Cardiovascular outcomes with SGLT-2 inhibitors and GLP-1 receptor agonist in Asians with type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials

Background and aimsBoth type 2 diabetes and cardiovascular (CV) disease develops at a younger age in Asians and often have a higher risk of mortality. Both sodium-glucose co-transport-2 inhibitors (SGLT-2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown a significant reduction in CV end-points in CV outcome trials (CVOTs). Whether similar CV benefit exists in Asians, is not yet clearly known.MethodsWe systematically searched relevant medical database up to January 31, 2020 and retrieved all the dedicated CVOTs conducted with SGLT-2Is and GLP-1RAs. Subsequently, we meta-analyzed the pooled data of hazard ratio (HR) of major adverse cardiac events (MACE) in Asians. We additionally analyzed the data of heart failure hospitalization (HHF) or CV-death with SGLT-2Is in Asians.ResultsThe meta-analysis of three CVOTs conducted with SGLT-2Is (N = 4987), did not find any significant reduction in MACE (HR, 0.88; 95% CI, 0.67 to 1.15; P = 0.35) and HHF or CV-death (HR, 0.86; 95% CI, 0.55 to 1.36; P = 0.53) in Asians, compared to the placebo. In contrast, the meta-analysis of seven CVOTs conducted with GLP-1RAs (N = 4298) demonstrated a significant reduction in MACE, compared to the placebo (HR, 0.71; 95% CI, 0.59 to 0.86; P < 0.0001).ConclusionsThis meta-analysis found a significant reduction in MACE with GLP-1RAs but not with SGLT-2Is in Asians. No significant reduction in HHF or CV-death demonstrated either with SGLT-2Is in Asians. Whether these results are related to an inadequate statistical power, or due to underrepresentation of Asians, or a true ethnic difference, remains to be established.     

Cardiovascular benefits of GLP-1RA and SGLT-2i in women with type 2 diabetes

Given the CV benefit noted in the CVOTs, GLP-1RAs and SGLT-2is are given preference in T2DM guidelines. While guidelines do not report potential gender difference, those differences exist. On restricting the CVOTs results to women with increased CV risk or established ASCVD, GLP-1RAs significantly reduced MACE while SGLT-2is resulted in a non-significant reduction.     

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.     

Cardiovascular Outcomes with SGLT-2 inhibitors in patients with heart failure with or without type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials

Background and aimsWe conducted a systematic review and meta-analysis of all the randomized controlled trials (RCTs) with SGLT-2 inhibitors (SGLT-2i) in patients with known heart failure (HF) with or without type 2 diabetes (T2DM), that have studied the outcomes of cardiovascular (CV) death, hospitalization due to HF (HHF), and composite of CV death or HHF.MethodsA systematic search in PubMed, Embase and Cochrane Library database were made up till November 20, 2020 using specific keywords. RCTs that qualified underwent a meta-analysis by applying the inverse variance-weighted averages of pooled logarithmic hazard ratio (HR) using both random- and fixed-effects model.ResultsThis meta-analysis of 9 RCTs (N = 19,741) have found a significant 26% relative risk reduction in composite of CV death or HHF (HR 0.74; 95% CI, 0.69–0.79; p < 0.001) with SGLT-2i in patients with HF. The meta-analysis of 8 RCTs (N = 16,460) also showed a significant reduction in CV death (HR 0.86; 95% CI, 0.78–0.95; p = 0.003) and HHF (HR 0.68; 95% CI, 0.62–0.74; p < 0.001) outcomes with SGLT-2i in patients with HF. Subgroup analysis stratified on baseline ejection fraction (EF) showed a similar benefit in the composite of CV death or HHF in patients with HF with reduced EF (HFrEF) or preserved EF (HFpEF).ConclusionsSGLT-2i significantly reduces the composite of CV death or HHF, CV death, and HHF in patients with HF. Although subgroup analysis suggested an insignificant P_heterogenity for these outcomes irrespective of the types of HF, however, reduction in both CV death and HHF were more pronounced in patients with HFrEF.     

