Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

This review examines recent randomized controlled cardiovascular (CV) outcome trials of glucose-lowering therapies in type 2 diabetes and their impact on the treatment of patients with type 2 diabetes. The trials were designed to comply with regulatory requirements to confirm that major adverse cardiac events (MACE) are not detrimentally affected by such therapies. Trials involving dipeptidyl peptidase-4 (DPP-4) inhibitors did not alter a composite MACE outcome comprising CV deaths, non-fatal myocardial infarction and non-fatal stroke; however, the possibility that some members of this class might incur a small increased risk or worsening of heart failure cannot be excluded. Some studies on glucagon-like peptide-1 receptor agonists (liraglutide: LEADER trial; semaglutide: SUSTAIN-6 trial) found significant benefits for MACE, while treatment with sodium-glucose co-transporter-2 inhibitors (empagliflozin: EMPA-REG OUTCOME trial; canagliflozin: CANVAS trial) also significantly reduced MACE and reduced hospitalization for heart failure. Comparisons among trials are complicated by variance in the populations recruited, particularly CV status at randomization, and differences in trial design, data collection and analyses. A large proportion of patients recruited into these trials have previously experienced adverse CV events; thus, the therapies are mostly assessing secondary prevention of a further event. This contrasts with the overall type 2 diabetes population receiving glucose-lowering therapies, of whom the majority will not have had MACE and will be regarded as primary prevention. Overall, the trials provide reassuring evidence that new glucose-lowering medications do not adversely affect CV events and some of these agents may offer CV protection.     

Network meta-analysis of nine large cardiovascular outcome trials of new antidiabetic drugs

The aim of this network meta-analysis (NMA) was to indirectly compare the cardiovascular (CV) safety of new antidiabetic medications in patients with type 2 diabetes mellitus (T2DM).Data synthesisA search of the Embase and MEDLINE databases was conducted systematically to identify cardiovascular outcome trials (CVOTs) of new antidiabetic medications (DPP-4 inhibitors, GLP-1 agonists and SGLT-2 inhibitors) in patients with T2DM. The primary outcomes were the composite endpoint of CV death, nonfatal MI, and nonfatal stroke (MACE), death from CV causes, nonfatal MI, nonfatal stroke and death from any cause. Hospitalization for HF and unstable angina were evaluated as secondary endpoints. A total of 9 trials, including 87,162 patients, met the eligibility criteria and were retained for the analysis.The NMA results showed no significant differences among the DPP-4 inhibitors (sitagliptin, alogliptin, and saxagliptin) in any of the CV endpoints. Similarly, no significant changes were seen in the NMA among the GLP-1 receptor agonists nor the SGLT-2 inhibitors. The pairwise meta-analysis showed that DPP-4 inhibitors have a CV safety profiled comparable to placebo. GLP-1 agonists on the other hand, showed significant reduction in MACE (RR 0.92; 95% CI 0.87–0.97), death from CV causes (RR = 0.88; 95% CI 0.80–0.97), and death from any cause (RR = 0.89; 95% CI 0.82–0.96). SGLT-2 inhibitors showed significant reduction in hospitalization for heart failure events (RR 0.72; 95% CI 0.6–0.86) compared to placebo.ConclusionThis meta-analysis has shown that new antidiabetic medications do not impose any additional CV risk. The indirect comparison among the medications of each class resulted in no significant changes regarding CV endpoints and death from any cause.     

Effects of sodium-glucose cotransporter-2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have been shown to mitigate the risks of cardiovascular (CV) and renal complications in patients with type 2 diabetes (T2D) and CV risk factors or CV disease (CVD). In CV outcomes trials (CVOTs) of patients with T2D and established CVD or multiple CV risk factors, empagliflozin and canagliflozin were associated with significant reductions in the risks of major adverse CV events (MACE), hospitalization for heart failure (HF) and kidney disease progression. In the DECLARE–TIMI 58 study, in which the majority of patients did not have established CVD, dapagliflozin was associated with significant reductions in the composite end point of CV death or hospitalization for HF and was noninferior to placebo with regard to MACE; although patients had relatively good renal function, dapagliflozin also showed renal benefits similar to those seen with empagliflozin and canagliflozin. This article reviews the increased risk of CVD and renal disease in patients with T2D and discusses the potential mechanisms of the cardioprotective and renoprotective effects of SGLT-2i therapy. The observed improvements in CV and renal outcomes with SGLT-2is in CVOTs suggest a class effect in this patient population and have influenced treatment guidelines for the way add-on therapy to metformin is initiated in patients with T2D and high CV risk. The overall cardioprotective and renoprotective effects of SGLT-2is in patients with T2D and high CV risk are most likely attributable to multiple mechanisms, including cardiac, haemodynamic, metabolic, anti-inflammatory and renal effects.     

