Inhibitor Cardiovascular Outcome Trials Research Articles

GLP-1 receptor agonists and cardiovascular outcomes in patients with type 2 diabetes: Clinical evidence and best practice.

Cardiovascular disease (CVD) is a major cause of death and disability among people with type 2 diabetes (T2D), presenting a significant impact on longevity, patient quality of life, and health care costs. In the United States, attainment of recommended glycemic targets is low and T2D-related cardiovascular complications remain a significant burden. Many glucose-lowering treatment options are available, but glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are recommended in recent guidelines as the preferred add-on therapy to metformin to improve glycemic control. This is particularly the case for patients with T2D and established atherosclerotic CVD, at high risk of atherosclerotic CVD, and/or with chronic kidney disease. Recommendations were based on GLP-1RA and SGLT-2 inhibitor cardiovascular outcomes trials (CVOTs), which consistently showed that these agents pose no additional cardiovascular risk compared with placebo. Three GLP-1RAs (liraglutide, dulaglutide, and subcutaneous semaglutide) demonstrated significantly lower major adverse cardiovascular events versus placebo and are now approved for this indication. However, to realize improvement in outcomes in the clinical setting, organized, systematic, and coordinated approaches to patient management are also needed. For example, nurse-led diabetes self-management education and support programs have been shown to be effective. This article explores T2D management with emphasis on cardiovascular risk and CVOTs performed to date and reviews the clinical experience with GLP-1RAs for managing hyperglycemia and their impact on cardiovascular risk. In addition, practical guidance is given for key health care providers involved in the care of patients with T2D with cardiovascular risk outside of diabetes clinics/endocrinology centers.

External applicability of SGLT2 inhibitor cardiovascular outcome trials to patients with type 2 diabetes and cardiovascular disease

BackgroundRecent treatment guidelines support the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and cardiovascular disease based on the results of cardiovascular outcome trials (CVOTs). Applicability of these trials to everyday patients with type 2 diabetes and cardiovascular disease is however unknown. The aim of this study is to assess the external applicability of SGLT2i CVOTs in daily clinical practice type 2 diabetes patients with established cardiovascular disease.MethodsTrial in- and exclusion criteria from EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS-CV were applied to 1389 type 2 diabetes patients with cardiovascular disease in the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART). To evaluate the difference in cardiovascular risk (MACE) and all-cause mortality between trial eligible and ineligible patients, age and sex-adjusted Cox-regression analyses were performed.ResultsAfter applying trial in- and exclusion criteria, 48% of UCC-SMART patients with type 2 diabetes and cardiovascular disease would have been eligible for DECLARE-TIMI 58, 35% for CANVAS, 29% for EMPA-REG OUTCOME and 21% for VERTIS-CV. Without the eligibility criteria of HbA1c, eligibility was 58–88%. For all trials the observed risk for cardiovascular events and all-cause mortality was similar in eligible and ineligible patients after adjustment for age and gender.ConclusionA large proportion of patients with type 2 diabetes and cardiovascular disease in daily clinical practice would have been eligible for participation in the SGLT2i CVOTs. Trial eligible and ineligible patients have the same risk for MACE and all-cause mortality.

Evaluation of cardiovascular and renal outcomes with ertugliflozin: what is the VERdict from the VERTIS-CV trial?

ABSTRACT Introduction A growing number of antidiabetic agents have demonstrated cardiovascular and renal benefits in cardiovascular outcome trials (CVOTs), despite such trials being principally required to rule out excess cardiovascular risk. Areas covered This article addresses the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS-CV) trial, its background, design, results, and implications. In patients at least 40 years of age with atherosclerotic cardiovascular disease (ASCVD), the VERTIS-CV trial demonstrated ertugliflozin was non-inferior to placebo for major adverse cardiovascular events, though not superior. Ertugliflozin significantly reduced hospitalization for heart failure compared to placebo. The composite renal outcome was not significantly different between groups. Ertugliflozin was generally well tolerated with a safety profile commensurate with other sodium-glucose co-transporter-2 inhibitors (SGLT-2) inhibitors. Expert opinion In patients with type 2 diabetes and ASCVD, ertugliflozin appears safe with a noted non-significant trend toward improved renal outcomes. Approximately 23.7% of patients in the VERTIS-CV trial had heart failure, the highest among SGLT-2 inhibitor CVOTs. The VERTIS-CV trial reaffirms the reduction in heart failure hospitalizations as a likely class effect of SGLT-2 inhibitors. While the trial supports the use of ertugliflozin beyond glycemic control, agents with confirmed superiority for improved cardiovascular outcomes and mortality may be preferred.