Comparative efficacy of 5 sodium glucose cotransporter 2 inhibitor and 7 glucagon-like peptide 1 receptor agonists interventions on cardiorenal outcomes in type 2 diabetes patients: A network meta-analysis based on cardiovascular or renal outcome trials

Background:Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been demonstrated to be able to improve the cardiovascular and renal prognosis in patients with type 2 diabetes (T2D). However, the relative efficacy of various SGLT2 inhibitors and GLP-1 RAs on cardiorenal outcomes is unestablished.Methods:We searched PubMed and Embase for relevant cardiovascular or renal outcome trials (CVOTs). Endpoints of interest were major adverse cardiovascular events (MACE), stroke, myocardial infarction (MI), cardiovascular death (CVD), all-cause death (ACD), kidney function progression (KFP), and hospitalization for heart failure (HHF). Bayesian network meta-analysis was conducted to produce pooled hazard ratio (HR) and 95% confidence interval (CI). We calculated the probability values of surface under the cumulative ranking curve to rank active and placebo interventions.Results:Fourteen COVTs were included in analysis. Sotagliflozin (HR 0.76, 95% CI 0.61–0.94), subcutaneous semaglutide, and albiglutide lowered MACE versus lixisenatide among others. Sotagliflozin (HR 0.59, 95% CI 0.40–0.89), canagliflozin, and empagliflozin lowered HHF versus subcutaneous semaglutide among others. Dapagliflozin and empagliflozin lowered KFP versus exenatide among others. Empagliflozin and oral semaglutide lowered CVD versus dapagliflozin among others. Sotagliflozin (HR 0.65, 95% CI 0.47–0.91) and albiglutide lowered MI versus ertugliflozin among others. Sotagliflozin (HR 0.56, 95% CI 0.37–0.85) and subcutaneous semaglutide lowered stroke versus empagliflozin among others. Oral semaglutide and empagliflozin lowered ACD versus subcutaneous semaglutide among others. The maximum surface under the cumulative ranking curve values followed sotagliflozin, subcutaneous semaglutide, and albiglutide in lowering MACE; sotagliflozin, canagliflozin, and empagliflozin in lowering HHF; dapagliflozin and empagliflozin in lowering KFP; empagliflozin and oral semaglutide in lowering CVD; sotagliflozin and albiglutide in lowering MI; sotagliflozin and subcutaneous semaglutide in lowering stroke; and oral semaglutide and empagliflozin in lowering ACD.Conclusions:This updated network meta-analysis reproduced the findings in the first network meta-analysis, and moreover revealed that sotagliflozin was one of the most effective drugs as for lowering MI, stroke, MACE, and HHF, whereas ertugliflozin was not. These findings will provide the according evidence regarding the usage of specific SGLT2 inhibitors and GLP-1 RAs in T2D patients for prevention of specific cardiorenal endpoints.     

GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: An updated meta-analysis including the REWIND and PIONEER 6 trials

A meta-analysis of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) and placebo concerning cardiorenal outcomes in patients with type 2 diabetes (T2D) is presented. An electronic search without language restrictions up to June 15, 2019 was conducted to determine eligible trials. A meta-analysis of available trial data was undertaken, using a random-effects model to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Data from seven CVOTs, comprising 56 004 patients (68.9% with established cardiovascular disease) were included. GLP-1RA reduced major cardiovascular events (MACE) by 13% (HR, 0.87; 95% CI, 0.80–0.96; P = 0.011) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (CVD) (P = 0.220). GLP-1RA also reduced the risk of cardiovascular death by 12%, of non-fatal stroke by 16%, of hospitalization for heart failure by 9%, of all-cause mortality by 11%, and the broad composite kidney outcome by 17%; the latter appeared to be driven only by a reduction in macroalbuminuria (HR, 0.76 [0.68–0.86]; P = 0.003). GLP-1RAs have moderate benefits concerning MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also robustly reduce the incidence of macroalbuminuria, without affecting the progression of diabetic renal disease.     

