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. Author manuscript; available in PMC: 2019 Nov 25.
Published in final edited form as: Curr Opin Cardiol. 2019 Nov;34(6):687–692. doi: 10.1097/HCO.0000000000000673

Review of cardiovascular outcomes trials of sodium – glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists

Emily J North a, Jonathan D Newman b
PMCID: PMC6876849  NIHMSID: NIHMS1059650  PMID: 31436559

Abstract

Purpose of review

In recent years, there have been several cardiovascular outcomes trials (CVOT) of two new classes of glucose-lowering medications: sodium–glucose cotransporter-2 inhibitors (SGLT2-i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA). It is important examine their potential for cardiovascular benefit and possible side effects among patients with type 2 diabetes (T2D) mellitus.

Recent findings

The current article reviews the findings of recent CVOT of SGLT2-i and GLP-1 RA, including their impact on cardiovascular events and relevant side effects.

Summary

For all T2D patients, with or without established cardiovascular disease, the SGLT2-i have demonstrated impressive reductions in hospitalization for heart failure and renoprotection. For T2D patients with established cardiovascular disease, SGLT2-i demonstrated an additional benefit of reduced major adverse cardiac events, on top of reductions in hospitalizations for heart failure, renoprotection, and in some instances, mortality. Similarly, all GLP-1 RA CVOTs demonstrated noninferiority compared with placebo for safety. In comparison, GLP-1 RA appear to preferentially reduce ischemic events (stroke or myocardial infarction) over hospitalization for heart failure, and demonstrated renoprotection in several of the CVOTs.

Keywords: cardiovascular outcomes trials, glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter-2 inhibitors

INTRODUCTION

It is well known that diabetes is a significant risk factor for cardiovascular disease (CVD), and that CVD is the most common cause of mortality in diabetic patients [1]. However, to date studies have failed to demonstrate reductions in macrovascular disease with a strategy of more intensive compared with more lenient glycemic control [2]. When rosiglitazone, a thiazolidinedione, was found to have a possible association with an increased risk of myocardial infarction (MI) and cardiovascular death, the US Food and Drug Association (FDA) required that all new glucose-lowering medications for type 2 diabetes (T2D) first demonstrate cardiovascular safety [3–5]. If cardiovascular safety was demonstrated with prespecified margins of inferiority compared with placebo, these trials could then test for superiority for reduction in cardiovascular events [6]. In recent cardiovascular outcomes trials (CVOT), the glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium–glucose cotransporter-2 inhibitors (SGLT2-i) have demonstrated impressive cardiovascular safety compared with placebo and also significant reductions in cardiovascular events.

MECHANISM OF SODIUM–GLUCOSE COTRANSPORTER-2 INHIBITORS

SGLT2-i act selectively on the sodium–glucose 2 cotransporter (responsible for reabsorbing over 90% of filtered glucose) in the nephron to prevent glucose (and sodium) reuptake in the kidney [7,8]. Glycosuria occurs when the rate of filtered glucose exceeds the maximum rate at which it can be absorbed by SGLT2 cotransporters [9]. SGLT2-i function by decreasing the maximum rate of absorption, thus inducing glycosuria [9]. As the filtered glucose load depends on the serum glucose – and independent of insulin – the SGLT2-i achieve the greatest reduction in blood glucose during hyperglycemia, and the relative risk (RR) of hypoglycemia is lower than some other classes of diabetes medications, such as the thiazolidinediones [7].

POTENTIAL MECHANISMS OF CARDIOVASCULAR BENEFIT OF SODIUM–GLUCOSE COTRANSPORTER-2 INHIBITORS

It is thought that SGLT2-i are cardioprotective at least in part due to their primary mechanism reducing sodium and glucose uptake in the nephron, leading to a decrease in preload and afterload through osmotic diuresis [7,10▪]. However, there are additional other proposed cardiovascular benefits of SGLT2-i. Studies have found an association between SGLT2-i and improvement of the composition of proinflammatory and anti-inflammatory cytokines in the body, as well as reduction in cardiac fibrosis [10▪,11]. Another potential cardioprotective mechanism of SGLT2-i includes an increase in hematocrit, which may be secondary to their diuretic effect, increasing red blood cell concentration [12]. With the use of SGLT2-i, renal fibroblasts appear to increase erythropoietin production when the stimuli of hyperglycemia and excess glucose reabsorption are removed [12]. Finally, SGLT2-i have been associated with an increase in production of alternative fuels for the heart, whose use has been associated with increased cardiac metabolic efficiency; these include beta-hydroxybutyrate and the products of branched-chain amino acid degradation [11].

