Matthew A. Cavender

Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial.

Background— Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point. Methods and Results— A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07–1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15–1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ⩽60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups. Conclusions— In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01107886.

Prevalence, Predictors, and In-Hospital Outcomes of Non-Infarct Artery Intervention During Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction (from the National Cardiovascular Data Registry)

Guidelines support percutaneous coronary intervention (PCI) of the noninfarct-related artery during primary PCI for ST-segment elevation myocardial infarction (STEMI) in patients with hemodynamic compromise; however, in patients without hemodynamic compromise, PCI of the noninfarct-related artery is given a class III recommendation. We analyzed the National Cardiovascular Data Registry (n = 708,481 admissions, 638 sites) to determine the prevalence, predictors, and in-hospital outcomes of primary multivessel PCI from 2004 to 2007. Patients with STEMI and multivessel coronary artery disease who were undergoing primary PCI were identified (n = 31,681). After excluding the patients treated with staged PCI (n = 2,745), 10.8% (n = 3,134) of the remaining population (n = 28,936) were treated with multivessel PCI. Patients undergoing multivessel PCI were at higher risk and were more likely to be in cardiogenic shock. The overall in-hospital mortality rates were greater in patients undergoing multivessel PCI (7.9% vs 5.1%, p <0.01). Among patients with STEMI and cardiogenic shock (n = 3,087), those receiving multivessel PCI had greater in-hospital mortality (36.5% vs 27.8%; adjusted odds ratio 1.54, 95% confidence interval 1.22 to 1.95). In conclusion, these data suggest that performing multivessel PCI during primary PCI for STEMI does not improve short-term survival even for patients with cardiogenic shock. These findings suggest the need for definitive studies to evaluate the utility of noninfarct-related artery PCI among patients with STEMI.

Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)

Background -Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose co-transporter-2 inhibitor (SGLT-2i) empagliflozin in type 2 diabetes patients with atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose lowering drugs (oGLDs) in six countries to determine if these benefits are seen in real-world practice, and across SGLT-2i class. Methods -Data were collected via medical claims, primary care/hospital records and national registries from the US, Norway, Denmark, Sweden, Germany and the UK. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios (HRs) for HHF, death and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. Results -After propensity matching, there were 309,056 patients newly initiated on either SGLT-2i or oGLD (154,528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42% and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the two groups. There were 961 HHF cases during 190,164 person-years follow up (incidence rate [IR] 0.51/100 person-years). Of 215,622 patients in the US, Norway, Denmark, Sweden, and UK, death occurred in 1334 (IR 0.87/100 person-years), and HHF or death in 1983 (IR 1.38/100 person-years). Use of SGLT-2i, versus oGLDs, was associated with lower rates of HHF (HR 0.61; 95% CI 0.51-0.73; p<0.001); death (HR 0.49; 95% CI 0.41-0.57; p<0.001); and HHF or death (HR 0.54; 95% CI 0.48-0.60, p<0.001) with no significant heterogeneity by country. Conclusions -In this large multinational study, treatment with SGLT-2i versus oGLDs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of T2D patients in real-world practice (NCT02993614). Clinical Trial Registration -URL: ClinicalTrials.gov; Unique Identifier: NCT02993614.Background: Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class. Methods: Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. Results: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51–0.73; P<0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41–0.57; P<0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48–0.60; P<0.001) with no significant heterogeneity by country. Conclusions: In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02993614.

Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials.