Heart failure and type 2 diabetes: From cardiovascular outcome trials,with hope

An excess risk of heart failure (HF) persists in patients with type 2 diabetes (T2D) despite optimal control of an array of conventional risk factors, including hyperglycaemia. Twelve cardiovascular outcome trials (CVOTs) have been published to date, although none, with the exception of the DECLARE trial with dapagliflozin, has included HF as a primary endpoint. The four trials with dipeptidyl-peptidase inhibitors (DPP-4i) (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin and CARMELINA with linagliptin) failed to show any significant effect on HF risk in patients with T2D, with the notable exception of saxagliptin which was associated with a 27% increased risk. Five completed CVOTs with the GLP-1 RAs lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), exenatide once weekly (EXSCEL) and albiglutide (HARMONY) also failed to reveal any significant effect on HF risk. The three trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) (EMPA-REG OUTCOME with empagliflozin, CANVAS with canagliflozin and DECLARE with dapagliflozin) all revealed a robust and significant reduction in the hazard ratios of hospitalization for HF, from 27% to 35%, which remained consistent, significant and of similar magnitude regardless of the presence of a history of HF or established atherosclerotic cardiovascular disease. There is no association between reductions in HF risk and haemoglobin A1c (A1C) levels, while there is a significant association between reductions in HR for MACE and A1C levels (Spearman's correlation, r = 0.695; P = 0.013). All of the 12 CVOTs completed to date have provided reassurance of the overall cardiovascular safety of the newer anti-hyperglycaemic drugs. At present, the robust, consistent and reproducible reduction of approximately 30% in the risk of HF with SGLT-2i may be considered a class effect. The beneficial effect on MACE outcome observed with the use of some GLP-1RAs and SGLT-2i must be interpreted within the frame of the single trial.     

Heart failure outcomes and glucagon-like peptide-1 receptor agonists: A systematic review of observational studies

Aim/objectiveRecently, the glucagon-like peptide-1 receptor agonists (GLP-1RA) class showed a significant reduction in heart failure (HF) hospitalization in several meta-analyses of cardiovascular outcome trials (CVOTs). The objective of this systematic review is to summarize the real-world evidence regarding HF outcomes of GLP-1RAs.MethodsWe searched the PubMed and EMBASE databases for observational studies that investigated HF outcomes of GLP-1RAs.ResultsOur search yielded 10 observational studies. Of those, 7 were cohort studies, and 3 were nested case-control studies. The risk of HF was the outcome in four cohort studies. One study that compared exenatide and exenatide combined with insulin to insulin showed a reduction in HF risk in the exenatide and exenatide plus insulin groups (HR 0.34, 95% CI 0.22−0.52, p-value <0.001 and HR 0.40, 95% CI 0.32−0.50, p-value <0.001, respectively). The other three cohort studies did not show a statistically significant result. In the three cohort studies that investigated HF hospitalization as an outcome, two showed a lower rate of HF hospitalization [48 (16.7%) vs. 76 (28%), p-value <0.05 and HR 0.51, 95% CI 0.34−0.77, p = 0.002] in the GLP-1RA groups. Conversely, the remaining study showed a reduction of 14% in HF hospitalization in the dipeptidyl peptidase-4 inhibitors (DPP-4i) group compared to the GLP-1RA group (HR 0.86, 95% CI 0.83−0.90). In contrast to the cohort studies, the three nested case-control studies showed similar results of no association of GLP-1RA use and HF hospitalization with OR 0.67 (95% CI 0.32–1.42), HR 0.95 (95% CI 0.83–1.10), and OR 0.84 (95% CI 0.48–1.47), respectively.ConclusionThe real-world evidence regarding the reduction in HF risk and hospitalization in GLP-1RA users is conflicting. Further well-designed, large multicenter, observational studies are needed to show clearer evidence.     

