardiorenal outcome trials that can holistically capture the multiorgan effects of these agents.
      • Ferro E.G.
      • Michos E.D.
      • Bhatt D.L.
      • et al.
      New decade, new FDA guidance for diabetes drug development.

      Sodium-glucose cotransporter-2 inhibitors: future directions

      Given the pleiotropic mechanism of action of SGLT2i (discussed earlier), ongoing clinical trials are exploring other potential therapeutic applications of these agents in the cardiometabolic field.
      Most importantly, HFpEF remains an extremely common but elusive disease for which no therapeutic option has convincingly reduced morbidity or mortality until SOLOIST and SCORED (both discussed earlier).
      • Solomon S.D.
      • McMurray J.J.V.
      • Anand I.S.
      • et al.
      Angiotensin–eprilysin inhibition in heart failure with preserved ejection fraction.
      Given their ability to reduce left ventricular mass and noxious stimuli that promote myocardial fibrosis (discussed earlier), SGLT2i have the right characteristics of a drug to treat patients with HFpEF, and this is being further studied by the following trials (Table 5):
      • 2020: For the first time in the history of SGLT inhibitor and HFpEF studies, in the SOLOIST-WHF trial (discussed earlier), a prespecified subgroup analysis suggested a significant reduction in the modified primary outcome (CV deaths, HHF, and urgent visits for HF) in both HFrEF (HR, 0.72; CI, 0.56–0.94) and patients with HFpEF (HR, 0.48; CI, 0.27–0.86) receiving the novel SGLT1/2 inhibitor sotagliflozin, compared with control. This finding was confirmed in a pooled analysis of SOLOIST and SCORED. These results with sotagliflozin are likely a class effect applicable to other SGLT2 inhibitors as well.
      • 2020: The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) trial will complete enrollment of patients with HFpEF (EF>40%), NYHA class II, III, or IV, and increased NT pro-BNP level, randomized to receive either empagliflozin or placebo in addition to GDMT. It will assess a primary outcome of CV mortality or HHF.
        EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure with preserved ejection fraction (EMPEROR-Preserved).
      • 2021: The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial will complete enrollment of patients with HFpEF (EF>40%), NYHA class II, III, or IV, and increased NT pro-BNP level, randomized to receive either dapagliflozin or placebo on top of GDMT. It will assess a primary outcome of CV mortality, HHF, or urgent HF visit.
        Dapagliflozin evaluation to improve the LIVEs of patients with PReserved ejection fraction heart failure. (DELIVER).
      Table 5Ongoing trials for sodium-glucose cotransporter-2 inhibitors in acute coronary syndrome and heart failure with preserved ejection fraction
      EMPACT-MIEMPEROR-PreservedDELIVER
      Trial MedicationEmpagliflozinEmpagliflozinDapagliflozin
      Expected Year of Completion202220212021
      Target PopulationACSHFpEFHFpEF
      Expected Trial Participants (n)331259886100
      Median Expected Follow-up (y)2.03.22.8
      Primary End PointCV Mortality + HHFCV Mortality + HHFCV Mortality + HHF
      Abbreviations: ACS, acute coronary syndrome; EMPACT-MI, Study to Test Whether Empagliflozin Can Lower the Risk of Heart Failure and Death in People Who Had a Heart Attack; EMPEROR-Preserved, Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure.
      Another therapeutic area that will actively be explored is for patients with acute MI, because SGLT2i may help prevent the postinfarction cardiac remodeling that has been associated with the development and progression of ventricular dysfunction:
      • 2022: The Study to Test Whether Empagliflozin Can Lower the Risk of Heart Failure and Death in People Who Had a Heart Attack (EMPACT-MI) trial will complete enrollment of patients with a recent (<14 days) type I myocardial infarction and no prior HF (both with and without T2DM), randomized to receive either empagliflozin or placebo on top of background medical therapy. It will assess a primary outcome of all-cause mortality and first HHF.
        Dapagliflozin evaluation to improve the LIVEs of patients with PReserved ejection fraction heart failure. (DELIVER).