SODIUM–GLUCOSE COTRANSPORTER-2 INHIBITORS CARDIOVASCULAR OUTCOME TRIALS

The safety and efficacy of SGLT2-i have been tested in several recent major cardiovascular outcome trials.

The first major published trial was EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), which was a double-blind, randomized trial evaluating the reductions in the primary composite outcome of three major adverse cardiac events (MACE): cardiovascular death, nonfatal MI, and nonfatal stroke (MACE-3) when comparing empagliflozin at 10 mg, and 25 mg daily with placebo in adult patients with T2D and known CVD [13]. This trial spanned a median treatment duration of 2.6 years, and found that the primary outcome occurred in a significantly lower percentage of patients in the empagliflozin groups [10.5 versus 12.1%, hazard ratio 0.86, 95% confidence interval (CI) 0.74–0.99, P < 0.001 for noninferiority and P = 0.04 for superiority] with both 10 and 25 mg with similar hazard ratios; this was primarily driven by a lower rate of cardiovascular death [13]. The EMPA-REG OUTCOME trial also found a significantly lower risk of hospitalization from heart failure (HHF) (hazard ratio 0.65, 95% CI 0.50–0.85, P = 0.002) [13], a finding that calls attention to the importance of heart failure as a clinically relevant cardiovascular outcome for T2D patients [14].

The CANVAS (Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes) trial was a double-blind, multinational, randomized controlled trial comparing daily canagliflozin at 100 mg daily (with optional increase to 300 mg at week 13) versus placebo with respect to MACE-3 in adult patients with symptomatic atherosclerotic CVD, or without known history of CVD but with significant risk factors (this subgroup comprised nearly 35% of patients in the trial) [15]. The primary outcome was lower for participants randomized to canagliflozin compared with placebo (hazard ratio 0.86, 95% CI 0.75–0.97, P < 0.001 for noninferiority; P = 0.02 for superiority) [15]. The primary outcome, however, was driven by HHF; differences in cardiovascular death and all-cause mortality did not differ between canagliflozin and placebo [15].

The DECLARE-TIMI (Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes) randomized diabetic patients with established CVD (approximately 40%) or cardiovascular risk factors alone to dapagliflozin or placebo for a median of 4.2 years of follow-up [16▪]. No reduction in the three-point composite of cardiovascular death, MI, or stroke (MACE-3) was observed (8.8 and 9.4%, hazard ratio 0.93, 95% CI 0.84–1.03, P = 0.17) [16▪]. However, there was a lower rate of the secondary primary outcome, a composite of cardiovascular death and HHF [16▪]. This was driven by a significant decrease in the rate of HHF (hazard ratio 0.73, 95% CI 0.61–0.88) [16▪].

Most recently, the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial was notable for its inclusion of patients with albuminuric chronic kidney disease of estimated glomerular filtration rate (eGFR) 30–90 ml/min [17▪]. The design of CREDENCE is noteworthy as T2D is the most common cause of renal failure, and known effects of SGLT2-i such as blood pressure lowering have been associated in prior research with delayed progression of nephropathy and adverse renal outcomes [18,19]. CREDENCE compared canagliflozin with placebo in patients with T2D and albuminuric chronic kidney disease for a primary composite of end-stage renal disease, doubling of serum creatinine, or renal or cardiovascular death [17▪]. Participants in CREDENCE randomized to canagliflozin had a 30% reduction in RR of the primary outcome. In addition, there were significant decreases in secondary outcomes of MACE-3 (hazard ratio 0.80, 95% CI 0.67–0.95), HHF (hazard ratio 0.61, 95% CI 0.47–0.80), or and the composite of HHF or cardiovascular death (hazard ratio 0.69, 95% CI 0.57–0.83) [17▪].

In summary, EMPA-REG OUTCOME, CANVAS, and CREDENCE demonstrated superiority with respect to MACE-3, and DECLARE-TIMI found superiority with respect to the combined outcome of cardiovascular death and HHF; all were noninferior to placebo with respect to safety [13,15,16▪,17▪]. To date, EMPA-REG and CREDENCE have demonstrated improved mortality with SGLT2-i. Although MACE-3 was the primary outcome tested for in these trials, reductions in heart failure-related outcomes with the use of SGLT2-i were especially prominent and may reflect some of the known physiologic effects of SGLT2 inhibition with this class of medication [13,15,16▪,17▪].