Cardiovascular and mortality outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A meta-analysis with the FREEDOM cardiovascular outcomes trial

Background and aimsFREEDOM, a cardiovascular outcome trial with a GLP-1 receptor agonist, testing a continuous subcutaneous infusion of exenatide (ITCA 650), recently reported its findings.MethodsWe meta-analysed its results with eight prior GLP-1 receptor agonists trials.ResultsGLP-1 receptor agonists reduced MACE by 13% (HR 0.87 [95% CI 0.81–0.94]; p = 0.00065) and all-cause mortality by 11% (HR 0.89 [0.83–0.95]; p = 0.00084). However, FREEDOM results appear dissimilar to prior GLP-1 receptor agonist trials.ConclusionFREEDOM results should not influence current considerations about the benefits or harms of approved formulations of GLP-1 receptor agonists. There is also an ongoing debate about the safety of ITCA 650.     

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.     

Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect?

Purpose of Review

Mimetics and analogs that extend the half-life of native glucagon-like peptide-1 (GLP-1), i.e., glucagon-like peptide-1 receptor agonists (GLP-1 RAs), at therapeutic doses, are indicated as adjuncts to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). In patients with T2DM, GLP-1 RAs not only affect improvements in impaired beta cell and alpha cell function, suppress appetite, and induce weight loss but also possess multiple cardiovascular protective properties that potentially have a beneficial impact on atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality.

Recent Findings

Required to demonstrate CV safety, compared to standard-of-care antidiabetic therapies, GLP-1 RAs have revealed statistically significant non-inferiority (p?<?0.001), among CV outcome trials (CVOTs) thus far completed. Once-daily liraglutide and once-weekly semaglutide demonstrated significant superiority (p?=?0.01 and p?=?0.02, respectively), reducing 3-point composite major adverse cardiovascular events (MACE) in extreme risk secondary prevention adults with T2DM. Once-weekly exenatide demonstrated only a non-significant (p?=?0.06) favorable trend for CV superiority, possibly due to in-trial mishaps, including placebo drop-ins with other CV protective medications. The short half-life lixisenatide was neutral (p?=?0.81) in reducing MACE, most likely due to ineffective once-daily dosing. Structural differences among GLP-1 mimetics and analogs may explain potency differences in both A1C reduction and weight loss that may parallel important cardiovascular protective properties of the GLP-1 RA class.

Summary

Significant superiority in reducing 3-point composite MACE in adults with T2DM with GLP-1 RAs has been limited to liraglutide and semaglutide. Careful attention to within-trial drop-in of cardioprotective antidiabetic agents assuring equipoise between placebo and investigational product groups might demonstrate significant MACE risk reduction with once-weekly exenatide. Maintenance of 24-h circulating levels, by an alternative administration method, may resurrect lixisenatide as a cardioprotective agent. Before a GLP-1 RA bioequivalence “class effect” claim for composite MACE risk reduction superiority can be fully discussed, we are obliged to wait for the pending results of CVOTs with other GLP-1 RAs, particularly albiglutide and dulaglutide, where steric hindrance may potentially inhibit full mimicry of pharmacologic GLP-1.

     

Association between sodium glucose co-transporter 2 inhibitors and incident glaucoma in patients with type 2 diabetes: A multi-institutional cohort study in Taiwan

PurposeType 2 diabetes (T2D) is an important risk factor for glaucoma, and sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to protect the optic nerves. We therefore aimed to evaluate the association between SGLT2 inhibitors and incident glaucoma.MethodsThis retrospective cohort study analyzed the largest multi-institutional electronic medical records database in Taiwan, containing data of over a million individuals. We included T2D patients newly prescribed SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) from 2016 to 2018. Our primary outcome was incident glaucoma diagnosis between initiation of SGLT2 inhibitors or GLP-1 RAs, and 31st March 2021. After applying inverse probability of treatment weighting (IPTW) to increase homogeneity between the two treatment groups, we estimated hazard ratios (HR) with 95% confidence intervals (CI) for the risk of glaucoma, based on Cox proportional hazards regression models.ResultsWe included 9,927 and 1,065 T2D patients who had been newly prescribed SGLT2 inhibitors or GLP-1 RAs, respectively. Lower risk of incident glaucoma was observed in patients receiving SGLT2 inhibitors (7.9 events per 1,000 person-years), compared to those receiving GLP-1 RAs (10.0 events per 1,000 person-years), with an HR of 0.81 (95% CI: 0.69–0.95). Multiple sensitivity analyses and a negative control outcome analysis confirmed the robustness of our main findings.ConclusionThis study suggests that T2D patients newly prescribed SGLT2 inhibitors have a reduced risk of incident glaucoma, compared to those prescribed GLP-1 RAs, in clinical practice. Future prospective studies are suggested to confirm this association.     

