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This double-blind, randomized trial compared canagliflozin with placebo in patients with type 2 diabetes and evidence of kidney disease that was treated with renin–angiotensin system blockade. The canagliflozin group had a lower risk of kidney disease progression or cardiovascular events than the placebo group.

Large traditional clinical trials suggest that sodium-glucose co-transporter 2 inhibitors improve symptoms in patients with heart failure and reduced ejection fraction (HFrEF) and in patients with heart failure and preserved ejection fraction (HFpEF). In the midst of the Coronavirus Disease 2019 pandemic, we sought to confirm these benefits in a new type of trial that was patient centered and conducted in a completely remote fashion. In the CHIEF-HF trial ( NCT04252287 ), 476 participants with HF, regardless of EF or diabetes status, were randomized to 100 mg of canagliflozin or placebo. Enrollment was stopped early due to shifting sponsor priorities, without unblinding. The primary outcome was change in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at 12 weeks. The 12-week change in KCCQ TSS was 4.3 points (95% confidence interval, 0.8–7.8; P  = 0.016) higher with canagliflozin than with placebo, meeting the primary endpoint. Similar effects were observed in participants with HFpEF and in those with HFrEF and in participants with and without diabetes, demonstrating that canagliflozin significantly improves symptom burden in HF, regardless of EF or diabetes status. This randomized, double-blind trial, conducted without in-person interactions between doctor and patient, can serve as a model for future all-virtual clinical trials. The potential of all-virtual clinical trials in cardiology is shown by the CHIEF-HF trial, conducted in the midst of the COVID-19 pandemic, which found that an SGLT2 inhibitor can alleviate heart failure symptoms in patients irrespective of ejection fraction or diabetes status.

In this report of two randomized trials, patients with type 2 diabetes at risk for cardiovascular disease received the sodium–glucose cotransporter 2 inhibitor canagliflozin or placebo and were followed for 188 weeks. Canagliflozin reduced the risk of cardiovascular events.

Aims/hypothesisThe primary analysis of the Canagliflozin cardioVascular Assessment Study (CANVAS) Program showed canagliflozin to have a beneficial effect on cardiovascular and renal outcomes in people with type 2 diabetes at high cardiovascular risk, but also an unexpected increased risk of major or minor lower extremity amputation. These secondary analyses explore this finding in more detail.MethodsThe effect of canagliflozin on amputation risk in the CANVAS Program was calculated for amputations of different types and proximate aetiologies and different canagliflozin doses. Univariate and multivariate associations of baseline characteristics with amputation risk were determined and proportional and absolute effects of canagliflozin were compared across subgroups.ResultsThere were 187 (1.8%) participants with atraumatic lower extremity amputations (minor 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was similar for ischaemic and infective aetiologies and for 100 mg and 300 mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted.Conclusions/interpretationThe CANVAS Program demonstrated that canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for canagliflozin was identified.