Sodium-glucose co-transporter-2 inhibitor cardiovascular outcome trials and generalizability to English primary care.

AimTo identify people in English primary care with equivalent cardiovascular risk to participants in the sodium–glucose co‐transporter‐2 inhibitor (SGLT‐2i) cardiovascular outcome trials (CVOTs). A secondary objective was to report the usage of SGLT‐2is.MethodsCross‐sectional analysis of people registered with participating practices in the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network on the 31 December 2016. We derived: (1) proportions of the primary care population eligible for inclusion in each SGLT‐2i CVOT (CANVAS, DECLARE, EMPA‐REG and VERTIS); (2) characteristics of the eligible population compared with trial participants (demographics, disease duration and vascular risk); and (3) differences within the eligible population prescribed SGLT‐2is.ResultsThe proportions of people with type 2 diabetes (N = 84 394) meeting the inclusion criteria for each CVOT were: DECLARE 27% [95% confidence interval (CI) 26.5–27.1]; CANVAS 17% (16.6–17.1); VERTIS 7% (7.1–7.4); and EMPA‐REG 7% (6.5–6.8). Primary care populations fulfilling inclusion criteria were 5–8 years older than trial cohorts, and <10% with inclusion criteria of each trial were prescribed an SGLT‐2i; a greater proportion were men, and of white ethnicity.ConclusionsThere was variation in proportions of the primary care type 2 diabetes population fulfilling inclusion criteria of SGLT‐2i CVOTs. The more stringent the inclusion criteria, the lower the proportion identified in a primary care setting. Prescription rates for SGLT‐2is were low in this national database, and there were demographic disparities in prescribing.

How Does CREDENCE Inform Best Use of SGLT2 Inhibitors in CKD?

CKD is a common complication in people with diabetes ([1][1]) and contributes to approximately half of all incident cases of ESKD in the developed world ([2][2]). CKD occurs in approximately 40% of people with type 2 diabetes ([3][3]); given the health-related effects of CKD, there is great need for

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

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

Eligibility of patients with type 2 diabetes for sodium-glucose co-transporter-2 inhibitor cardiovascular outcomes trials: An assessment using the Diabetes Collaborative Registry.

Generalizability of findings from cardiovascular outcomes trials (CVOTs) to patients with type 2 diabetes (T2D) in clinical practice is unknown. We assessed the proportions of patients in the Diabetes Collaborative Registry who would have met enrolment criteria for pivotal CVOTs of sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is): EMPA‐REG OUTCOME, CANVAS, DECLARE and VERTIS CV. In 172 643 patients, mean [standard deviation (SD)] age and HbA1c were 68.1 (11.8) years and 7.8% (2.2), respectively; 56.8% of patients were men and SGLT‐2i use was 4.4%. Atherosclerotic cardiovascular disease (ASCVD) prevalence was 64.3% and mean 10‐year ASCVD risk was 28.6% in patients without ASCVD. Proportions of patients eligible for CVOTs ranged from 26% (EMPA‐REG OUTCOME) to 44% (DECLARE); 48% of patients were ineligible for all CVOTs. Mean (SD) ASCVD risk was 25.4% (22.6), 32.1% (20.6) and 37.7% (19.4) in patients eligible for no, one or two CVOTs, respectively. SGLT‐2i use was low in patients eligible for no CVOTs (3.5%) and at least one CVOT (5.2%). In conclusion, applicability of CVOT results to patients with T2D in clinical practice varies based on trial eligibility criteria.

