Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial

Status Epilepticus and Subsequent Epilepsy

Preoperative considerations of new long-acting glucagon-like peptide-1 receptor agonists in diabetes mellitus

New Glucose-Lowering Agents for Diabetic Kidney Disease.

The growing epidemic of obesity and diabetes represents a growing health emergency, exemplified by a marked increase in cardiovascular and renal disease. As such, healthcare systems are increasingly focussing on therapeutic approaches to address these challenges. Cardiovascular outcome trials (CVOTs) evaluating glucagon-like peptide-1 (GLP-1) analogues have previously observed significant improvements in major adverse cardiac events in people with type 2 diabetes (T2D). However, their impact in obese people without T2D is unknown. The SELECT study is the first pharmacotherapy study in obesity powered for cardiovascular superiority and investigates the impact of semaglutide on cardiovascular disease outcomes in overweight and obese people without T2D. The results of this study will potentially redefine obesity management, especially as secondary outcomes of the study will include evaluation of health-related quality of life and incident diabetes rates. In another potentially evolutionary therapeutic step for the incretin class of therapeutic agents, the FLOW study is the first dedicated study to investigate the effects of GLP-1 receptor analogues on renal and cardiovascular outcomes in people with renal impairment and T2D. Post-hoc analyses of GLP-1 analogue CVOTs have demonstrated reduced adverse renal outcomes associated with their use. In this review we discuss the known impact of GLP-1 analogues on cardiovascular, weight and renal outcomes in previous CVOTs. We further discuss the importance of the ongoing SELECT and FLOW studies on shifting the paradigm of obesity pharmacotherapy and in adding to our understanding of renal disease management in people with T2D.

OBJECTIVEPeople receiving dialysis are at high risk of cardiovascular and all-cause mortality. Semaglutide reduces major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D) and those without T2D with obesity and high cardiovascular risk. Data to establish safety and efficacy in dialysis-dependent kidney failure are scarce. We aimed to assess the safety of semaglutide in people who initiate dialysis.RESEARCH DESIGN AND METHODSIn this post hoc analysis of four randomized, placebo-controlled trials (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [SUSTAIN-6], Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity [SELECT], Evaluate Renal Function With Semaglutide Once Weekly [FLOW], and Semaglutide Cardiovascular Outcomes [SOUL]), we evaluated systematically collected adverse events (AEs) from participants who initiated dialysis during study follow-up. We compared the proportion and event rates of systematically collected serious AEs (SAEs), including adjudicated MACE, and AEs leading to permanent treatment discontinuation in participants originally randomized to semaglutide or placebo who remained on treatment after dialysis initiation.RESULTSAmong 34,064 participants randomized across the trials, 307 initiated dialysis, of whom 165 participants randomized to semaglutide (n = 71) or placebo (n = 94) remained on treatment. After dialysis initiation, SAEs were reported in 32 of 71 (45%) and 54 of 94 (57%) participants, and the proportion of participants who permanently discontinued trial medication was 8.5% and 10.6% in the semaglutide and placebo groups, respectively. The MACE event rates were 9.7 and 16.1 events per 100 person-years, and all-cause mortality event rates were 13.8 and 18.1 events per 100 person-years, in the semaglutide and placebo groups, respectively.CONCLUSIONSAlthough more evidence is needed, continuation of semaglutide after dialysis initiation appears safe and warrants efficacy testing regarding reduction in MACE and death.