Aims/hypothesisIntra-abdominal or visceral obesity is associated with insulin resistance and an increased risk for cardiovascular disease. This study aimed to compare the effects of semaglutide 1.0 mg and canagliflozin 300 mg on body composition in a subset of participants from the SUSTAIN 8 Phase IIIB, randomised double-blind trial who underwent whole-body dual-energy x-ray absorptiometry (DXA) scanning.MethodsAdults (age ≥18 years) with type 2 diabetes, HbA1c 53–91 mmol/mol (7.0–10.5%), on a stable daily dose of metformin (≥1500 mg or maximum tolerated dose) and with an eGFR ≥60 ml min−1 [1.73 m]−2 were randomised 1:1 to semaglutide 1.0 mg once weekly and canagliflozin placebo once daily, or canagliflozin 300 mg once daily and semaglutide placebo once weekly. Body composition was assessed using whole-body DXA scans. The study participants and investigator remained blinded throughout the trial, and quality of DXA scans was evaluated in a blinded manner. Change from baseline to week 52 in total fat mass (kg) was the confirmatory efficacy endpoint.ResultsA subset of 178 participants (semaglutide, n = 88; canagliflozin, n = 90) underwent DXA scanning at screening and were randomised into the substudy. Of these, 114 (semaglutide, n = 53; canagliflozin, n = 61) participants had observed end-of-treatment data included in the confirmatory efficacy analysis. Of the 178 participants in the substudy, numerical improvements in body composition (including fat mass, lean mass and visceral fat mass) were observed after 52 weeks with both treatments. Total fat mass (baseline 33.2 kg) was reduced by 3.4 kg and 2.6 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: –0.79 [95% CI −2.10, 0.51]). Although total lean mass (baseline 51.3 kg) was also reduced by 2.3 kg and 1.5 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: −0.78 [−1.61, 0.04]), the proportion of lean mass (baseline 59.4%) increased by 1.2%- and 1.1%-point, respectively (estimated treatment difference 0.14 [−0.89, 1.17]). Changes in visceral fat mass and overall changes in body composition (assessed by the fat to lean mass ratio) were comparable between the two treatment groups.Conclusions/interpretationIn individuals with uncontrolled type 2 diabetes on stable-dose metformin therapy, the changes in body composition with semaglutide and canagliflozin were not significantly different. Although numerical improvements in body composition were observed following treatment in both treatment arms, the specific impact of both treatments on body composition in the absence of a placebo arm is speculative at this stage.Trial registrationClinicalTrials.gov NCT03136484.FundingThis trial was supported by Novo Nordisk A/S, Denmark.

BackgroundWe aimed to investigate the efficacy of canagliflozin (based on its effect on liver function and blood glucose levels) and its safety in high alanine aminotransferase (ALT) patients (ALT >30 U/L).MethodsThis post hoc analysis of canagliflozin in type 2 diabetes mellitus (T2DM) patients was divided into Study 1 (pooled analysis of 12- and 24-week placebo-controlled, monotherapy studies) and Study 2 (52-week monotherapy/combination therapy study). The canagliflozin 100 mg group data were compared with placebo or baseline ALT subgroup (baseline ALT >30 or ≤30 U/L) data. The primary endpoint was change in ALT level from baseline. Secondary endpoints were changes in efficacy-related parameters. Adverse events (AEs) were evaluated.ResultsThe mean ALT change at 12 weeks was −10.3 ± 11.7 and −3.2 ± 17.6 U/L in the canagliflozin vs. placebo group in the high ALT subgroup (P = 0.0206); no significant difference was shown in the low ALT subgroup (Study 1). In both ALT subgroups, glycosylated hemoglobin (HbA1c) and body weight were significantly reduced in the canagliflozin vs. placebo group (all P < 0.0001). The mean change in ALT at 52 weeks was −16.0 ± 18.8 U/L in the high ALT subgroup (P < 0.0001, Study 2). The incidence of AEs or serious AEs in the high ALT subgroup in the canagliflozin group was similar to that in the placebo group (Study 1) or low ALT subgroup (Studies 1 and 2).ConclusionsIn T2DM patients with impaired liver function, canagliflozin may improve liver function, reduce HbA1c and body weight, and be well tolerated.