Notable side effects with SGLT2-i include significant increases in genital and urinary tract infections, likely related to the SGLT2-i mechanism of action [7]. In the CVOT to date, these infections were rarely associated with drug discontinuation [20]. There have been other noteworthy side effects predominantly associated with the use of canagliflozin. The CANVAS trial found an association between randomization to canagliflozin with increased rates of amputation (6.3 versus 3.4%, hazard ratio 1.97, 95% CI 1.41–2.75) that has not been replicated in other CVOTs of SGLT2-i [13,15,16▪]. Finally, as canagliflozin was found to be associated with increased fracture rates in prior trial data, there was concern for detrimental effects on bone mineral density due to SGLT2-i use [21]. CREDENCE found no increased risk for fracture or amputation with canagliflozin; a meta-analysis of 40 randomized controlled trials also found no difference in fracture risk with use of canagliflozin, dapagliflozin, or empagliflozin [17,21].

MECHANISMS OF GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS AND POTENTIAL CARDIOVASCULAR BENEFIT

The second major class of glucose-lowering agents that have been studied for cardiovascular safety and found to have cardiovascular benefit are the GLP-1 RA. The incretin hormones, including GLP-1, were discovered after determination that enteral glucose leads to increased insulin secretion compared with intravenous glucose infusions [22]. Additional research found that GLP-1 slows gastric emptying and reduces appetite, among other effects [22,23]. This led to the development of a class of medications, the GLP-1 RA, to reduce blood glucose and improve metabolic control [22]. Further studies found that GLP-1 receptor is expressed also in cardiomyocytes and coronary endothelial cells; cardiovascular effects include both improved left ventricular function and endothelial function [22]. These may be some of the mechanisms by which the GLP-1 RA medications improve cardiovascular outcomes [22].

GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS CARDIOVASCULAR OUTCOME TRIALS

The first major trial of cardiovascular outcomes in GLP-1-receptor agonists was ELIXA (Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome), which studied lixisenatide versus placebo in patients with T2D and who were diagnosed with acute coronary syndrome within 6 months of screening [24]. This study found lixisenatide to be noninferior, but not superior, to placebo with respect to the primary outcome of a composite of MACE-3 (composite of cardiovascular death, nonfatal MI, and nonfatal stroke) and hospitalization for unstable angina over a median follow-up of 25 months (hazard ratio 1.02, 95% CI 0.89–1.17) [24].

The next major GLP-1-receptor agonist trial, LEADER (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes), studied the effect of liraglutide versus placebo on MACE-3 in diabetic patients with established CVD (81.3%) or with known risk factors (18.7%) [25]. After a median treatment duration of 3.5 years, this study found liraglutide decreased the primary outcome compared with placebo (13.0 versus 14.9%, hazard ratio 0.87, 95% CI 0.78–0.97). Notably, randomization to liraglutide in LEADER is the only GLP-1 RA CVOT thus far to demonstrate a reduction in cardiovascular (hazard ratio 0.78, 95% CI 0.66–0.93) and all-cause mortality (hazard ratio 0.85, 95% CI 0.74–0.97) [25].

The SUSTAIN-6 trial (Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes) studied the effect of semaglutide versus placebo in diabetic patients with established CVD (83%) or multiple cardiovascular risk factors (17%) on MACE-3 over an observation period of 2.1 years [26]. This trial found a significant decrease in the primary outcome in patients on semaglutide versus placebo (6.6 versus 8.9% with hazard ratio 0.74; 95% CI, 0.58–0.95; P = 0.02 for superiority) [26]. The difference in the MACE-3 composite outcome was driven by a trend toward a decrease in nonfatal MI (hazard ratio 0.74, 95% CI 0.51–1.08) and a significant decrease in nonfatal stroke (hazard ratio 0.61, 95% CI 0.38–0.99) [26]. Rates of cardiovascular death were similar between the treatment and placebo arms [26].

The EXSCEL trial (Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes) studied exenatide versus placebo over median 3.2 years of follow-up in patients with T2D, approximately 70% of whom had established CVD [27]. Exenatide did not meet superiority for the primary MACE-3 outcome (cardiovascular death, nonfatal MI, or nonfatal stroke) compared with placebo (hazard ratio 0.91, 95% CI 0.83–1.00) but demonstrated noninferiority compared with placebo for safety (11.4 versus 12.2%, 95% CI 0.83–1.00, P < 0.0001 for noninferiority) [27].