Impact of cardiovascular outcomes on the development and approval of medications for the treatment of diabetes mellitus

All medications currently approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus are indicated to improve glycemic control. Since 1995, FDA has used HbA1c as the primary basis for approval of these therapies because a reduction in blood glucose lessens the symptoms of hyperglycemia and lowering of HbA1c has been shown to reduce the risk for some of the chronic complications of diabetes. Despite evidence of clinical benefit with therapies that reduce HbA1c, concerns have been raised that some diabetes medications may increase cardiovascular risk in a patient population that is already vulnerable to cardiovascular disease. Therefore, FDA convened a public advisory committee meeting to discuss the role of cardiovascular assessment in the pre-approval and post-approval settings for medications developed for the treatment of type 2 diabetes. After considering the advisory panel’s recommendations and other data, FDA published a guidance document requesting evidence showing that new treatments for type 2 diabetes do not result in an unacceptable increase in cardiovascular risk. This review article begins by summarizing the events leading up to publication of this guidance. Subsequent sections discuss the guidance itself as well as general considerations for implementing the new cardiovascular recommendations. The new approach to developing medications for the treatment of type 2 diabetes will lead to evaluation in patients more representative of those who will use these therapies, if approved, and will help healthcare providers make informed decisions when choosing a medication within the growing treatment armamentarium for type 2 diabetes.     

Navigating the “MACE” in Cardiovascular Outcomes Trials and decoding the relevance of Atherosclerotic Cardiovascular Disease benefits versus Heart Failure benefits

The publication of results from recent cardiovascular outcome trials (CVOTs) has transformed the landscape of diabetes treatment. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose co-transporter-2 (SGLT2) inhibitors have demonstrated CV benefits in large, well-conducted, randomized studies. Today, empagliflozin, canagliflozin and liraglutide are US Food and Drug Administration-approved not only for glucose-lowering, but also to reduce the risk of cardiovascular (CV) events/CV mortality in people with type 2 diabetes (T2DM) and established CV disease (CVD)/high CVD risk. Although the CVOTs were primarily powered for CV safety (non-inferiority), they also demonstrated CV efficacy (superiority). This initially surprised many in the diabetes community, but the replication of the CV benefits with different compounds in the same class alleviated concerns about the CV benefits being chance findings. However, many questions remain. While the heterogeneity in the CV benefits in the various CVOTs can be attributed to the variability in CV risk in the different studies, the reason(s) for the differences in the CV benefits between the GLP-1RA class and the SGLT2 inhibitor class appear to be more complex. An analysis of major adverse cardiovascular events (MACE) in the CVOTs shows that the CV benefits of GLP-1RAs are predominantly specific to atherosclerotic CV events (non-fatal myocardial infarction [MI], non-fatal stroke and CV death). By contrast, the SGLT2 inhibitors do not have any significant effects on atherosclerotic CV events (non-fatal MI/stroke). Their benefits are predominantly on hospitalization for heart failure (HF), suggesting effects primarily on myocardial function (“the pump”), and not on the “pipes” (coronary arteries). In the present review, we discuss the rationale for the conduct of CVOTs, highlight the inability of the classic three-point MACE to capture the entire spectrum of atherosclerotic and non-atherosclerotic CVD morbidity, especially HF in T2DM, and discuss the results of the CVOTs with a focus on the clinical significance of atherosclerotic CVD (ASCVD) versus HF, which develops in a sizeable proportion of people with diabetes and without prior ASCVD.     

What have we learned about renal protection from the cardiovascular outcome trials and observational analyses with SGLT2 inhibitors?