      Sodium-glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor agonist: guideline recommendations and real-world uptake

      The broad cardiometabolic benefits of SGLT2i and GLP-1 RA were so well received by the medical community that they led to a fundamental revision of treatment protocols for patients with diabetes, CVD, and renal disease. This revision is reflected in all major international guidelines, which now recommend these agents as first-line treatment concurrently with metformin (if renal clearance allows), or even as first line and independently of glycemic control:
      • The 2020 expert consensus decision pathway on novel therapies for CV risk reduction in patients with type 2 diabetes by the American College of Cardiology (ACC) recommends initiation of SGLT2i or GLP-1 RA in patients with established atherosclerotic CVD (ASCVD) or high CV risk, and preferentially SGLT2i in patients with HF or diabetic kidney disease with eGFR greater than 30; there is no need to start metformin before these agents for the purpose of cardioprotection; metformin should be considered primarily for glucose-lowering purposes.
        • Das S.R.
        • Everett B.M.
        • Birtcher K.K.
        • et al.
        2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology solution set oversight committee.
      • The 2020 consensus statement on the comprehensive type 2 diabetes management by the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) recommends that, independent of glycemic control, SGLT2i and/or GLP-1 RA be initiated in patients with either established ASCVD or high CV risk; metformin is required in any combination therapy for glucose-lowering purposes, but not for cardioprotection.
        • Garber A.J.
        • Handelsman Y.
        • Grunberger G.
        • et al.
        Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 executive summary.
      • The 2019 consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends that, after first-line background therapy with metformin, GLP-1 RA be initiated in patients with predominant ASCVD, and SGLT2i be initiated in patients with predominant HF (especially HFrEF with EF <45%) and/or CKD (with eGFR 30–60 and/or urine albumin/creatinine ratio >30 mg/g), independent of glycemic control.
        • Buse J.B.
        • Wexler D.J.
        • 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).
      • The 2019 guidelines on diabetes, prediabetes, and CVDs developed by the European Society of Cardiology (ESC) and EASD have a class I recommendation to use of either SGLT2i or GLP-1 RA as first-line monotherapy in patients with T2DM and either ASCVD or high CV risk, with the option to subsequently add metformin for glucose-lowering purposes. Among those, the SGLT2i empagliflozin and the GLP-1 RA liraglutide have a class I recommendation to reduce the risk of death in this population.
        • Cosentino F.
        • Grant P.J.
        • Aboyans V.
        • et al.
        2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      These recommendations should be interpreted with the understanding that SGLT2i and GLP-1 RA are not interchangeable medications: although the broad benefits of SGLT2i on CKD and HFrEF have been repeatedly shown in dedicated trials, there is limited and inconclusive evidence on the effect of GLP-1 RA beyond reduction of ischemic events.
      Nonetheless, it is hoped that recommendations from professional guidelines will increase the much-needed uptake of these novel antidiabetes medications in routine medical practice; despite their robust benefit in patients with diabetes but also HFrEF and CKD, the real-world use of these agents is currently low. For example, a retrospective study evaluated the use of SGLT2i and GLP-1 RA in a nationwide United States registry designed to describe longitudinal cholesterol treatment patterns among patients with ASCVD.
      • Arnold S.V.
      • de Lemos J.A.
      • Rosenson R.S.
      • et al.
      Use of guideline-recommended risk reduction strategies among patients with diabetes and atherosclerotic cardiovascular disease.
      This study examined 5006 patients (of whom 35% had T2DM and 17% had HF) enrolled between 2016 and 2018, namely 1 to 2 years after the publication of the aforementioned key CVOTs. Surprisingly, they found that SGLT2i and GLP-1 RA use was low at 9.0% and 7.9%, respectively, compared with concurrent high use of ACEi or ARB (72%), or even sulfonylureas (>20%); as a result, only 6.9% of the patients met criteria for optimal medical management for secondary prevention.
      • Arnold S.V.
      • de Lemos J.A.
      • Rosenson R.S.
      • et al.
      Use of guideline-recommended risk reduction strategies among patients with diabetes and atherosclerotic cardiovascular disease.
      The slow uptake of these medications may be caused by their being particularly underused outside of endocrine practices. Another retrospective study calculated the first-time outpatient prescriptions of SGLT2i across the largest multicenter health care system in Massachusetts (Mass General Brigham) from 2013 (when the first SGLT2i gained FDA approval for T2DM) to 2017 (1 year after FDA label expansion for empagliflozin for CV risk reduction).
      • Vaduganathan M.
      • Sathiyakumar V.
      • Singh A.
      • et al.
      Prescriber patterns of SGLT2i after expansions of U.S. Food and Drug Administration labeling.
      Of a sample of 1874 patients who were prescribed an SGLT2i, most were prescribed by endocrinologists (40%), followed by primary care physicians (PCPs; 23.1%), whereas cardiologists prescribed only 5.1% of them. Even in the year after addition of the CV indication for empagliflozin, endocrinologists continued to prescribe the highest proportion of SGLT2i (45.4%), followed by PCPs (22.7%), whereas cardiologists remained at 4.5%.
      • Vaduganathan M.
      • Sathiyakumar V.
      • Singh A.
      • et al.
      Prescriber patterns of SGLT2i after expansions of U.S. Food and Drug Administration labeling.
      As these antidiabetes medications progressively become a powerful resource that is shared by primary care, endocrinology, cardiology, and nephrology specialists, these data highlight the urgent need to empower physicians from all specialties with the knowledge needed to readily integrate these medications into their routine clinical practices.
      • Ferro E.G.
      • Michos E.D.
      • Bhatt D.L.
      • et al.
      New decade, new FDA guidance for diabetes drug development.
      ,
      • Verma S.
      • Anker S.D.
      • Butler J.
      • et al.
      Early initiation of SGLT2 inhibitors is important, irrespective of ejection fraction: SOLOIST-WHF in perspective.