The HARMONY OUTCOMES trial found that albiglutide was superior to placebo in reducing MACE-3 in diabetic patients with established cardiovascular, cerebrovascular, or peripheral vascular disease over a median follow-up of at least 1.5 years (7 versus 9%, hazard ratio 0.78, 95% CI 0.68–0.90, P = 0.0006) [28▪]. The reduction in MACE-3 was driven by a reduction in MI (hazard ratio 0.75, 95% CI 0.61–0.90); there were numerically fewer cardiovascular deaths and nonfatal strokes with albiglutide but this difference was NS. No difference in the secondary outcome, a composite of cardiovascular death or HHF, was observed (hazard ratio 0.85, 95% CI 0.70–1.04) [28▪].

Most recently the REWIND trial studied dulaglutide versus placebo in patients with cardiovascular risk factors (68.5% of participants) or established CVD, with a primary outcome of MACE-3 over a median follow-up of 5.4 years [29▪]. This study found a reduced incidence of MACE-3 in patients taking dulaglutide versus placebo (12 versus 13.4%, hazard ratio 0.88, 95% CI 0.76–0.99, P = 0.026), driven by a reduction in nonfatal stroke [29▪]. The magnitude of reduction in the primary outcome was similar for REWIND participants with risk factors only compared with those established CVD [29▪]. Multiple prespecified secondary outcomes were reported, including a composite of microvascular outcomes of retinopathy or renal disease. Treatment with dulaglutide was associated with a lower incidence of microvascular disease compared with placebo (3.8 versus 4.3%, hazard ratio 0.87, 95% CI 0.79–0.95), driven by decreases in nephropathy and renal outcomes [29▪]. The incidence of all-cause mortality and heart failure was not significantly different between patients on dulaglutide and placebo [29▪].

With respect to side effects with use of GLP-1 RA; the number of serious adverse events did not differ significantly between the study drug and placebo in all of the above trials except for an increase in acute gallstone disease with liraglutide compared with placebo in LEADER, and fewer adverse events were found in the semaglutide group versus placebo in SUSTAIN-6 [25,26]. Gastrointestinal disorders were found to be more frequent with lixisenatide, liraglutide, semaglutide, and dulaglutide versus placebo in the above CVOT; these were also the most common reasons for discontinuing the study drug in ELIXA, LEADER, and SUSTAIN-6 [24–26,29▪]. These events were primarily mild or moderate in severity: in ELIXA, nausea or vomiting were the largest contributing adverse events to discontinuation of the study drug versus placebo (4.1 versus 0.6%, P < 0.001) [24], and the majority of adverse events in the SUSTAIN-6 trial were gastrointestinal (50.7%), comprised of diarrhea (17.9%), nausea (17.3%), and vomiting (10.5%) [26]. SUSTAIN-6 also found an increased risk of diabetic retinopathy complications with semaglutide compared with placebo (3.0 versus 1.8%, hazard ratio 1.76, 95% CI 1.11–2.78) [26]. All GLP-1 RA CVOT did not detect an increased risk of pancreatitis or pancreatic cancer, initial concerns with GLP-1-receptor agonists due to reports of adverse events made to the FDA [30].

All CVOT of GLP-1 RA above demonstrated cardiovascular safety with noninferiority compared with placebo for MACE-3, with semaglutide, liraglutide, albiglutide, and dulaglutide demonstrating superiority [24–27,28▪,29▪]. REWIND found reduction in MACE-3 in patients without known CVD [29▪]. However, it appears that GLP-1 RA do not share similar benefits to SGLT2-i with respect to preventing HHF. For example, the LEADER trial of liraglutide found lower (but insignificant) rates of HHF; the other GLP-1 RAs found no difference on the endpoint of heart failure, though heart failure was not rigorously defined in CVOTs to date [25].

It remains unclear as to the differences in cardiovascular benefit across GLP-1 RA trials. Possible reasons for heterogeneity of effect across trials includes structural differences between the medications themselves, but may also represent differences in the trial designs with respect to inclusion criteria, trial duration and whether or not an initial run-in period was included [28▪].

