The effect of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across baseline blood pressure categories: Analysis of the LEADER and SUSTAIN 6 trials

It is unknown if the cardioprotective and renal effects of glucagon-like peptide-1 receptor agonists are consistent across blood pressure (BP) categories in patients with type 2 diabetes and at high risk of cardiovascular events. Using data from the LEADER (9340 patients) and SUSTAIN 6 (3297 patients) trials, we evaluated post hoc the cardiorenal effect of liraglutide and semaglutide on major adverse cardiovascular events (MACE) and nephropathy by baseline BP categories using a Cox proportional hazards model (treatment and subgroup as factors; adjusted for cardiorenal risk factors). Data from the two trials were analysed separately. In the LEADER and SUSTAIN 6 trials, the prevalence of stage 1 hypertension was 30% and 31%, respectively, and of stage 2 hypertension 41% and 43%, respectively. There was no statistical heterogeneity across the BP categories for the effects of liraglutide (P = .06 for MACE; P = .14 for nephropathy) or semaglutide (P = .40 for MACE; P = .27 for nephropathy) versus placebo. This implies that liraglutide and semaglutide may be beneficial for patients with type 2 diabetes, irrespective of their baseline BP.     

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.     

Safety and tolerability of semaglutide across the SUSTAIN and PIONEER phase IIIa clinical trial programmes

Aim

Glucagon-like peptide-1 receptor agonists improve glycaemic control: some are now available as oral and subcutaneous formulations, and some have indications for reducing cardiovascular risk. The expanded scope for these therapies warrants comprehensive safety evaluations. We report the safety/tolerability of subcutaneous and oral semaglutide from the SUSTAIN and PIONEER clinical trial programmes, respectively.

Materials and methods

Adverse events (AEs) from 16 randomized placebo- or active-controlled phase IIIa trials in patients with type 2 diabetes (n = 11 159) including once-weekly subcutaneous semaglutide (n = 3150; SUSTAIN trials) or once-daily oral semaglutide (n = 4116; PIONEER trials) were analysed. Data pools were analysed for each programme, with separate analyses of cardiovascular outcomes trials (CVOTs; n = 6480).

Results

In the phase IIIa pools, gastrointestinal disorders were reported in 41.9%/39.1% of patients with subcutaneous/oral semaglutide, respectively (most prevalent during initiation/escalation) versus 22.0%/24.8% with comparators. Rates of kidney disorders, acute pancreatitis, malignant neoplasms, hypoglycaemia, diabetic retinopathy, heart failure and other cardiovascular events were similar for semaglutide versus comparators. Cholelithiasis incidence was higher with subcutaneous and oral semaglutide versus placebo. Diabetic retinopathy incidence was higher with subcutaneous semaglutide versus placebo in SUSTAIN 6. Small pulse rate increases occurred with both formulations; there was no increased rate of arrhythmias. Fatal AE incidence was similar between semaglutide and comparators. Versus placebo, CVOTs showed a reduced risk of major adverse cardiovascular events with subcutaneous semaglutide and non-inferiority criteria were met with oral semaglutide.

Conclusions

The most common AEs with semaglutide were gastrointestinal disorders, which decreased with continued therapy. These comprehensive safety/tolerability data may better inform patient selection and guidance in care.     

Effects of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials

Associations between body mass index (BMI) and the cardiovascular (CV) and kidney efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) are uncertain; therefore, data analysed separately from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. These international, randomized, placebo-controlled trials investigated liraglutide and semaglutide (both subcutaneous) in patients with T2D and at high risk of CV events. In post hoc analyses, patients were categorized by baseline BMI (<25, ≥25-<30, ≥30-<35 and ≥35 kg/m²), and CV and kidney outcomes with GLP-1 RA versus placebo were analysed. All baseline BMI data from LEADER (n = 9331) and SUSTAIN 6 (n = 3290) were included (91% and 92% of patients with overweight or obesity, respectively). In SUSTAIN 6, nominally significant heterogeneity of semaglutide efficacy by baseline BMI was observed for CV death/myocardial infarction/stroke (major adverse CV events, primary outcome of both; P_interaction = .02); otherwise, there was no statistical heterogeneity for either GLP-1 RA versus placebo across BMI categories for key CV and kidney outcomes. The lack of statistical heterogeneity from these cardiorenal outcomes implies that liraglutide and semaglutide may be beneficial for many patients and is probable not to depend on their baseline BMI, but further study is needed.     