The glucagon-like peptide-1 analog liraglutide reduced cardiovascular events and mortality in patients with type 2 diabetes mellitus in the LEADER trial (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes). In a post hoc analysis, we evaluated the efficacy of liraglutide in those with and without a history of myocardial infarction (MI) and/or stroke. LEADER was a randomized trial of liraglutide (1.8 mg or maximum tolerated dose) versus placebo in 9340 patients with type 2 diabetes mellitus and high cardiovascular risk, with a median follow-up of 3.8 years. The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke (major adverse cardiovascular events). Risk groups in this post hoc analysis were defined by history of MI/stroke, established atherosclerotic cardiovascular disease without MI/stroke, or cardiovascular risk factors alone. Of the 9340 patients, 3692 (39.5%) had a history of MI/stroke, 3083 (33.0%) had established atherosclerotic cardiovascular disease without MI/stroke, and 2565 (27.5%) had risk factors alone. Major adverse cardiovascular events occurred in 18.8% of patients with a history of MI/stroke (incidence rate, 5.0 per 100 patient-years), 11.6% of patients with established atherosclerotic cardiovascular disease without MI/stroke (incidence rate, 3.0 per 100 patient-years), and 9.8% of patients with cardiovascular risk factors alone (incidence rate, 2.6 per 100 patient-years). Liraglutide reduced major adverse cardiovascular events in patients with a history of MI/stroke (322 of 1865 [17.3%] versus 372 of 1827 patients [20.4%]; hazard ratio, 0.85; 95% CI, 0.73-0.99) and in those with established atherosclerotic cardiovascular disease without MI/stroke (158 of 1538 [10.3%] versus 199 of 1545 patients [12.9%]; hazard ratio, 0.76; 95% CI, 0.62-0.94) compared with placebo. In patients with risk factors alone, the hazard ratio for liraglutide versus placebo was 1.08 (95% CI, 0.84-1.38, Pinteraction=0.11). Similar results were seen for secondary outcomes across risk groups. In this post hoc analysis of patients with type 2 diabetes mellitus and high cardiovascular risk, liraglutide reduced cardiovascular outcomes both in patients with a history of MI/stroke and in those with established atherosclerotic cardiovascular disease without MI/stroke. The cardiovascular effect appeared neutral in patients with cardiovascular risk factors alone. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01179048.

BACKGROUND:Both GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose cotransporter-2) inhibitors (SGLT2i) improve cardiovascular outcomes in people with type 2 diabetes and cardiovascular or chronic kidney disease. However, there are limited data about the effect of combining these agents on cardiovascular and safety outcomes.METHODS:The SOUL trial (Semaglutide Cardiovascular Outcomes Trial; NCT03914326) randomized 9650 participants with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease to oral semaglutide or placebo. As prespecified, participants were analyzed according to baseline use of SGLT2i (yes, n=2596; no, n=7054), and subsequently for any use of SGLT2i during the trial (yes, n=4718; no, n=4932). The primary outcome was time to first major adverse cardiovascular event, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Safety was evaluated by comparing the incidence of serious adverse events.RESULTS:Over a mean follow-up of 47.5±10.9 months, the risk of the primary outcome in the overall trial population was 14% lower for oral semaglutide versus placebo (hazard ratio, 0.86; 95% CI, 0.77–0.96). In those taking SGLT2i at baseline, there were 143 of 1296 (semaglutide) versus 158 of 1300 (placebo) primary outcome events (hazard ratio, 0.89; 95% CI, 0.71–1.11); and 436 of 3529 versus 510 of 3525, respectively, in participants not taking SGLT2i at baseline (hazard ratio, 0.84; 95% CI, 0.74–0.95; P-interaction, 0.66). An analysis of major adverse cardiovascular events by any in-trial SGLT2i use versus no use also showed no evidence of heterogeneity in the effects of oral semaglutide. The adverse event profiles of oral semaglutide with or without concomitant SGLT2i were similar.CONCLUSIONS:Oral semaglutide reduced major adverse cardiovascular event outcomes independently of concomitant SGLT2i treatment, and this combination appeared to be safe.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03914326.