Prognostic Value of Stress Cardiac Magnetic Resonance in Patients With Known Coronary Artery Disease

ObjectivesThis study sought to determine whether stress cardiac magnetic resonance (CMR) provides clinically relevant risk reclassification in patients with known coronary artery disease (CAD) in a multicenter setting in the United States.BackgroundDespite improvements in medical therapy and coronary revascularization, patients with previous CAD account for a disproportionately large portion of CV events and pose a challenge for noninvasive stress testing.MethodsFrom the Stress Perfusion Imaging in the United States (SPINS) registry, we identified consecutive patients with documented CAD who were referred to stress CMR for evaluation of myocardial ischemia. The primary outcome was nonfatal myocardial infarction (MI) or cardiovascular (CV) death. Major adverse CV events (MACE) included MI/CV death, hospitalization for heart failure or unstable angina, and late unplanned coronary artery bypass graft. The prognostic association and net reclassification improvement by ischemia for MI/CV death were determined.ResultsOut of 755 patients (age 64 ± 11 years, 64% male), we observed 97 MI/CV deaths and 210 MACE over a median follow-up of 5.3 years. Presence of ischemia demonstrated a significant association with MI/CV death (HR: 2.30; 95% CI: 1.54-3.44; P < 0.001) and MACE (HR: 2.24 ([95% CI: 1.69-2.95; P < 0.001). In a multivariate model adjusted for CV risk factors, ischemia maintained strong association with MI/CV death (HR: 1.84; 95% CI: 1.17-2.88; P = 0.008) and MACE (HR: 1.77; 95% CI: 1.31-2.40; P < 0.001) and reclassified 95% of patients at intermediate pretest risk (62% to low risk, 33% to high risk) with corresponding changes in the observed event rates of 1.4% and 5.3% per year for low and high post-test risk, respectively.ConclusionsIn a multicenter cohort of patients with known CAD, CMR-assessed ischemia was strongly associated with MI/CV death and reclassified patient risk beyond CV risk factors, especially in those considered to be at intermediate risk. Absence of ischemia was associated with a <2% annual rate of MI/CV death. (Stress CMR Perfusion Imaging in the United States [SPINS] Study; NCT03192891)     

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.     

Cardiovascular outcomes trials with glucagon-like peptide-1 receptor agonists: A comparison of study designs,populations and results

Despite treatment advances leading to improved outcomes over the past 2 decades, cardiovascular (CV) disease (CVD) remains the leading cause of morbidity and mortality in people with diabetes. People with type 2 diabetes (T2D) have a 2- to 4-fold increased risk of CVD and CV death. Individuals with T2D have not seen the same improvements in CV morbidity and mortality as those without T2D. Given this, it is important to understand the CV impact of drugs used to treat T2D. In patients with T2D, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a reduction in HbA1c and body weight regardless of their differences in chemical structure and pharmacokinetic variables. Glycaemic efficacy, accompanied by the potential for weight reduction and a low risk of hypoglycaemia, has moved GLP-1 RAs to the first treatment of choice following metformin monotherapy in the latest American Diabetes Association treatment guidelines. Additionally, all GLP-1 RAs have shown CV safety and several have proven CV benefit. GLP-1 RAs have been evaluated in cardiovascular outcomes trials (CVOTs) of varying sizes, designs and patient populations with differing reported effects on CV outcomes. The purpose of this article is to review the completed GLP-1 RA CVOTs with special attention to how their design, size, patient populations and conduct may influence the interpretation of results.     