BACKGROUND Bivalirudin is an alternative to heparin in patients undergoing percutaneous coronary intervention (PCI). We aimed to define the effects of a bivalirudin-based anticoagulation regimen compared with a heparin-based anticoagulation regimen on ischaemic and bleeding outcomes. METHODS We searched Medline, the Cochrane Library, and relevant meeting abstracts (search done on April 9, 2014) for randomised trials that assessed bivalirudin versus heparin in patients planned for PCI. The primary efficacy endpoint was the incidence of major adverse cardiac events (MACE) up to 30 days. Secondary efficacy endpoints were death, myocardial infarction, ischaemia-driven revascularisation, and stent thrombosis. The primary safety endpoint was major bleeding up to 30 days. We calculated pooled risk ratios and 95% CIs using random-effects models. FINDINGS We included data from 16 trials involving 33 958 patients, of whom 2422 experienced MACE and 1406 had a major bleed. There was an increase in the risk of MACE with bivalirudin-based regimens compared with heparin-based regimens (risk ratio 1·09, 95% CI 1·01-1·17; p=0·0204), which was largely driven by increases in myocardial infarction (1·12, 1·03-1·23) and seemingly also by ischaemia-driven revascularisation (1·16, 0·997-1·34) with bivalirudin compared with heparin, with no effect on mortality (0·99, 0·82-1·18). Bivalirudin increased the risk of stent thrombosis (risk ratio 1·38, 95% CI 1·09-1·74; p=0·0074), which was primarily due to an increase in acute cases in ST-segment elevation myocardial infarction (4·27, 2·28-8·00; p<0·0001). Overall, bivalirudin-based regimens lowered the risk of major bleeding (risk ratio 0·62, 95% CI 0·49-0·78; p<0·0001), but the magnitude of this effect varied greatly (p<0·0001) depending on whether glycoprotein IIb/IIIa inhibitors were used predominantly in the heparin arm only (0·53, 0·47-0·61; p<0·0001), provisionally in both arms (0·78, 0·51-1·19; p=0·25), or planned in both arms (1·07, 0·87-1·31; p=0·53). INTERPRETATION Compared with a heparin-based regimen, a bivalirudin-based regimen increases the risk of myocardial infarction and stent thrombosis, but decreases the risk of bleeding, with the magnitude of the reduction depending on concomitant glycoprotein IIb/IIIa inhibitor use. Physicians should weigh the trade-off between ischaemic and bleeding events when choosing between different anticoagulant regimens. FUNDING None.

Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome The VISTA-16 Randomized Clinical Trial

IMPORTANCE Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE To determine the effects of sPLA2 inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES The primary efficacy measure was a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95% CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2 inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01130246.

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

BACKGROUND Some glucose-lowering drugs or strategies adversely affect cardiovascular outcomes. We aimed to assess the extent to which glucose lowering by various drugs or strategies increases the risk of heart failure in patients with or at risk for type 2 diabetes, and to establish whether risk is associated with achieved differences in glycaemia or weight control. METHODS We searched Ovid Medline, the Cochrane Library, and meeting abstracts up to Feb 20, 2015, for large randomised controlled trials of glucose-lowering drugs or strategies that assessed cardiovascular outcomes. The primary endpoint was incidence of heart failure. We derived pooled risk ratios (RRs) with random-effects models. FINDINGS We included data from 14 trials, with mean duration 4·3 (2·3) years, comprising 95 502 patients, of whom 3907 (4%) patients developed a heart failure event. Glucose-lowering drugs or strategies were associated with a 0·50% (SD 0·33) reduction in HbA1c and a 1·7 kg (2·8) weight gain. Overall, glucose-lowering drugs or strategies increased the risk of heart failure compared with standard care (RR 1·14, 95% CI 1·01-1·30; p=0·041). The magnitude of this effect varied dependent on the method of glucose lowering (p for interaction=0·00021). Across drug classes, risk was highest with peroxisome proliferator-activated receptor agonists (RR 1·42, 95% CI 1·15-1·76; six trials), intermediate with dipeptidyl peptidase-4 inhibitors (1·25, 1·08-1·45; two trials), and neutral with insulin glargine (0·90, 0·77-1·05; one trial). Target-based intensive glycaemic control strategies (RR 1·00, 95% CI 0·88-1·13; four trials) and intensive weight loss (0·80, 95% CI 0·62-1·04; one trial) were also not associated with development of heart failure. Meta-regression analysis showed that for every 1·0 kg of weight gain associated with glucose-lowering drugs or strategies, there was a 7·1% (95% CI 1·0-13·6) relative increase in the risk of heart failure compared with standard care (p=0·022). INTERPRETATION Compared with standard care, glycaemic lowering by various drugs or strategies might increase the risk of heart failure, with the magnitude of risk dependent on the method of glucose lowering and, potentially, weight gain. FUNDING None.

Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Moderate or Severe Renal Impairment: Observations From the SAVOR-TIMI 53 Trial

OBJECTIVE The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with few treatment options. We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial according to baseline renal function. RESEARCH DESIGN AND METHODS Patients with T2DM at risk for cardiovascular events were stratified as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m2; n = 13,916), moderate renal impairment (eGFR 30–50 mL/min/1.73 m2; n = 2,240), or severe renal impairment (eGFR <30 mL/min/1.73 m2; n = 336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ≥0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95–2.91], P < 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28–6.28], P < 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50 mL/min/1.73 m2 (HR 1.23 [95% CI 0.99–1.55]), eGFR 30–50 mL/min/1.73 m2 (HR 1.46 [95% CI 1.07–2.00]), and in patients with eGFR <30 (HR 0.94 [95% CI 0.52–1.71]). Patients with renal impairment achieved reductions in microalbuminuria with saxagliptin (P = 0.041) that were similar to those of the overall trial population. CONCLUSIONS Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function.

Impact of Diabetes Mellitus on Hospitalization for Heart Failure, Cardiovascular Events, and Death Outcomes at 4 Years From the Reduction of Atherothrombosis for Continued Health (REACH) Registry

Background —Despite the known association of diabetes with cardiovascular events, there are few contemporary data on the long-term outcomes from international cohorts of patients with diabetes. We sought to describe cardiovascular outcomes at 4 years and identify predictors of these events in patients with diabetes. Methods and Results —The REACH registry is an international registry of patients at high risk of atherothrombosis or established atherothrombosis. Four-year event rates in patients with diabetes were determined using the corrected group prognosis method. Of the 45,224 patients in the REACH registry who had follow-up at 4 years, 43.6% (n=19,699) had diabetes at baseline. The overall risk and hazard rate of cardiovascular death, non-fatal MI, or non-fatal stroke was greater in patients with diabetes compared to patients without (16.5% vs. 13.1%, HR adj 1.27, 95% CI 1.19-1.35). There was also an increase in both cardiovascular death (8.9% vs. 6.0%, HR adj 1.38, 95% CI 1.26-1.52) and overall death (14.3% vs. 9.9%, HR adj 1.40, 95% CI 1.30-1.51). Diabetes was associated with a 33% greater risk of hospitalization for heart failure (9.4% vs. 5.9%, OR adj 1.33, 95% CI 1.18-1.50). In patients with diabetes, heart failure at baseline was independently associated with CV death (HR adj 2.45, 95% CI 2.17-2.77, p adj 4.72, 95% CI 4.22-5.29, p<0.001). Conclusions —Diabetes increases substantially the risk of death, ischemic events and heart failure. Patients with both diabetes and heart failure are at particularly elevated risk of cardiovascular death, highlighting the need for additional therapies in this high-risk population.Background— Despite the known association of diabetes mellitus with cardiovascular events, there are few contemporary data on the long-term outcomes from international cohorts of patients with diabetes mellitus. We sought to describe cardiovascular outcomes at 4 years and to identify predictors of these events in patients with diabetes mellitus. Methods and Results— The Reduction of Atherothrombosis for Continued Health (REACH) registry is an international registry of patients at high risk of atherothrombosis or established atherothrombosis. Four-year event rates in patients with diabetes mellitus were determined with the corrected group prognosis method. Of the 45 227 patients in the REACH registry who had follow-up at 4 years, 43.6% (n=19 699) had diabetes mellitus at baseline. The overall risk and hazard ratio (HR) of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were greater in patients with diabetes compared with patients without diabetes (16.5% versus 13.1%; adjusted HR, 1.27; 95% confidence interval [CI] 1.19–1.35). There was also an increase in both cardiovascular death (8.9% versus 6.0%; adjusted HR, 1.38; 95% CI, 1.26–1.52) and overall death (14.3% versus 9.9%; adjusted HR, 1.40; 95% CI, 1.30–1.51). Diabetes mellitus was associated with a 33% greater risk of hospitalization for heart failure (9.4% versus 5.9%; adjusted odds ratio, 1.33; 95% CI, 1.18–1.50). In patients with diabetes mellitus, heart failure at baseline was independently associated with cardiovascular death (adjusted HR, 2.45; 95% CI, 2.17–2.77; P<0.001) and hospitalization for heart failure (adjusted odds ratio, 4.72; 95% CI, 4.22–5.29; P<0.001). Conclusions— Diabetes mellitus substantially increases the risk of death, ischemic events, and heart failure. Patients with both diabetes mellitus and heart failure are at particularly elevated risk of cardiovascular death, highlighting the need for additional therapies in this high-risk population.