Background To summarize the four recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials: Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin CardioVascular Assessment Study (CANVAS) Program, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA–REG OUTCOME), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and explore the potential determinants for their cardiovascular, renal, and safety outcomes. Results The composite renal outcome event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 3.7, 7.0, 47%; 5.5, 9.0, 40%; 6.3, 11.5, 46%; 43.2, 61.2, 30% for DECLARE-TIMI 58, CANVAS, EMPA–REG OUTCOME, and CREDENCE, respectively (event definitions varied across trials). The major adverse cardiovascular (CV) event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14%; 38.7, 48.7, 20% for DECLARE-TIMI 58, CANVAS, EMPA–REG OUTCOME, and CREDENCE, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events and CREDENCE the most. These differences were presumably due to varying inclusion criteria resulting in DECLARE-TIMI 58 having the best baseline renal filtration function and CREDENCE the worst (mean estimated glomerular filtration rate 85.2, 76.5, 74, 56.2 mL/min/1.73 m 2 for DECLARE-TIMI 58, CANVAS, EMPA–REG OUTCOME, and CREDENCE, respectively). Additionally, CREDENCE had considerably higher rates of albuminuria (median urinary albumin-creatinine ratios (UACR) were 927, 12.3, and 13.1 mg/g for CREDENCE, CANVAS, and DECLARE-TIMI 58, respectively; EMPA–REG OUTCOME had 59.4% UACR < 30, 28.6% UACR > 30–300, 11.0% UACR > 300 mg/g). Conclusions Dapagliflozin, empagliflozin, and canagliflozin have internally and externally consistent and biologically plausible class effects on cardiorenal outcomes. Baseline renal filtration function and degree of albuminuria are the most significant indicators of risk for both CV and renal events. Thus, these two factors also anticipate the greatest clinical benefit for SGLT2i.

We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P < .001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.

Aims/hypothesis Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces HbA 1c , body weight and systolic BP (SBP) in patients with type 2 diabetes. As weight loss is known to reduce both HbA 1c and SBP, these analyses were performed to evaluate the contribution of weight loss resulting from treatment with canagliflozin to HbA 1c and SBP reductions in patients with type 2 diabetes. Methods Pooled data from four placebo-controlled Phase 3 studies ( N  = 2,250) in patients with type 2 diabetes were used in the analyses. In each study, patients were treated with placebo, canagliflozin 100 mg or canagliflozin 300 mg, once daily for 26 weeks. Changes from baseline in body weight, HbA 1c and SBP were measured at week 26, and the contribution of weight loss to the lowering of HbA 1c and SBP was obtained using ANCOVA. Results Canagliflozin 100 and 300 mg reduced mean body weight, HbA 1c and SBP compared with placebo ( p  < 0.001 for each), and more patients had body-weight reductions >0%, ≥5% and ≥10% with canagliflozin treatment than with placebo. Weight-loss-independent and weight-loss-associated mechanisms contributed to HbA 1c and SBP lowering with canagliflozin: ~85% of HbA 1c lowering and ~60% of SBP lowering was independent of weight loss. Conclusions/interpretation In patients with type 2 diabetes, canagliflozin provided clinically meaningful body-weight reductions, and the weight loss contributed to reductions in HbA 1c and SBP. Trial registration : ClinicalTrials.gov NCT01081834; NCT01106625; NCT01106677; and NCT01106690

DJT1116PG, which selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter type 2, was developed as an insulin-independent treatment for type 2 diabetes mellitus. This Phase I trial evaluated the pharmacokinetic and pharmacodynamic properties of DJT1116PG at steady state in healthy Chinese individuals. This was a multiple ascending dose study of DJT1116PG (20, 50, and 100 mg once daily for 7 days) that included 36 healthy individuals. There were no serious adverse events or deaths in these studies, and no adverse event led to study discontinuation. Oral DJT1116PG was rapidly absorbed with a Tmax of 0.75–1.5 h and a t½ of 12–16.2 h. Systemic exposure (Cmax and AUC) of DJT1116PG and its inactive metabolites (T1444, T1454, and T1830) increased in a dose-dependent manner. Urinary glucose excretion (UGE) plateaued at 50 mg of DJT1116PG in a previous single ascending dose study and on day 1 of this study. UGE plateaued at 20 mg of DJT1116PG on day 7 of this study. Serum glucose parameters were similar in individuals who received DJT1116PG or placebo. DJT1116PG was well tolerated in healthy Chinese individuals. At steady state, UGE plateaued at 20 mg of DJT1116PG in these individuals. These findings will inform the selection of doses for further early-stage clinical trials of DJT1116PG. Chinese Drug Trial Identifier: CTR20160986.