Effects of glucagon-like peptide-1 receptor agonists on major coronary events in patients with type 2 diabetes

Aims

To perform a meta-analysis to assess the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on major coronary events, including myocardial infarction (MI), unstable angina and coronary revascularization, in patients with type 2 diabetes mellitus (T2DM).

Materials and methods

We systematically searched the PubMed, CENTRAL, EMBASE and clinicaltrial.gov databases to seek eligible studies with a cardiovascular endpoint comparing GLP-1RAs with a placebo in T2DM patients. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated for the outcomes.

Results

Nine studies, with a total of 64 236 patients, were included. GLP-1RA treatment reduced fatal and nonfatal MI by 8% (OR 0.92, 95% CI 0.86–0.99; P = 0.02, I² = 39%). The reduction reached 15% in human-based GLP-1RA-treated patients. Similarly, once-weekly GLP-1RA treatment reduced the risk of MI by 13%. In contrast, GLP-1RA treatment did not reduce the risk of hospitalization for unstable angina (OR 1.11, 95% CI 0.97–1.28; P = 0.13, I² = 21%). GLP-1RAs exhibited a tendency to lower the risk of coronary revascularization (OR 0.95, 95% CI 0.89–1.02; P = 0.15, I² = 22%), but without statistical significance. Human-based GLP-1RAs decreased the risk by 11%.

Conclusions

In high-risk patients with T2DM, GLP-1RAs were associated with a decrease in MI, especially the human-based and once-weekly GLP-1RAs. No benefit was seen for hospitalization for unstable angina or coronary revascularization. Further research is urgently needed to ascertain improvements in coronary events.     

Biologic Agents Reduce Cardiovascular Events in Rheumatoid Arthritis Not Responsive to Tumour Necrosis Factor Inhibitors: A National Cohort Study

BackgroundTumour necrosis factor inhibitors (TNFis) improve joints outcomes and reduce cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). However, 20%-45% of RA patients are TNFi poor responders and have a significantly higher risk of CV events. In these TNFi nonresponders, the use of second-line biologic agents to improve synovial outcomes is supported by clinical trials and real-world experience. However, it remains unknown what kind of immune-mediated agent has the best CV prevention effect in this high-risk population.MethodsA nationwide RA cohort obtained from Taiwan’s National Health Insurance claims database was constructed. RA patients first treated with TNFis who then received either rituximab, tocilizumab, or abatacept were enrolled and followed for 2 years.ResultsA total of 89,973 RA patients were screened and 1,584 patients ultimately included. The incidences of major adverse cardiac events (MACE) at 2 years in the rituximab, tocilizumab, and abatacept groups were 7.17%, 2.75% and 2.38%, respectively. Multivariate adjusted Cox analysis showed that tocilizumab had significantly lower risk than rituximab in myocardial infarction (hazard ratio [HR] 0.12, 95% confidence interval [CI] 0.02-0.56; P = 0.008), and MACE (HR 0.41, 95% CI 0.23-0.72; P = 0.002). In addition, abatacept also had significant lower adjusted risk than rituximab in stroke (HR 0.18, 95% CI 0.05-0.64; P = 0.008), heart failure (HR 0.20, 95% CI 0.05-0.83; P = 0.027), and MACE (HR 0.25, 95% CI 0.11-0.55; P < 0.001) in multivariate analysis.ConclusionsTNFi-nonresponder patients with RA who received second-line tocilizumab or abatacept had more benefit on CV events prevention compared with those who received rituximab.     