CONCLUSION

We have reviewed the remarkable advances that the recent CVOTs with SGLT2-i and GLP-1 RA have shown for patients with diabetes and their care teams, including cardiologists. All SGLT2-i CVOT have demonstrated noninferiority compared with placebo for safety. For all T2D patients, with or without established CVD, the SGLT2-i have demonstrated impressive reductions in hospitalization for heart failure and renoprotection. For T2D patients with established CVD, SGLT2-i demonstrated an additional benefit of reduced MACE, on top of reductions in hospitalizations for heart failure, renoprotection and in some instances, mortality.

Similarly, all GLP-1 RA CVOTs demonstrated noninferiority compared with placebo for safety. In contrast, GLP-1 RA appear to preferentially reduce ischemic events (stroke or MI) over hospitalization for heart failure. Some trials demonstrated heterogeneity of benefit for a reduction in MACE for patients with compared with without established CVD. To date, only the LEADER trial demonstrated a mortality benefit with GLP-1 RA. In line with the American Diabetes Association and the European Association for the Study of Diabetes [31▪] and endorsed by the American College of Cardiology [32], if atherosclerotic stable CVD predominates a GLP-1 RA or an SGLT2-i with proven benefit can be chosen. If heart failure or CKD predominates, an SGLT2-i with proven outcome benefit may be preferred over a GLP-1 RA. As previously noted [33], future studies may consider investigating the use of these agents in patients with prediabetes, as they represent a third of the US population and are also at elevated cardiovascular risk [34,35]. The role of these medications for the primary prevention of cardiometabolic disease and risk may be the next frontier in management for this high-risk population.

KEY POINTS.

  • Evidence so far supports safety and benefit of SGLT2-i with respect to cardiovascular death and hospitalization from heart failure.

  • All trials of GLP-1 RA demonstrated noninferiority to placebo with respect to cardiovascular safety and ischemic events; some demonstrated superiority.

  • GLP-1 RA do not appear to have the same heart failure benefits as SGLT2-i.

Acknowledgements

Conflicts of interest

J.D.N., MD, MPH reports research grants from the National Institutes of Health (NIH) National Heart Lung and Blood Institute (NHLBI) K23HL125991 and honoraria from Creative Educational Concepts.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