In the AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes) cardiovascular outcomes trial, adding either 4 mg or 6 mg weekly of the glucagon-like peptide-1 receptor agonist efpeglenatide to usual care reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes at high cardiovascular risk. Whether these benefits are dose related remains uncertain. Participants were randomly assigned in a 1:1:1 ratio to placebo, 4 mg or 6 mg of efpeglenatide. The effect of 6 mg versus placebo and of 4 mg versus placebo on MACE (a nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or unknown causes) and on all the secondary composite cardiovascular and kidney outcomes was assessed. A dose-response relationship was assessed using the log-rank test and χ2 statistic for trend. During a median follow-up of 1.8 years, MACE occurred in 125 (9.2%) participants assigned to placebo, 84 (6.2%) participants assigned to 6 mg of efpeglenatide (hazard ratio [HR], 0.65 [95% CI, 0.5-0.86]; P=0.0027), and 105 (7.7%) assigned to 4 mg of efpeglenatide (HR, 0.82 [95% CI, 0.63-1.06]; P=0.14). Participants receiving high-dose efpeglenatide also experienced fewer secondary outcomes, including the composite of MACE, coronary revascularization, or hospitalization for unstable angina (HR, 0.73 for 6 mg, P=0.011; HR, 0.85 for 4 mg, P=0.17), a kidney composite outcome comprising sustained new macroalbuminuria, a ≥40% decline in estimated glomerular filtration rate or renal failure (HR, 0.63 for 6 mg, P<0.0001; HR, 0.73 for 4 mg, P=0.0009), MACE or any death (HR, 0.67 for 6 mg, P=0.0021; HR, 0.81 for 4 mg, P=0.08), a kidney function outcome comprising a sustained ≥40% decline in estimated glomerular filtration rate, renal failure, or death (HR, 0.61 for 6 mg, P=0.0072; HR, 0.97 for 4 mg, P=0.83), and the composite of MACE, any death, heart failure hospitalization, or the kidney function outcome (HR, 0.63 for 6 mg, P=0.0002; HR, 0.81 for 4 mg, P=0.067). A clear dose-response was noted for all primary and secondary outcomes (all P for trend ≤0.018). The graded salutary relationship between efpeglenatide dose and cardiovascular outcomes suggests that titrating efpeglenatide and potentially other glucagon-like peptide-1 receptor agonists to high doses may maximize their cardiovascular and renal benefits. URL: https://www. gov; Unique identifier: NCT03496298.

ObjectiveWe aimed to evaluate the impact of early initiation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) with known or at risk of atherosclerotic cardiovascular disease (ASCVD).Research design and methodsT2D with first prescription of SGLT2i (Dx-to-Rx time) ≤12 months were matched with >12 months using propensity score derived from logistic regression. T2D were divided into 3 groups: (i) known ASCVD; (ii) additional CV risk factor(s) and; (iii) without ASCVD or additional CV risk factors. Incidence rates of 3-point major adverse cardiovascular events (MACE, including non-fatal stroke, non-fatal myocardial infarction and CV death) were compared between Dx-to-Rx time ≤12 months and >12 months across 3 subgroups.ResultsMedian follow-up was 2.8 years (IQR 2.2 to 3.4). Among 29,309 T2D (mean age 57.6±11.4 years, 59.0% men), 23.6% had established ASCVD and 66.6% had additional CV risk factors. Overall, 19.0% of patients had Dx-to-Rx time ≤12 month which was associated with lower rates of MACE [hazard ratio (HR) = 0.27, 95%CI: 0.17–0.42]. Benefits of early initiation of SGLT2i was observed in patients with additional CV risk factors or known ASCVD but not in those without CV risk factors or ASCVD (P for interaction = 0.001).ConclusionEarly initiation of SGLT2 inhibitor was associated with lower MACE rates in T2D with known or at risk of ASCVD.