Impact of microvascular disease on cardiovascular outcomes in type 2 diabetes: Results from the LEADER and SUSTAIN 6 clinical trials

The randomized, double-blind, cardiovascular outcomes trials LEADER (NCT01179048) and SUSTAIN 6 (NCT01720446) showed cardiovascular risk reduction in patients with type 2 diabetes treated with liraglutide and semaglutide, respectively, compared with placebo. This post hoc analysis examined the impact of microvascular disease at baseline on cardiovascular outcomes in these trials, and the efficacy of liraglutide (1.8 mg) and once-weekly semaglutide (0.5-1.0 mg) in patients with and without microvascular disease. In total, 9340 patients from LEADER and 3297 patients from SUSTAIN 6 were included in this analysis; of these, 5761 and 2356 had a history of microvascular disease at baseline and 3835 and 1640 had a history of both microvascular and macrovascular disease, respectively. Patients with microvascular disease were shown to have an increased risk of major adverse cardiovascular events compared with patients without microvascular disease (hazard ratio [95% confidence interval] in LEADER: 1.15 [1.03; 1.29], P = .0136; SUSTAIN 6: 1.56 [1.14; 2.17], P = .0064). Liraglutide and semaglutide consistently reduced cardiovascular risk in patients with and without microvascular disease.     

Effects of SGLT2 inhibitors on cardiovascular and renal outcomes in type 2 diabetes: A meta-analysis with trial sequential analysis

Background:It is unclear whether there are false positive or negative results in the effects of sodium-glucose transporter 2 (SGLT2) inhibitors on various cardiovascular and renal outcomes in patients with type 2 diabetes. We aimed to explore this issue by a meta-analysis with trial sequential analysis.Methods:We included randomized trials evaluating the effects of SGLT2 inhibitors on cardiorenal endpoints in type 2 diabetic patients. Eight endpoints evaluated in the study were fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, major adverse cardiovascular events (MACE), cardiovascular death or hospitalization for heart failure (CVD or HHF), all-cause death (ACD), cardiovascular death (CVD), hospitalization for heart failure (HHF), and kidney function progression (KFP). Meta-analysis and trial sequential analysis was conducted for each endpoint.Results:Seven randomized trials of SGLT2 inhibitors were included for pooled analysis. Compared with placebo, SGLT2 inhibitors significantly reduced the risk of MACE (HR 0.89, 95% confidence interval [CI] 0.84–0.94), MI (HR 0.91, 95% CI 0.84–0.99), CVD (HR 0.86, 95% CI 0.79–0.93), CVD or HHF (HR 0.77, 95% CI 0.73–0.82), HHF (HR 0.67, 95% CI 0.62–0.74), KFP (HR 0.63, 95% CI 0.56–0.70), and ACD (HR 0.88, 95% CI 0.83–0.94), whereas SGLT2 inhibitors did not have significant effects on stroke (HR 0.98, 95% CI 0.88–1.09). Trial sequential analyses for MI and stroke showed that cumulative Z curve did not cross trial sequential monitoring boundary and required information size, whereas those for the other 6 endpoints showed that cumulative Z curve crossed trial sequential monitoring boundary and/or required information size.Conclusions:Compared with placebo, SGLT2 inhibitors conclusively reduce the risk of MACE, CVD or HHF, ACD, CVD, HHF, and KFP in patients with type 2 diabetes, whereas the effects of SGLT2 inhibitors on MI and stroke are not conclusive and need to be further assessed in future studies with the adequate sample size to reject or accept the effect size.     

Semaglutide,reduction in glycated haemoglobin and the risk of diabetic retinopathy

Aims

To evaluate diabetic retinopathy (DR) data from across the SUSTAIN clinical trial programme.