  • 1.Matheus AS, Tannus LR, Cobas RA, et al. Impact of diabetes on cardiovascular disease: an update. Int J Hypertens 2013; 2013:653789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Terry T, Raravikar K, Chokrungvaranon N, Reaven PD. Does aggressive glycemic control benefit macrovascular and microvascular disease in type 2 diabetes? Insights from ACCORD, ADVANCE, and VADT. Curr Cardiol Rep 2012; 14:79–88. [DOI] [PubMed] [Google Scholar]
  • 3.Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess? Diabetes Care 2016; 39:738–742. [DOI] [PubMed] [Google Scholar]
  • 4.Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–2471. [DOI] [PubMed] [Google Scholar]
  • 5.US Food and Drug Administration. Guidance for industry. Diabetes mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008; Available from: www.fda.gov/downloads/Drugs/Guidance-ComplianceRegulatoryInfrormation/Guidances/ucm071627.pdf. [Accessed 2 July 2019]
  • 6.Standl E, Schnell O, McGuire DK, et al. Integration of recent evidence into management of patients with atherosclerotic cardiovascular disease and type 2 diabetes. Lancet Diabetes Endocrinol 2017; 5:391–402. [DOI] [PubMed] [Google Scholar]
  • 7.Kalra S Sodium glucose co-transporter-2 (SGLT2) inhibitors: a review of their basic and clinical pharmacology. Diabetes Ther 2014; 5:355–366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Heerspink HJL, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 2016; 134:752–772. [DOI] [PubMed] [Google Scholar]
  • 9.Garcia-Ropero A, Badimon JJ, Santos-Gallego CG. The pharmacokinetics and pharmacodynamics of SGLT2 inhibitors for type 2 diabetes mellitus: the latest developments. Expert Opin Drug Metab Toxicol 2018; 14:1287–1302. [DOI] [PubMed] [Google Scholar]
  • 10.Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 2018; 61:2108–2117. [DOI] [PubMed] [Google Scholar]; ▪ The article is a review of potential mechanisms of cardiovascular benefit for the sodium–glucose cotransporter-2 inhibitors (SGLT2-i), particularly with respect to heart failure.
  • 11.Kaplan A, Abidi E, El-Yazbi A, et al. Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects. Heart Fail Rev 2018; 23:419–437. [DOI] [PubMed] [Google Scholar]
  • 12.Sano M, Takei M, Shiraishi Y, et al. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res 2016; 8:844–847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373:2117–2128. [DOI] [PubMed] [Google Scholar]
  • 14.Cavender MA, Steg G, Smith SC, et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death. Circulation 2015; 132:923–931. [DOI] [PubMed] [Google Scholar]
  • 15.Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377:644–657. [DOI] [PubMed] [Google Scholar]
  • 16.Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380:347–357. [DOI] [PubMed] [Google Scholar]; ▪ The DECLARE-TIMI demonstrated a reduction in cardiovascular death or hospitalization for heart failure among in a trial population with a majority (59%) having cardiovascular risk factors alone.
  • 17.Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–2306. [DOI] [PubMed] [Google Scholar]; ▪ The trial demonstrated that canagliflozin, an SGLT2-i, reduced MACE-3, hospitalization from heart failure (HHF), and progression of renal disease in type 2 diabetes (T2D) patients with albuminuric chronic kidney disease (59% with eGFR < 60 ml/min), extending the benefit of SGLT2 inhibition to the high-risk T2D population with renal dysfunction.
  • 18.Doshi SM, Friedman AN. Diagnosis and management of type 2 diabetic kidney disease. Clin J Am Soc Nephrol 2017; 12:1366–1373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Sharaf El Din UA, Salem MM, Abdulazim DO. Stop chronic kidney disease progression: time is approaching. World J Nephrol 2016; 5:258–273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Hsia DS,Grove O,Cefalu WT.An update on SGLT2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 2017; 24:73–79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Azharuddin M, Adil M, Ghosh P, et al. Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with diabetes mellitus: a systematic literature review and Bayesian network meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 2018; 146:180–190. [DOI] [PubMed] [Google Scholar]
  • 22.Koliaki C, Doupis J. Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus. Diabetes Ther 2011;2:101–121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368:1696–1705. [DOI] [PubMed] [Google Scholar]
  • 24.Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015; 373:2247–2257. [DOI] [PubMed] [Google Scholar]
  • 25.Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375:311–322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375:1834–1844. [DOI] [PubMed] [Google Scholar]
  • 27.Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017; 377:1228–1239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018; 392:1519–1529. [DOI] [PubMed] [Google Scholar]; ▪ The recent glucagon-like peptide-1 receptor agonists (GLP-1 RA) cardiovascular outcomes trials demonstrated superiority of albiglutide over placebo for MACE-3 in T2D patients with established atherosclerotic disease; no difference in HHF was appreciated.
  • 29.Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): double-blind, randomized placebo-controlled trial. Lancet 2019; 394:121–130. [DOI] [PubMed] [Google Scholar]; ▪ This is the most recently published CVOT of GLP-1 RA. It included the largest proportion (68%) of primary prevention T2D participants; it demonstrated a reduction in MACE-3 and nephropathy with dulaglutide compared with placebo.
  • 30.Storgaard H, Cold F, Gluud LL, et al. Glucagon-like peptide-1 receptor agonists and risk of acute pancreatitis in patients with type 2 diabetes. Diabetes Obes Metab 2017; 19:906–908. [DOI] [PubMed] [Google Scholar]
  • 31.Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018; 41:2669–2701. [DOI] [PMC free article] [PubMed] [Google Scholar]; ▪ These consensus guidelines by the American Diabetes Association and European Association for the Study of Diabetes and endorsed by the American College of Cardiology for management of hyperglycemia among T2D patients. These guidelines made recommendations as to specific subsets of patients with T2D and when SGLT2-i versus GLP-1 RA may be preferred.
  • 32.American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes - 2019. Diabetes Care 2019; 42(Suppl 1):S103–S123. [DOI] [PubMed] [Google Scholar]
  • 33.Newman JD, Vani AK, Aleman JO, et al. The changing landscape of diabetes therapy for cardiovascular risk reduction: JACC state-of-the-art review. J Am Coll Cardiol 2018; 72:1856–1869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Centers for Disease Control and Prevention. Diabetes: prevalence of prediabetes. 2018. Available from https://www.cdc.gov/diabetes/data/statistics-report/prevalence.html. [Accessed 12 June 2019].
  • 35.Huang Y, Cai X, Mai W, et al. Association between prediabetes and risk of cardiovascular disease and all-cause mortality: systematic review and meta-analysis. BMJ 2016; 355:i5953. [DOI] [PMC free article] [PubMed] [Google Scholar]

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