Impact of Diabetes on Hospitalization for Heart Failure, Cardiovascular Events, and Death: Outcomes at 4 Years from the REACH Registry

Background —Despite the known association of diabetes with cardiovascular events, there are few contemporary data on the long-term outcomes from international cohorts of patients with diabetes. We sought to describe cardiovascular outcomes at 4 years and identify predictors of these events in patients with diabetes. Methods and Results —The REACH registry is an international registry of patients at high risk of atherothrombosis or established atherothrombosis. Four-year event rates in patients with diabetes were determined using the corrected group prognosis method. Of the 45,224 patients in the REACH registry who had follow-up at 4 years, 43.6% (n=19,699) had diabetes at baseline. The overall risk and hazard rate of cardiovascular death, non-fatal MI, or non-fatal stroke was greater in patients with diabetes compared to patients without (16.5% vs. 13.1%, HR adj 1.27, 95% CI 1.19-1.35). There was also an increase in both cardiovascular death (8.9% vs. 6.0%, HR adj 1.38, 95% CI 1.26-1.52) and overall death (14.3% vs. 9.9%, HR adj 1.40, 95% CI 1.30-1.51). Diabetes was associated with a 33% greater risk of hospitalization for heart failure (9.4% vs. 5.9%, OR adj 1.33, 95% CI 1.18-1.50). In patients with diabetes, heart failure at baseline was independently associated with CV death (HR adj 2.45, 95% CI 2.17-2.77, p adj 4.72, 95% CI 4.22-5.29, p<0.001). Conclusions —Diabetes increases substantially the risk of death, ischemic events and heart failure. Patients with both diabetes and heart failure are at particularly elevated risk of cardiovascular death, highlighting the need for additional therapies in this high-risk population.Background— Despite the known association of diabetes mellitus with cardiovascular events, there are few contemporary data on the long-term outcomes from international cohorts of patients with diabetes mellitus. We sought to describe cardiovascular outcomes at 4 years and to identify predictors of these events in patients with diabetes mellitus. Methods and Results— The Reduction of Atherothrombosis for Continued Health (REACH) registry is an international registry of patients at high risk of atherothrombosis or established atherothrombosis. Four-year event rates in patients with diabetes mellitus were determined with the corrected group prognosis method. Of the 45 227 patients in the REACH registry who had follow-up at 4 years, 43.6% (n=19 699) had diabetes mellitus at baseline. The overall risk and hazard ratio (HR) of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were greater in patients with diabetes compared with patients without diabetes (16.5% versus 13.1%; adjusted HR, 1.27; 95% confidence interval [CI] 1.19–1.35). There was also an increase in both cardiovascular death (8.9% versus 6.0%; adjusted HR, 1.38; 95% CI, 1.26–1.52) and overall death (14.3% versus 9.9%; adjusted HR, 1.40; 95% CI, 1.30–1.51). Diabetes mellitus was associated with a 33% greater risk of hospitalization for heart failure (9.4% versus 5.9%; adjusted odds ratio, 1.33; 95% CI, 1.18–1.50). In patients with diabetes mellitus, heart failure at baseline was independently associated with cardiovascular death (adjusted HR, 2.45; 95% CI, 2.17–2.77; P<0.001) and hospitalization for heart failure (adjusted odds ratio, 4.72; 95% CI, 4.22–5.29; P<0.001). Conclusions— Diabetes mellitus substantially increases the risk of death, ischemic events, and heart failure. Patients with both diabetes mellitus and heart failure are at particularly elevated risk of cardiovascular death, highlighting the need for additional therapies in this high-risk population.

Cardiovascular Actions and Clinical Outcomes With Glucagon-like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors

Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], −13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], −24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of type 2 diabetes mellitus, obesity, and nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of cardiovascular disease.