Effect of new glucose-lowering drugs on stroke in patients with type 2 diabetes: A systematic review and Meta-analysis

AimsPeople with diabetes tend to face a higher risk of stroke. Randomized controlled trials (RCTs) have demonstrated the different outcomes of new glucose-lowering drugs marketed in recent years on cardiovascular outcome events. The effects of glucagon-like peptide-1 (GLP-1) agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors on stroke risk were evaluated in published RCTs.MethodsA search of Embase, Cochrane Library, and PubMed databases identified studies with stroke as an outcome event up to 3 December 2021. Risk ratios for stroke outcomes were analyzed using a fixed-effects model. I² was used to assess the heterogeneity of the study.Results19 RCTs with 155,027 participants with type 2 diabetes were identified. Pooled analysis showed that compared to placebo, GLP-1 agonists reduced non-fatal stroke by 15 % (RR = 0.85, 95%CI 0.77–0.94, P = 0.002, I² = 0 %) and total stroke (RR = 0.84, 95%CI 0.77–0.93, P = 0.000, I² = 0 %) by 16 %. SGLT-2 inhibitors and DPP-4 inhibitors were not significantly associated with lower stroke risk.ConclusionsThis meta-analysis indicates that GLP-1 agonists have potential benefits for stroke. However, further studies are needed if GLP-1 agonists are to be used to reduce the risk of stroke in patients with type 2 diabetes. More research is also needed to investigate the effects of new glucose-lowering drugs on different stroke subtypes.Systematic review registrationThis protocol was registered on the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/PROSPERO/; registration number: CRD42022326382).     

Glucagon-like peptide-1 receptor agonists or sodium–glucose cotransporter-2 inhibitors as add-on therapy for patients with type 2 diabetes? A systematic review and meta-analysis of surrogate metabolic endpoints

ObjectiveAs sodium–glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are second-line treatment options in type 2 diabetes mellitus (T2DM), our study sought to provide precise effect estimates regarding the role of GLP-1RAs vs SGLT-2is as add-on treatments in patients uncontrolled by metformin monotherapy.Research design and methodsPubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) and ‘grey literature’ were searched from their inception up to December 2019 for randomized controlled trials (RCTs) with durations ≥ 12 weeks to evaluate the safety and efficacy of adding a GLP-1RA vs an SGLT-2i in patients with T2DM.ResultsThree eligible RCTs were identified. Administration of GLP-1RAs vs SGLT-2is resulted in significant decreases in HbA1c with no significant impact on either body weight or fasting plasma glucose. GLP-1RA treatment led to a significant increase in odds for achieving an HbA1c < 7% compared with SGLT-2is, whereas no difference was detected in body weight reductions of > 5%. Significantly greater risk for any hypoglycaemia, nausea and diarrhoea, and lower risk for genital infections, was also observed with GLP-1RAs, while no differences regarding severe hypoglycaemia, treatment discontinuation and impact on blood pressure levels were identified. No other major safety issues arose.ConclusionOur meta-analysis suggests that GLP-1RAs provide better glycaemic effects than SGLT-2is in patients with T2DM uncontrolled by metformin, albeit while increasing risk for hypoglycaemia and gastrointestinal adverse events.     

Comparison of glucagons like peptide-1 receptor agonists and dipeptidyl peptide-4 inhibitors regarding cardiovascular safety and mortality in type 2 diabetes mellitus: A network meta-analysis

AimThe effects of dipeptidyl peptide-4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) on type 2 diabetes mellitus (T2DM) on cardiovascular events and all-cause mortality were compared.MethodsThe literature on DPP-4is and SGLT-2is treatment of T2DM was searched through Pubmed, Embase, and the web of science databases with the search deadline May 15, 2020. Network meta-analysis (NMA) was used to compare the effects of two types of inhibitors on cardiovascular events (major adverse cardiovascular events (MACE), nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular (CV) death) and all-cause mortality in T2DM patients.ResultsA total of 15 articles were screened, including 125,796 patients. Compared with DPP-4is, SGLT-2is can significantly reduce MACE [OR: 0.86 95% CI (0.78, 0.92)], CV death [OR: 0.85 95% CI (0.71, 1.01)], nonfatal MI [OR: 0.84 95%CI (0.74, 0.95)] and all-cause mortality [OR: 0.78 95% CI (0.69, 0.89)]. For nonfatal stroke, DPP-4is and SGLT-2is have no statistically significant difference [OR: 0.99 95% CI (0.91, 1.07)].ConclusionThese data indicate that SGLT-2is is more beneficial to MACE and all-cause mortality in T2DM patients than DPP-4is.