Management of type 2 diabetes mellitus (T2DM), a progressive metabolic disorder associated with substantial cardiovascular (CV) and kidney complications, includes risk factor optimization of glucose, blood pressure (BP) and lipids. Although there may be minor differences between guidance, treatment targets recommended by international clinical practice guidelines include maintaining glycated haemoglobin (HbA1c) ≤7.0% (with individual adaptation), BP <130/80 mmHg and low-density lipoprotein cholesterol (LDL-C) <2 mmol/L (<77 mg/dl), along with an annual evaluation of urinary albumin/creatinine ratio (UACR) to assess CV and kidney risk.1-4 The sodium-glucose co-transporter 2 inhibitor class showed improvements in CV and kidney outcomes in patients with T2DM in CV outcome trials.3 Canagliflozin reduced the risk of CV outcomes, including major adverse CV events (MACE; CV death, non-fatal myocardial infarction and non-fatal stroke), a composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and kidney outcomes in patients with T2DM and high CV risk [CANagliflozin cardioVascular Assessment Study (CANVAS) programme]5 and in patients with diabetic nephropathy [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial].6 Consequently, treatment guidelines now recommend sodium-glucose co-transporter 2 inhibitors for reducing the risk of CV and kidney events in patients with T2DM.1-4 As patients have varying control over their CV risk factors, it is important to know whether the clinical benefits of canagliflozin extend across the spectrum of attained treatment targets. This post-hoc analysis assessed the effects of canagliflozin versus placebo on CV and kidney outcomes in patients with T2DM and high CV risk, and/or chronic kidney disease according to baseline treatment target achievement and risk factors. This post-hoc analysis is an integrated, pooled, patient-level, meta-analysis from the CANVAS programme and CREDENCE. The CANVAS programme comprised two multicentre, double-blind, placebo-controlled, randomized trials: CANVAS and CANVAS-R.5, 7 Eligible participants had T2DM (HbA1c ≥7.0% and ≤10.5%) and an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73m2 and were either aged ≥30 years with a history of symptomatic atherosclerotic CV disease or aged ≥50 years with ≥2 CV disease risk factors.5, 7 CREDENCE included participants with T2DM (HbA1c ≥6.5% and ≤12.0%), an eGFR of 30 to <90 ml/min/1.73m2, and a UACR of >33.9 to ≤565.6 mg/mmol (>300 to ≤5000 mg/g).6, 8 Participants in all studies were randomized to canagliflozin or placebo. Participants had similar characteristics, with some differences related to inclusion criteria. In the CANVAS programme, 18% of participants had a history of nephropathy, ~20% had an eGFR <60 ml/min/1.73m2, and 70% had normoalbuminuria at baseline.5, 9 In contrast, all CREDENCE participants had advanced nephropathy at baseline.6 Lastly, 66% of CANVAS programme participants had established CV disease versus 50% in CREDENCE. This post-hoc analysis of the CANVAS programme and CREDENCE trial included participants who were randomized to canagliflozin or placebo and had values for all selected treatment targets.5, 6 Categorical variables are represented as percentages, and continuous variables are represented as mean (standard deviation) or median (interquartile range). The effects of canagliflozin versus placebo were examined for the time to the first occurrence of MACE, the composite of HHF/CV death, and the kidney composite of end-stage kidney disease (ESKD) or doubling of serum creatinine (dSCr). Patients were categorized by treatment target achievement and number of target levels achieved (0, 1, 2, and 3 or 4) at baseline. The targets were defined as: HbA1c ≤7.0%, LDL-C <2 mmol/L (<77 mg/dl), BP <130/80 mmHg, or UACR <2 mg/mmol (18 mg/g). Hazard ratios and 95% confidence intervals for each outcome were estimated using Cox regression models stratified by the achievement of treatment targets and, in separate models, by the number of targets achieved at baseline. Interaction p values were calculated by including the treatment group by achievement of treatment targets and treatment group by number of targets achieved at baseline in the model. A two-sided p < .05 for the interaction term was deemed probable to reflect a difference beyond chance. This post hoc analysis is not intended for inference, so no type 1 error adjustments were made. Thus, p values are descriptive only. Analyses were performed using SAS version 9.4 (SAS Institute). The pooled analysis included 14 543 participants from the CANVAS programme (n = 10 142) and CREDENCE trial (n = 4401), with mean (SD) baseline HbA1c of 8.3% (1.1), LDL-C of 2.4 (1.0) mmol/L [92.8 (38.7) mg/dl], and BP of 138/78 (16/10) mmHg, and median (range) baseline UACR of 3.8 (1.0–59.2) mg/mmol [33.6 (8.9–523.9) mg/g]. At baseline, 3683 (26%) participants had achieved no treatment targets, 5851 (41%) had achieved one, 3680 (25%) had achieved two, and 1218 (8%) had achieved three or four targets (Table 1). In addition, 8415 (58%) participants had a UACR >2 mg/mmol. Regardless of whether baseline targets were met or UACR was elevated, canagliflozin consistently reduced the risk of MACE, HHF/CV death, and ESKD/dSCr versus placebo (Figure 1). Among participants who experienced a CV event and did not achieve HbA1c, LDL-C or BP targets or a reduction in UACR, canagliflozin still reduced CV risk (all p interaction ≥.38). The beneficial effects of canagliflozin on ESKD/dSCr were observed irrespective of achievement of HbA1c, LDL-C and BP baseline targets (all p interaction ≥.45). Canagliflozin reduced kidney events similarly as to whether UACR was elevated (>2 mg/mmol), and reduced CV outcomes