Materials and methods

The SUSTAIN clinical trial programme evaluated the efficacy and safety of semaglutide, a glucagon‐like peptide‐1 analogue, for the treatment of type 2 diabetes (T2D). In SUSTAIN 6, a 2‐year, pre‐approval cardiovascular outcomes trial, semaglutide was associated with a significant increase in the risk of DR complications (DRC) vs placebo. DR data from across the SUSTAIN trials were evaluated, and post hoc analyses of the SUSTAIN 6 data were conducted. These included subgroup analyses to identify at‐risk patients and a mediation analysis with initial change in glycated haemoglobin (HbA1c; percentage‐points at week 16) as a covariate, to examine the role of the magnitude of reduction in HbA1c as an intermediate factor affecting risk of DRC.

Results

There was no imbalance in DR adverse events across the SUSTAIN 1 to 5 and Japanese trials. The majority of the effect with semaglutide vs placebo in SUSTAIN 6 may be attributed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients who had pre‐existing DR and poor glycaemic control at baseline, and who were treated with insulin.

Conclusions

Early worsening of DR is a known phenomenon associated with the rapidity and magnitude of improvement in glycaemic control with insulin; the DRC findings in SUSTAIN 6 are consistent with this. Guidance regarding the early worsening of DR is recommended with insulin. Similar recommendations may be appropriate for semaglutide.     

Effects of glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors on major adverse cardiovascular events in type 2 diabetes by race,ethnicity, and region: A meta-analysis

Background:The effects of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists on major adverse cardiovascular events (MACE) in type 2 diabetic subgroups defined by race, ethnicity, and region are unestablished.Methods:We searched PubMed and Embase for related randomized controlled trials. We conducted random-effects meta-analysis, stratified by drug class, on MACE in various subgroups defined by 3 factors of interest (ie, race, ethnicity, and region) to estimate pooled hazard ratio (HR) and 95% confidence interval. Random-effects meta-regression was conducted to evaluate the differences between 2 drug classes.Results:We included 11 randomized controlled trials for pooled analysis. Compared with placebo, SGLT2is and GLP-1 RAs significantly reduced the risk of MACE (HR ranged from 0.76 to 0.93) in most diabetic subgroups defined by 3 factors of interest. The 2 drug classes did not significantly reduced this risk in the Black race group (HR 0.92, 95% confidence interval 0.70–1.20). The effect of the 2 drug classes on MACE was not significantly different in all diabetic subgroups of interest (P-value for subgroup differences ranged from .101 to .971).Conclusions:SGLT2is and glucagon-like peptide 1 receptor agonists can significantly reduce the risk of MACE in most type 2 diabetic subgroups defined by race, ethnicity, and region, whereas they fail to do it in Black individuals.     

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

Background and aimsType 2 diabetes confers a differential risk of cardiovascular (CV) disease according to the gender. Whether newly approved anti-diabetic drugs like sodium-glucose co-transport-2 inhibitors (SGLT-2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) that have shown a significant reduction in the CV end-points in CV outcome trials (CVOTs) also have a differential impact gender-wise, is still not clearly known.MethodsWe systematically searched the medical database up to December 31, 2019 and retrieved all the dedicated CVOTs conducted with SGLT-2Is and GLP-1RAs that explicitly reported the outcome of major adverse cardiac events (MACE). Subsequently, we pooled the hazard ratio (HR) of MACE in both sexes separately and meta-analyzed the result gender-wise.ResultsThe meta-analysis of three CVOTs conducted with SGLT-2Is (N = 34,322), demonstrated a significant reduction in MACE in men but not in women (Men - HR, 0.90; 95% CI, 0.83 to 0.97; P = 0.006; Women - HR, 0.88; 95% CI, 0.77 to 1.00; P = 0.06) compared to placebo. The meta-analysis of seven CVOTs conducted with GLP-1RAs (N = 56,004) demonstrated a significant reduction in MACE in both sex (Men - HR, 0.88; 95% CI, 0.82 to 0.93; P < 0.0001; Women - HR, 0.88; 95% CI, 0.79 to 0.99; P = 0.03), against the placebo.ConclusionsThe reduction in MACE with SGLT-2Is appears to be significantly less in women with diabetes vs men, while GLP-1RAs confers a similar reduction in MACE, irrespective of the gender. Whether these results are related to inadequate statistical power (underrepresentation of women) in CVOT, or it reflects a true gender difference, still remains to be established.     