Review of the cardiovascular safety of dipeptidyl peptidase-4 inhibitors and the clinical relevance of the CAROLINA trial

BackgroundCardiovascular (CV) disease (CVD) is a well-recognized complication of type 2 diabetes mellitus (T2DM) and there is a clinical need for glucose-lowering therapies that do not further increase CV risk in this population. Although sulfonylureas (SUs) may be used as second-line therapy for patients requiring additional therapy after first-line metformin to improve glycemic control, their long-term effects on CV outcomes remain uncertain, and a wide range of alternative agents exist including dipeptidyl peptidase-4 (DPP-4) inhibitors.MethodsLiterature searches in PubMed (2013–2018) were conducted with terms for DPP-4 inhibitors combined with CV terms, with preference given to cardiovascular outcomes trials (CVOTs). Reference lists from retrieved articles and diabetes guidelines were also considered.ResultsThis narrative review discusses current evidence for the CV safety of these agents, describes the long-term CV effects of DPP-4 inhibitors, including effects on CV events, mortality, the risk for heart failure hospitalization, and highlights the need for further research into the CV effects of SU therapy. Although SUs remain a treatment option for T2DM, the long-term effects of these agents on CV outcomes are unclear, and further long-term studies are required. For DPP-4 inhibitors, uncertainties have been raised about their long-term effect on hospitalization for heart failure in light of the results of SAVOR-TIMI 53, although the findings of other DPP-4 inhibitor CVOTs in T2DM and data analyses have suggested these agents do not increase the occurrence of adverse CV outcomes.ConclusionsBased on recent CVOTs and guideline updates, the choice of add-on to metformin therapy for patients with T2DM and established CV disease should be a sodium-glucose co-transporter-2 inhibitor or a glucagon-like peptide-1 agonist with proven CV benefit. Additional treatment options for those individuals who require therapy intensification, as well as in patients with T2DM and without established CVD include DPP-4 inhibitors and SUs. Since few head-to-head trials have compared the effects of different oral glucose-lowering agents on CV outcomes in T2DM, with most CVOTs using placebo as a comparator, the CAROLINA trial will provide important information on the comparative CV safety of a commonly prescribed SU and a DPP-4 inhibitor.

Eligibility of patients with type 2 diabetes for sodium–glucose cotransporter 2 inhibitor cardiovascular outcomes trials: a global perspective from the DISCOVER study

ObjectiveTo assess the eligibility of patients participating in DISCOVER (a 3-year, prospective, observational study program of 15 992 patients with type 2 diabetes [T2D] initiating a second-line glucose-lowering therapy across...

Treatment of Heart Failure with Sodium-Glucose Cotransporter 2 Inhibitors and Other Anti-diabetic Drugs.

Patients with type 2 diabetes are at increased risk of developing heart failure, cardiovascular death and renal failure. The recent results of three large sodium-glucose cotransporter 2 inhibitor cardiovascular outcomes trials have demonstrated a reduction in heart failure hospitalisation and progressive renal failure. One trial also showed a fall in cardiovascular and total death. A broad spectrum of patients with diabetes benefit from these salutary effects in cardiac and renal function and so these trials have important implications for the management of patients with type 2 diabetes. Selected glucagon-like peptide 1 receptor agonists have also been shown to reduce adverse cardiovascular outcomes.

Lessons learned from cardiovascular outcome clinical trials with dipeptidyl peptidase 4 (DPP-4) inhibitors.

Previous trials of glucose-lowering strategies in subjects with type 2 diabetes have demonstrated a beneficial effect of intensive glycemic control on microvascular complications but failed to show a clear benefit on cardiovascular complications. The findings of meta-analyses of rosiglitazone trials suggesting that rosiglitazone might increase the risk of myocardial infarction have cast doubt on the cardiovascular safety of glucose-lowering drugs. In 2008, the US Food and Drug Administration has implemented rigorous criteria to approve new glucose-lowering drugs, requiring proof of cardiovascular safety. These regulatory requirements have led to a considerable increase in the number of cardiovascular outcome trials in type 2 diabetes to ensure that newer glucose-lowering drugs are not associated with increased cardiovascular risk. Incretin-based therapies including dipeptidyl peptidase 4 (DPP-4) inhibitors, and injectable glucagon-like peptide 1 (GLP-1) receptor agonists are novel treatment options for patients with inadequate glucose control. Although DPP-4 inhibitors have shown neutral effects on risk factors for cardiovascular diseases, it remains unclear whether treatment with these new glucose-lowering agents might be associated with a reduction in cardiovascular events. The results of the three cardiovascular outcome trials comparing DPP-4 inhibitors treatment to placebo in addition to other glucose-lowering drugs have been published. All the three DPP-4 inhibitor cardiovascular outcome trials have shown non-inferiority with regard to cardiovascular safety, compared with placebo, when added to usual care. In this review, we summarize cardiovascular outcome trials of DPP-4 inhibitors, and provide an overview of these trials and their limitations.