with elevated or normal UACR, at baseline. Furthermore, the number of uncontrolled targets at baseline did not impact the beneficial effect of canagliflozin on CV and kidney outcomes (all p interaction ≥.17; Figure S1). In this pooled analysis of the CANVAS programme and CREDENCE trial, participants with T2DM and high CV risk, and/or chronic kidney disease who were randomized to canagliflozin treatment showed consistent CV and kidney benefits versus placebo, regardless of whether T2DM-related or other CV-risk treatment targets were met at baseline. Our findings highlight the importance of canagliflozin's protective effect on key CV and kidney outcomes irrespective of baseline risk factor control. This is particularly important in outpatient clinical settings where, despite best efforts, patients with T2DM may only achieve partial composite target goals.10, 11 The DM-SCAN study, which included primary care physician surveys and chart data from adults with T2DM, showed that 50%, 57% and 36% of patients achieved target levels of HbA1c, LDL-C and BP, respectively, with only 13% achieving all three targets.10 Similarly, a low proportion of participants in the current analysis achieved the recommended treatment targets. Thus, our data show the benefits of canagliflozin for preventing cardiorenal complications in patients who have not yet achieved risk factor targets. Strengths of this study include the multicentre, randomized, controlled trial designs, which were conducted to a high standard and with many participants. CV and kidney outcomes were pre-specified and adjudicated by expert committees. This analysis also has inherent limitations applicable to any post-hoc analysis of a randomized trial. The CANVAS programme and CREDENCE trial were not designed specifically to test outcomes in these subgroups, nor were there adjustments for multiple baseline test comparators. Thus, our findings should be considered exploratory. In addition, generalizability of the results may be limited to individuals with previous CV events, high CV risk or nephropathy, similar to the patients enrolled in the CANVAS programme and CREDENCE trial. While control of CV and kidney risk factors in high-risk patients with T2DM is critical, this study showed that canagliflozin provides consistent CV and kidney benefits, regardless of whether treatment targets for these risk factors are met at baseline. MAT, SWT, WR, FGA, JS, BLN, CA, KWM and DCW contributed to the study design and data interpretation. AS performed the statistical analysis. MAT and VW drafted the manuscript, and the final version was critically revised and approved by all the authors. The CANVAS Program and CREDENCE trial were sponsored by Janssen Research & Development, LLC. This analysis was supported by Janssen Canada Inc. Medical writing support was provided by Kim Caldwell, PhD, of Lumanity Communications Inc., and was funded by Janssen, Inc. Canagliflozin was developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. MAT has received speakers bureau and advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk and Sanofi Genzyme. VW has received honoraria for speaking, advisory boards, and clinical research from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen and Novo Nordisk. SWT has received a KMH Clinic unrestricted grant and in-kind support for the Zero to Five study paid to Sunnybrook Research Institute; has received consulting fees from AstraZeneca paid to Sunnybrook Research Institute; has received payment or honoraria for lectures from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Novo Nordisk, Pfizer and Sanofi paid to the CHEP Plus education program; and has served as a volunteer for the American Hypertension Specialist Certification Program. AS is an employee of New Arch Consulting; and received funding from Janssen for this analysis. WR and FGA are employees of Janssen Inc. JS has received honoraria for talks and/or consultancy and/or research funding from Apitope, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GI-Dynamics, GlaxoSmithKline, Intarcia, Ipsen, Janssen, LifeScan, MedScape, Merck Sharp & Dohme, Novartis, Novo Nordisk, Omniamed, Pfizer, Roche, Sanofi, Servier, Takeda and Ypsomed. BLN has received fees for travel support, advisory boards, scientific presentations, and steering committee roles from AstraZeneca, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research and Janssen, with all honoraria paid to his institution. CA has received honoraria from Amgen; has received support from an NHMRC/MRFF Priority Fellowship and an NSW Health EMC Grant; and is an employee of The George Institute for Global Health. KWM's financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. DCW has received fees for advisory boards, committee work, educational activities, and scientific presentations form Amgen, Astellas, AstraZeneca (ongoing), Bayer, Boehringer Ingelheim, CSL Vifor, Gilead, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Mundipharma, Tricida, and Zydus. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. Figure S1. Effects of canagliflozin versus placebo on CV and kidney events by the number of T2DM treatment targets achieved at baseline. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

GLP-1 receptor agonists and cardiovascular outcomes: an updated synthesis

Weekly Journal Scan: SELECT renoprotective effects of semaglutide in non-diabetic, obese patients with cardiovascular disease.

Erectile function in men with type 2 diabetes treated with dulaglutide: an exploratory analysis of the REWIND placebo-controlled randomised trial

La disfunción sexual en pacientes en rehabilitación cardiaca es mucho más que un simple «epifenómeno» y debe ser más estudiada