Association of cardiovascular disease and traditional cardiovascular risk factors with the incidence of dementia among patients with rheumatoid arthritis

ObjectiveTo determine the incidence of dementia in patients with rheumatoid arthritis (RA) 65 years and older, and compare the incidence of dementia in patients with RA with prevalent cardiovascular (CV) disease (CVD), CV risk factors but no prevalent CVD and neither (referent group).MethodsWe analyzed claims data from the Center for Medicare & Medicaid Services (CMS) from 2006–2014. Eligibility criteria included continuous medical and pharmacy coverage for ≥ 12 months (baseline period 2006), > 2 RA diagnoses by a rheumatologist and at least 1 medication for RA. CVD and CV risk factors were identified using codes from the Chronic Condition Data Warehouse. Incident dementia was defined by 1 inpatient or 2 outpatient claims, or one dementia specific medication. Age-adjusted incident rates were calculated within each age strata. Univariate and multivariate Cox proportional hazard models were used to calculate Hazard Ratios (HR) and 95% confidence intervals.ResultsAmong 56,567 patients with RA, 11,789 (20.1%) incident cases of dementia were included in the main analysis. Age adjusted incident rates were high among all groups and increased with age. After adjustment for age, sex, comorbidities and baseline CV and RA medications, patients with CVD and CV risk factors between 65 and 74 years had an increased risk for incident dementia compared to those without CVD and without CV risk factors (HR 1.18 (95% CI 1.04–1.33) and HR 1.03 (95% CI 1.00–1.11), respectively). We observed a trend towards increased risk in patients between 75 and 84 years with CVD at baseline.ConclusionPatients with RA with both CVD and CV risk factors alone are at an increased risk for dementia compared to those with neither CVD nor CV risk factors; however, this risk is attenuated with increasing age. The impact of RA treatment and CV primary prevention strategies in the prevention of dementia in patients with RA warrants further studies.     

Advanced glycation end products via skin autofluorescence as a new biomarker for major adverse cardiovascular events: A meta-analysis of prospective studies

AimsThis meta-analysis aimed to systematically evaluate the prospective association between advanced glycation end products (AGEs) and major adverse cardiovascular events (MACE).Data synthesisProspective studies that reported the association of AGEs (measured by skin autofluorescence) with MACE were searched in PubMed and EMBASE from inception up to July 2021. Multivariable-adjusted hazard ratios (HRs) and their respective 95% confidence intervals (CIs) reflecting the risk of MACE associated with AGEs were determined using random-effects meta-analysis. Fourteen articles with sixteen items involving 79,389 participants were included. A significant association was found between AGEs and MACE (pooled HR: 1.54, 95% CI: 1.31–1.81, I² = 68%). Moreover, AGEs were associated with a significant increase in fatal cardiovascular disease (CVD) (HR: 1.88, 95% CI: 1.30–2.70) and nonfatal CVD (HR: 1.40, 95% CI: 1.12–1.74). The association between AGEs and MACE was also significant in patients with diabetes (HR: 1.88, 95% CI: 1.31–2.69) and kidney disease (HR: 1.50, 95% CI: 1.16–1.94).ConclusionsThis meta-analysis indicates that higher levels of AGEs measured by skin autofluorescence are significantly correlated with a higher pooled risk of MACE, and AGEs are closely related to both nonfatal and fatal cardiovascular events. AGEs are a valuable biomarker for predicting the occurrence of MACE.The PROSPERO registration numberCRD42021279714.     

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.     

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.     

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.     