Over the past 5 years, sodium-glucose cotransport 2 (SGLT2) inhibitors have been increasingly regarded as glycaemic agents with cardiovascular (CV) and renal protective effects. The CV benefits of SGLT2 inhibitors have been well established in patients with type 2 diabetes (T2D) and a range of CV comorbidities at baseline. Subsequently, the renal benefits of SGLT2 inhibitors were established in the CREDENCE trial, a dedicated renal outcome trial where canagliflozin reduced the primary composite renal outcome by 30%. In light of these trials, clinical practice guidelines have rapidly evolved, recommending the use of SGLT2 inhibitors as renal and cardioprotective agents in appropriate patient populations. Accordingly, it is important to have an in-depth understanding of the evidence underlying the use of SGLT2 inhibitors in patients with T2D based on published clinical trials and real-world evidence (RWE) studies, as well as information related to potential safety concerns. To accomplish this, we reviewed the evidence for renal protection and safety with SGLT2 inhibitors in the EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58 CV safety trials, and in the growing body of evidence emerging from real-world studies. This body of work has shown that SGLT2 inhibitors reduce the risk of surrogate renal endpoints such as albuminuria and mitigate the risk of hard renal endpoints including doubling of serum creatinine and end-stage kidney disease in patients with T2D.     

Improving heart failure outcomes with sodium-glucose cotransporter 2 inhibitors in different patient groups

Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) were originally developed for the treatment of hyperglycaemia in type 2 diabetes. Because of regulatory requirements to show the safety of this new class of drugs, a large randomized cardiovascular (CV) outcomes trial was completed but this showed that instead of having a neutral effect on heart failure (HF) outcomes, that these drugs could reduce HF outcomes in this population. Subsequent trials with SGLT-2is have shown that HF hospitalizations are reduced by 30% and CV death or HF hospitalization by 21% in patients with type 2 diabetes. These findings have extended to patients with HF with reduced and mildly reduced or preserved ejection fraction in whom further HF hospitalizations are reduced by 28% and CV death or HF hospitalizations reduced by 23%, and that it is becoming a central therapy for the treatment of HF. Moreover, the benefit in patients with HF is observed regardless of the presence or absence of type 2 diabetes. Similarly, in patients with chronic kidney disease and albuminuria, with and without type 2 diabetes, the benefit of SGLT-2is is clearly seen with a 44% reduction in HF hospitalization and 25% reduction in CV death or HF hospitalization. These trials support the use of SGLT-2is in improving HF outcomes in a broad range of patients, from those with type 2 diabetes, chronic kidney disease and those with pre-existing HF regardless of ejection fraction.     

Making sense of newer treatment options for type 2 diabetes

Over the past decade, several new medications have been developed to treat type 2 diabetes mellitus. Large‐scale outcome trials have been performed with patients at high cardiovascular risk to assess the cardiovascular safety of these agents. These trials are changing the landscape of diabetes therapy with evidence beyond safety to cardiovascular benefits of sodium‐glucose cotransporter 2 (SGLT‐2) inhibitors and some glucagon‐like peptide‐1 receptor agonists. This review provides an overview of incretin‐based therapies and SGLT‐2 inhibitors with a particular focus on the results of published cardiovascular outcome trials, which have also provided unique opportunities to evaluate uncommon but potentially serious adverse events of these newer agents. The cardiovascular benefits of SGLT‐2 inhibitors and some glucagon‐like peptide‐1 receptor agonists suggest that they may be the preferred choice, usually as an add‐on to metformin, for patients with type 2 diabetes mellitus at high cardiovascular risk.     

The effect of sodium‐glucose cotransporter 2 inhibitors and glucagon‐like peptide 1 agonists on cardiovascular disease in patients with type 2 diabetes

Patients with type 2 diabetes have a significantly increased risk of cardiovascular disease (CVD) compared to the general population—with CVD accounting for two out of every three deaths in patients with diabetes. In 2008, the FDA suggested that CVD risk should be evaluated for any new antidiabetic therapy, leading to a multitude of large CVD outcome trials to assess CVD risk from these medications. Interestingly, several of these outcome trials with new novel antidiabetic therapies have demonstrated a clear and definite CVD advantage at mid‐term follow up in high‐risk patients with T2DM. In this review, we discuss two relatively new classes of diabetic drugs, sodium‐glucose cotransporter 2 inhibitors and glucagon‐like peptide 1 agonists, and their efficacy in improving cardiovascular outcomes.     