      Clinics care points: how to integrate sodium-glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor agonists in clinical practice

      This article focuses on outpatient visits because hospitalized patients were often not included in most of the aforementioned CVOTs, and hospital inpatient formularies may not routinely include these agents. Nonetheless, the authors encourage inpatient providers to apply these interventions at the time of discharge, especially if close outpatient follow-up has been ensured, because initiation of medications at discharge may favorably influence outpatient adherence.
      • Das S.R.
      • Everett B.M.
      • Birtcher K.K.
      • et al.
      2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology solution set oversight committee.

      Clinics Care Points Applicable to Both Glucagon-like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors

      • In the patient panel, identify patients who benefit from initiation of SGLT2i and/or GLP-1 RA:
        • 1.
          Patients with poorly controlled T2DM who warrant escalation of glucose-lowering therapy
        • 2.
          Patients with T2DM who, independently of glycemic control, are at high CV risk, have established ASCVD, HFrEF, or CKD (eGFR>30)
        • 3.
          Patients without T2DM who have established diagnosis of HFrEF (SGLT2i)
      • At the next outpatient visit with eligible patients, proactively initiate a patient-physician discussion of the risk and benefits associated with initiation of SGLT2i and/or GLP-1 RA, and also discuss patient preferences when using injectable versus oral agents; clinicians should also offer resources to estimate the out-of-pocket cost associated with available medication options, because it can further influence selection of a specific agent.
      • Proactively seek a collaborative approach with primary care, endocrinology, cardiology, or nephrology colleagues with regard to side effects, drug-drug interactions, and/or adherence.
      • If patient has well-controlled HbA1c at baseline or known history of hypoglycemic events, when starting therapy consider dose reduction by 50% for sulfonylureas or 20% for insulin. If unable to tolerate dual or triple therapy, consider discontinuation of sulfonylurea in order to prioritize the agents with proven CV benefit.
      • The combination of SGLT2i and GLP-1 RA can be considered to enhance glucose-lowering goals. To date, no definitive evidence supports combination therapy to enhance CV or cardiorenal benefit.

      Clinics Care Points Applicable to Glucagon-like Peptide-1 Receptor Agonists

      • When choosing a specific agent and dose for GLP-1 RA:
        • 1.
          Current data support the use of dulaglutide, liraglutide, and semaglutide (injectable, not oral) for CV benefit.
        • 2.
          For any indication, initially prescribe the agent at the lowest dose (to minimize the risk of side effects such as nausea and vomiting) and then increase the dose as tolerated. The use of concurrent glucose-lowering therapy (including metformin) is not thought to decrease the CV benefit of these agents.
      • Although nausea and vomiting are self-limited when initiating GLP-1 RA therapy, special monitoring is needed with patients with clinically significant gastroparesis.
      • Avoid concurrent use with DPP4 inhibitors, because both agents affect the GLP-1 signaling pathway and they have not been studied together.
      • Semaglutide has been associated with increased risk of diabetic retinopathy. Therefore, consider an alternative GLP-1 RA in patients with proliferative retinopathy.