Efficacy and safety of oral semaglutide by baseline age in Japanese patients with type 2 diabetes: A subgroup analysis of the PIONEER 9 and 10 Japan trials

A post-hoc exploratory analysis of the PIONEER 9 and 10 trials evaluated the effect of baseline age (<65 and ≥65 years) on the efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes. In PIONEER 9 and 10, patients were randomized to once-daily oral semaglutide (3, 7 or 14 mg) or a comparator (placebo or once-daily subcutaneous liraglutide 0.9 mg [PIONEER 9]; once-weekly subcutaneous dulaglutide 0.75 mg [PIONEER 10]) for 52 weeks, with 5 weeks’ follow-up. In total, 701 patients were included (PIONEER 9: N = 243; PIONEER 10: N = 458). Glycaemic efficacy of oral semaglutide was similar in Japanese patients aged <65 years compared with those ≥65 years, and there did not appear to be a clear pattern between age subgroup and body weight changes. Across treatment arms, adverse events generally occurred in greater proportions of patients aged ≥65 versus <65 years. There was generally a higher rate of premature trial product discontinuation because of adverse events in the older age group. These results indicate that oral semaglutide is efficacious in Japanese patients irrespective of age.     

Comparative efficacy,safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1–7 trials

In individuals with type 2 diabetes, glycaemic control and cardiovascular risk factor management reduces the likelihood of late-stage diabetic complications. Guidelines recommend treatment goals targeting HbA_1c, body weight, blood pressure, and low-density lipoprotein cholesterol. Development of new treatments for type 2 diabetes requires an understanding of their mechanism and efficacy, as well as their relative effects compared to other treatment choices, plus demonstration of cardiovascular safety. Subcutaneous semaglutide is a glucagon-like peptide-1 receptor agonist currently approved in several countries for once-weekly treatment of type 2 diabetes. Semaglutide works via the incretin pathway, stimulating insulin and inhibiting glucagon secretion from the pancreatic islets, leading to lower blood glucose levels. Semaglutide also decreases energy intake by reducing appetite and food cravings, and lowering relative preference for fatty, energy-dense foods. Semaglutide was evaluated in the SUSTAIN clinical trial programme in over 8000 patients across the spectrum of type 2 diabetes. This review details the efficacy and safety profile of semaglutide in the SUSTAIN 1–5 and 7 trials, and its cardiovascular safety profile in the SUSTAIN 6 trial. Semaglutide consistently demonstrated superior and sustained glycemic control and weight loss vs. all comparators evaluated. In SUSTAIN 6, involving patients at high risk of cardiovascular disease, semaglutide significantly decreased the occurrence of cardiovascular events compared with placebo/standard of care (hazard ratio 0.74, P < 0.001 for non-inferiority). Through a comprehensive phase 3 clinical trial program, we have a detailed understanding of semaglutide’s efficacy, safety, cardiovascular effects and comparative role in the treatment of type 2 diabetes.     

Efficacy,safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended for glycaemic management in patients with type 2 diabetes (T2D). Oral semaglutide, the first oral GLP-1RA, has recently been approved for clinical use, based on the results of the randomized, Phase 3a Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) clinical trials. The PIONEER programme tested oral semaglutide in patients with T2D of duration ranging from 3.5 to 15 years, from monotherapy through to insulin add-on, in global populations and two trials dedicated to Japanese patients. Outcomes (glycated haemoglobin [HbA1c] and body weight reduction, plus other relevant efficacy and safety endpoints) were tested against both placebo and active standard-of-care medications. A separate trial evaluated the cardiovascular safety of oral semaglutide in patients with T2D at high cardiovascular risk. Over periods of treatment up to 78 weeks, oral semaglutide 7 and 14 mg once daily reduced HbA1c and body weight across the spectrum of T2D, and improved other diabetes-related endpoints, such as fasting plasma glucose. Oral semaglutide provided significantly better efficacy than placebo and commonly used glucose-lowering medications from the dipeptidyl peptidase-4 inhibitor (sitagliptin) and sodium-glucose co-transporter-2 inhibitor (empagliflozin) classes, as well as the subcutaneous GLP-1RAs liraglutide and dulaglutide. Oral semaglutide was well tolerated in line with the known safety profile of GLP-1RAs, with transient gastrointestinal events being the most common side effects reported. Cardiovascular safety was demonstrated for oral semaglutide in patients with cardiovascular disease or high cardiovascular risk. The results of the PIONEER programme suggest that oral semaglutide is efficacious and well tolerated for glycaemic control of T2D. The availability of oral semaglutide may help to broaden treatment choice and facilitate adoption of earlier GLP-1RA treatment in the paradigm of T2D management.     