Evaluating Cardiovascular Safety of Novel Therapeutic Agents for the Treatment of Type 2 Diabetes Mellitus

Type 2 diabetes increases the risk of developing cardiovascular (CV) complications such as myocardial infarction, heart failure, stroke, peripheral vascular disease, and CV-associated mortality. Strict glycemic control in diabetics has shown improvement in microvascular complications related to diabetes but has been unable to demonstrate major effects on macrovascular complications including myocardial infarction and stroke. Conventional therapies for diabetes that include insulin, metformin, sulfonylureas (SU), and alpha-glucosidase inhibitors have limited and/or controversial data on CV safety based on observational studies not designed or powered to assess CV safety of these medications. In 2008, the US Food and Drug Administration (FDA) revised regulations for the approval of medications for type 2 diabetes by requiring that enough CV events are accrued prior to approval to rule out an upper 95 % confidence interval (95 % CI) for HR of 1.8 for CV events, followed by ruling out an upper 95 % CI for HR of 1.3 in the post-approval period. To date, novel diabetes therapies including peroxisome proliferator-activated receptor (PPAR) gamma agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP 1) analogs, and sodium-glucose transporter-2 (SGL2) inhibitors have been evaluated in CV safety trials. Results from the first major CV outcome studies in type 2 diabetes, SAVOR-TIMI 53 and EXAMINE, have shown that neither saxagliptin nor alogliptin had increases in major CV events relative to placebo in high-risk patients. Ongoing and future trials will elucidate the CV safety for other DPP-4 inhibitors compared to SUs and the GLP-1 agonists versus placebo.     

Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL,a randomized trial

Aim

To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants.

Materials and methods

In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m²). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event-driven trial will continue until 1225 first adjudication-confirmed MACEs have occurred. Enrolment has been completed.

Results

Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m², glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium-glucose cotransporter-2 inhibitors (26.7%) and dipeptidyl peptidase-4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants.

Conclusion

SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD.     

Do GLP-1RAs and SGLT-2is reduce cardiovascular events in women with type 2 diabetes? A systematic review and meta-analysis

AimsThe risk of cardiovascular disease is often underestimated in women. This leads to a delay in controlling the risk factors for cardiovascular disease and even delays in prescribing medications with cardiovascular benefit. Our aim was to explore if glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter-2 inhibitor (SGLT-2i) medications would reduce cardiovascular events in women with type 2 diabetes when atherosclerotic cardiovascular disease (ASCVD) predominates.Materials and methodsWe searched for randomized trials comparing GLP-1RA or SGLT-2i to placebo in people with type 2 diabetes and had a primary outcome exploring major adverse cardiovascular events (MACE). Data concerning women were then extracted. A sensitivity and subgroup analyses were performed according to the class of diabetes medication.ResultsA total of 9 trials (GLP-1RA in 6 trials and SGLT-2i in 3) were included. Of the 84,258 participants enrolled, 30,784 (37%) participants were women. Pooled results showed a statistically significant lower incidence of MACE favouring diabetes medications (GLP-1RA or SGLT-2i) compared to placebo (RR [95%CI] = 0.87 [0.80, 0.94]). On restricting the analysis to GLP-1RA then to SGLT-2i, results remained significant with GLP-1RA but not SGLT-2i.ConclusionsIn women with type 2 diabetes who either have increased cardiovascular risk or established cardiovascular disease and ASCVD predominates, GLP-1RA significantly reduce the incidence of MACE while SGLT-2i result in a non-significant reduction. SGLT-2i may have comparable effect when examined in more studies. GLP-1RA and SGLT-2i should be considered without delay in women with type 2 diabetes and increased risk for cardiovascular disease.     

Heart failure and diabetes: Clinical significance and epidemiology of this two-way association

People with type 2 diabetes (T2DM) and those with prediabetes have an increased risk of heart failure (HF). Longer duration of T2DM correlates with a greater risk of HF, but HF is also seen in patients with recent-onset diabetes. Insulin resistance is more likely to be present in patients with HF. The risk of HF persists even in the face of standard-of-care preventive treatments for atherosclerotic cardiovascular (CV) disease. HF is commonly the presenting symptom of CV disease in people with diabetes and is the most expensive complication of diabetes because of the high cost of hospitalizations. Recently hospitalization for HF has been included in CV outcome trials (CVOTs), including for medications that are used to treat T2DM, which has led to new therapies for all HF patients. In addition, these CVOTs have shown that many drugs used in the therapy of diabetes are either neutral or detrimental in the HF patient and should be used with caution in patients with existing HF or those at high risk of HF. Most recently, sodium-glucose cotransporter-2 receptor blockers have shown efficacy in both HF with reduced ejection fraction (EF) and HF with preserved EF. The only other oral or injectable diabetes agent shown to improve outcomes in both is metformin.     

Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide

In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes in both the “established CV disease” (CVD) and “CV risk factor” subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD from those used in REWIND. The present post hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re-categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P-interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum.     

GLP-1 receptor agonists and cardiovascular outcome trials: An update

Major cardiovascular (CV) outcome trials with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are currently available. These agonists have proven their CV safety, in harmony with the US Food and Drug Administration (FDA) recommendation for antidiabetic drugs. The potential cardioprotective effect of incretin-based therapies is attributed to their multiple non-glycaemic actions in the CV system, including changes in insulin resistance, weight loss, reduction in blood pressure, improved lipid profile and direct effects on the heart and vascular endothelium. Liraglutide, semaglutide and albiglutide have been demonstrated to reduce the risk of major adverse cardiac events (MACE), whereas lixisenatide and extended-release exenatide had a neutral effect. Thus, it is conceivable that there are different drug-specific properties across the class of GLP-1 RAs. In this review, we discuss the results of the five recently published randomised CV outcome trials with GLP-1 RAs, along with the potential differences and the pleiotropic actions of these agents on the CV system.     

Association between uric acid levels and cardio-renal outcomes and death in patients with type 2 diabetes: A subanalysis of EMPA-REG OUTCOME

In the EMPA-REG OUTCOME trial, we explored the association between pre-randomization uric acid level tertile (<309.30 μmol/L; 309.30 to <387.21 μmol/L; ≥387.21 μmol/L) and cardiovascular (CV) death, hospitalization for heart failure (HHF), HHF or CV death, all-cause mortality, three-point major adverse CV events (MACE), and incident or worsening nephropathy. Patients with type 2 diabetes and CV disease received empagliflozin or placebo. The median baseline plasma uric acid level was 344.98 μmol/L, and patients’ baseline characteristics were mainly balanced across tertiles. Baseline uric acid levels were associated with cardio-renal outcomes: in the placebo group, for the highest versus lowest tertile, the multivariable hazard ratios for three-point MACE, HHF or CV death, and incident or worsening nephropathy were 1.22 (95% confidence interval [CI] 0.89–1.67; P = 0.2088), 1.51 (95% CI 1.02–2.23; P = 0.0396) and 1.77 (95% CI 1.33–2.34; P < 0.0001), respectively. When tested as a continuous variable, baseline uric acid was associated with all outcomes in the placebo group. Empagliflozin improved all cardio-renal outcomes across tertiles, with all interaction P values >0.05. Further investigation of these relationships is required.     

Saxagliptin and sitagliptin in adult patients with type 2 diabetes: a systematic review and meta-analysis

The objective of this study is to compare the efficacy and safety of sitagliptin and saxagliptin with placebo and other hypoglycaemic medications in adults with type 2 diabetes. We searched MEDLINE®, Embase, the Cochrane Library and the International Pharmaceuticals from their inception through 3 February 2011. Studies were included of adults with type 2 diabetes that were 12 weeks or more in duration. Meta‐analyses were conducted when included studies were homogenous enough to justify combining their results. A total of 32 articles met inclusion criteria. Sitagliptin 100 mg monotherapy and saxagliptin 5 mg resulted in greater HbA1c reduction compared to placebo [weighted mean difference (WMD) ?0.82%, 95% CI ?0.95 to ?0.70 and WMD ?0.70, 95% CI ?0.84 to ?0.56, respectively]. Sitagliptin was similar to sulfonylureas for HbA1c reduction (WMD 0.08%, 95% CI 0–0.16, 3 trials) and to saxagliptin in one head‐to‐head trial. There was no statistically significant difference in hypoglycaemia between sitagliptin (pooled RR 1.55, 95% CI 0.55–4.36) or saxagliptin (pooled RR 1.04, 95% CI 0.28–3.81) and placebo. Sitagliptin and saxagliptin result in similar modest HbA1c reductions and do not increase the risk of hypoglycaemia unless combined with other therapies. Their role in the long‐term treatment of type 2 diabetes remains unclear given the lack of long‐term data on efficacy, harms and health outcomes.     

Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus

Patients with type 2 diabetes mellitus (DM) have a very high risk for major adverse cardiovascular (CV) events. Previous studies have shown that traditional oral diabetic medications, despite lowering blood glucose levels, generally do not improve CV outcomes. The safety of some oral hypoglycemic medications has been questioned. We aimed to evaluate the CV safety of dipeptidyl peptidase-4 (DPP4) inhibitors, a novel class of oral diabetic medications, by performing a meta-analysis of DPP4 inhibitors for type 2 DM. A search of electronic databases of published and unpublished literature (until September 30, 2011) was performed to identify randomized controlled trials of ≥24 weeks that compared DPP4 inhibitors to other oral diabetic medications. A meta-analysis was performed using fixed and random effects to determine risk ratio (RR) for adverse CV events with DPP4 inhibitor monotherapy compared to other oral diabetic medications or to placebo. Eighteen randomized met our inclusion criteria, comprising 4,998 patients who were randomized to DPP4 inhibitors and 3,546 to a comparator, with a median duration of therapy of 46.4 weeks. In pooled analysis, the RR of any adverse CV event with a DPP4 inhibitor was 0.48 (0.31 to 0.75, p = 0.001), and the RR for nonfatal myocardial infarction or acute coronary syndrome was 0.40 (0.18 to 0.88, p = 0.02). In conclusion, this meta-analysis provides evidence that DPP4 inhibitors are safe from a CV standpoint and may possibly decrease risk of adverse CV events.     

European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose‐lowering drugs in patients with heart failure

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose‐lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase‐4 (DPP‐4) inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA), and sodium–glucose co‐transporter type 2 (SGLT‐2) inhibitors]. Regarding safety of DPP‐4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF hospitalisation. There is no compelling evidence of excess HF risk with the other DPP‐4 inhibitors. GLP‐1 RAs have an overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT‐2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT‐2 inhibitors could be recommended to prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors. The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess whether the results observed with dapagliflozin could be extended to other SGLT‐2 inhibitors in the treatment of HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose‐lowering therapies in patients with HF.     

Effects of sodium glucose cotransporter type 2 inhibitors on heart failure

Heart failure (HF) is emerging as one of the most common cardiovascular (CV) events in patients with type 2 diabetes (T2D), and the one associated with the worst prognosis. T2D and insulin resistance are strong predictors of incident HF, especially HF with preserved ejection fraction (HFpEF). Recent data suggest that even when all traditional risk factors for ASCVD are well controlled, patients with T2D continue to have a substantially greater risk of developing HF—indicating that traditional risk factor control is insufficient from a HF prevention standpoint, and highlighting the need for novel, more effective strategies for both prevention and treatment of heart failure in patients with T2D. Until recently, medications developed for glucose-lowering had, at best, neutral effect on heart failure outcomes in patients with T2D, while several classes of T2D medications had little data in regards to HF risk, and others actually increased the risk of HF hospitalization. Sodium glucose cotransporter type 2 inhibitors (SGLT-2i) have a novel and unique mechanism of action. By inhibiting sodium and glucose reabsorption in the proximal tubule, SGLT-2i result in a number of downstream effects, including glucosuria, weight loss, osmotic diuresis and natriuresis, which should theoretically be beneficial in HF. Three CVOTs of various SGLT-2i (EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58) enrolled markedly different patient populations in terms of ASCVD risk, but have demonstrated robust and consistent benefits in reduction of hospitalization for HF. In a meta-analysis of the three outcomes trials, SGLT-2i significantly reduced the risk of cardiovascular death or hospitalization for HF by 23% and hospitalization for HF by 31%. Although the declines in HF hospitalization with SGLT-2is are impressive, only a small proportion of patients with established HF were enrolled in these trials, and these benefits, therefore, represent primarily a HF prevention signal. Whether this prevention of HF benefit will translate to better outcomes for those patients with established HF (with or without diabetes), and whether it will extend across the spectrum of HF phenotypes (HFrEF and HFpEF) is yet to be determined, and is being actively investigated in several large ongoing trials.