      Clinics Care Points Applicable to Sodium-Glucose Cotransporter-2 Inhibitors

      • When choosing a specific agent and dose for SGLT2i:
        • 1.
          All of the currently available agents have broadly similar cardiorenal benefits.
        • 2.
          If the indication is cardiorenal benefit, independent of glycemic control, each agent can be prescribed at the lowest dose, with no need for uptitration. Similarly, the use of concurrent glucose-lowering therapy (including metformin) is not thought to decrease the cardiorenal benefit of these agents. If concurrent glycemic control is needed, the dose may be increased as tolerated.
      • Discuss the risk of genital mycotic infections in both men and women, and the importance of personal hygiene of the perineal area as prophylaxis. In case of mycotic infection, temporary discontinuation of SGLT2i should be considered for effective treatment.
      • Discuss the risk of hyperglycemic but also euglycemic diabetic ketoacidosis. Encourage patients to monitor glucose more closely at home for the first 4 weeks of therapy but also closely monitor for symptoms associated with euglycemic ketoacidosis (abdominal pain, generalized weakness, nausea, vomiting). If reduction of background antiglycemic therapy is needed, avoid greater than 20% insulin reduction to reduce the risk of ketoacidosis.
      • Discuss the risk of hypovolemia associated with the diuretic effect of SGLT2i. Encourage patients to closely monitor for symptoms of hypovolemia (lightheadedness, dizziness, orthostasis, generalized weakness). Concurrent diuretic therapy can be reduced if such symptoms occur.
      • Despite the established nephroprotective effect of SGLT2i, an initial decrease in eGFR can be seen in the first period after initiation of treatment. Monitoring of renal function is reasonable, but isolated initial decrease in eGFR should not prevent initiation or continuation of SGLT2i.
      • Canagliflozin has been associated with increased risk of toe amputations. Therefore, consider an alternative SGLT2i in patients with prior amputations, peripheral arterial disease, or neuropathy.

      Summary

      Since the 2008 FDA guidance to industry, several rigorous CVOTs have proved the CV safety of new antidiabetes medications. Among those, SGLT2i and GLP-1 RA have emerged as the most important noninsulin medications for patients with T2DM, because they cause a significant reduction in fatal and nonfatal ischemic events among patients with diabetes and atherosclerotic CVD. In addition, SGLT2i have been shown to reduce the risk for CV mortality and hospitalization for HF among patients with HFrEF, as well as MAREs among patients with CKD. Of note, recent trials in 2019 to 2020 also showed that the cardiorenal benefits of SGLT2i apply also to patients with HFrEF and CKD without diabetes, which broadens the use of SGLT2i compared with GLP-1 RA. Therefore, it is important to realize that the 2 agents have shared but not completely overlapping indications, and to tailor their use accordingly. Furthermore, ongoing trials are evaluating whether these medications may be beneficial in other patient populations, such as patients with HFpEF. Although most national and international clinical guidelines now recommend the use of these medications as first line together with metformin for patients with T2DM, their real-world uptake remains limited, especially outside of endocrinology practices. These medications are a powerful resource to be shared by primary care, endocrinology, cardiology, and nephrology specialists.

      Disclosure

      Dr D.L. Bhatt discloses the following relationships: advisory board with Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, MyoKardia, PhaseBio, PLx Pharma, Regado Biosciences; board of directors with Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; chair with American Heart Association Quality Oversight Committee; data monitoring committees with Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical , now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards ), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo ), Population Health Research Institute; honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim ; AEGIS-II executive committee funded by CSL Behring ), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals ), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Cochair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national coleader, funded by Bayer ), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees). Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); research funding from Abbott , Afimmune , Amarin , Amgen , AstraZeneca , Bayer , Boehringer Ingelheim , Bristol-Myers Squibb , Cardax , Chiesi , CSL Behring , Eisai , Ethicon , Ferring Pharmaceuticals , Forest Laboratories , Fractyl , Idorsia , Ironwood , Ischemix , Lexicon , Lilly , Medtronic , MyoKardia , Pfizer , PhaseBio , PLx Pharma , Regeneron , Roche , sanofi-aventis , Synaptic , and The Medicines Company ; royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Coinvestigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; trustee for ACC; unfunded research for FlowCo, Merck, Novo Nordisk, and Takeda.

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