Effect of SGLT-2 inhibitors on cardiovascular outcomes in heart failure patients: A meta-analysis of randomized controlled trials

BackgroundTo investigate the overall effect of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on cardiovascular outcomes in a broad spectrum of heart failure (HF) patients, and further stratified by status of ejection fraction and diabetes mellitus.MethodsElectronic databases were searched to identify randomized controlled trials that compared SGLT-2i with placebo in patients with HF. Efficacy outcomes included the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), individual CVD, individual HHF, and all-cause mortality (ACM).ResultsA total of 8 large trials comprising 16,460 HF patients were enrolled. Pooled data demonstrated that SGLT-2i significantly reduced the risk for primary composite outcome (CVD or HHF) by 23% (HR: 0.77, 95% CI: 0.72–0.82) in HF patients. Use of SGLT-2i was associated with a statistically significant 32% reduction in HHF (HR: 0.68, 95% CI: 0.62–0.75), a 15% reduction in CVD (HR: 0.85, 95% CI: 0.76–0.94) and a 16% reduction in ACM (HR: 0.84, 95% CI: 0.77–0.92). Sensitivity analyses using Mantel-Haenszel method displayed consistent results. Subgroup analyses demonstrated that SGLT-2i were robustly effective in HFrEF subgroup as well as in HF with absence/presence of T2DM, and displayed a strong trend to be effective in HFpEF. Safety analysis demonstrated SGLT-2i group had a lower proportion of serious adverse events than placebo group (RR 0.89, 95% CI: 0.86–0.93).ConclusionsCompared with placebo, SGLT-2 inhibitors have remarkable cardiovascular benefits in a broad range of HF patients. Beneficial effects were robust in HF patients regardless of T2DM status, and a strong trend to be effective in HFpEF.     

The effect of vitamin D supplementation on cardiovascular risk in patients with prediabetes: A secondary analysis of the D2d study

AimsLow blood 25(OH)D level is associated with increased cardiovascular disease (CVD) risk. Additionally, individuals with prediabetes are at higher risk for CVD than individuals with normoglycemia. We investigated the effects of vitamin D supplementation on CVD outcomes in the vitamin D and type 2 diabetes (D2d) study, a large trial among adults with prediabetes.Methods2423 participants were randomized to 4000 IU/day of vitamin D₃ or placebo and followed for median 3.0 years for new-onset diabetes. In pre-specified secondary analyses, we examined the effect of vitamin D supplementation on composite Major Adverse Cardiovascular Events (MACE); expanded MACE (MACE + revascularization); atherosclerotic CVD (ASCVD) risk score; and individual CVD risk factors (blood pressure, lipids, high-sensitivity C-reactive protein). Cox models compared hazard ratios (HR) between the two groups on MACE and expanded MACE.ResultsMean age was 60 years, 45 % were women, 13 % had history of CVD. Twenty-one participants assigned to vitamin D and 12 participants assigned to placebo met the MACE outcome (HR 1.81, 95%CI 0.89 to 3.69). There were 27 expanded MACE outcomes in each group (HR 1.02, 95%CI, 0.59 to 1.76). There were no significant differences between vitamin D and placebo in individual CVD risk factors, but change in ASCVD risk score favored the vitamin D group (?0.45 %, 95%CI -0.75 to ?0.15).ConclusionsIn people with prediabetes not selected for vitamin D insufficiency and with intermediate CVD risk, vitamin D supplementation did not decrease MACE but had a small favorable effect on ASCVD risk score.Trial registration: D2d ClinicalTrials.gov number, NCT01942694, prospectively registered September 16, 2013.