Sodium-glucose co-transporter-2 inhibition and ocular outcomes in patients with type 2 diabetes: A systematic review and meta-analysis.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are effective for the treatment of macrovascular complications and nephropathy in type 2 diabetes, but effects on microvascular eye outcomes are unclear. We conducted a systematic review and meta-analysis of randomized placebo-controlled trials to evaluate the effect of SGLT2 inhibition on total ocular events and retinopathy in patients with type 2 diabetes. We searched MEDLINE and Embase for the period from database inception date to October 11, 2019. Two reviewers working independently extracted relevant data. Random-effects models with inverse variance weighting were selected to estimate summary risk ratios (RRs) and 95% confidence intervals (CIs). We included nine studies, involving 39 982 patients with a mean follow-up of 2.8 years. There were 1414 total ocular events, of which 624 were retinopathy events. SGLT2 inhibition was not associated with a change in the risk of total ocular events (RR 0.97, 95% CI 0.85, 1.11) or retinopathy (RR 0.98, 95% CI 0.84, 1.16), with consistent effects across studies (P for heterogeneity = 0.35 and 0.45, respectively). The effects of SGLT2 inhibition on eye disease in individuals with type 2 diabetes are probably null, although the available data cannot exclude small to moderate benefits or harms.

Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function.

BACKGROUND: Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease, including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m2 in whom the drug is not currently approved for use. METHODS: The CANVAS Program randomized 10 142 participants with type 2 diabetes and eGFR >30 mL/min/1.73 m2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without chronic kidney disease, defined as eGFR <60 and ≥60 mL/min/1.73 m2, and according to baseline kidney function (eGFR <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2). RESULTS: At baseline, 2039 (20.1%) participants had an eGFR <60 mL/min/1.73 m2, 71.6% of whom had a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease (hazard ratio, 0.70; 95% CI, 0.55-0.90) and those with preserved kidney function (hazard ratio, 0.92; 95% CI, 0.79-1.07; P heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke ( P heterogeneity = 0.01), as were results for almost all safety outcomes. CONCLUSIONS: The effects of canagliflozin on cardiovascular and renal outcomes were not modified by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2. Reassessing current limitations on the use of canagliflozin in chronic kidney disease may allow additional individuals to benefit from this therapy. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629, NCT01989754.

Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study.

AIMS: To examine the incidence of amputation in patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose co-transporter 2 (SGLT2) inhibitors overall, and canagliflozin specifically, compared with non-SGLT2 inhibitor antihyperglycaemic agents (AHAs). MATERIALS AND METHODS: Patients with T2DM newly exposed to SGLT2 inhibitors or non-SGLT2 inhibitor AHAs were identified using the Truven MarketScan database. The incidence of below-knee lower extremity (BKLE) amputation was calculated for patients treated with SGLT2 inhibitors, canagliflozin, or non-SGLT2 inhibitor AHAs. Patients newly exposed to canagliflozin and non-SGLT2 inhibitor AHAs were matched 1:1 on propensity scores, and a Cox proportional hazards model was used for comparative analysis. Negative controls (outcomes not believed to be associated with any AHA) were used to calibrate P values. RESULTS: Between April 1, 2013 and October 31, 2016, 118 018 new users of SGLT2 inhibitors, including 73 024 of canagliflozin, and 226 623 new users of non-SGLT2 inhibitor AHAs were identified. The crude incidence rates of BKLE amputation were 1.22, 1.26 and 1.87 events per 1000 person-years with SGLT2 inhibitors, canagliflozin and non-SGLT2 inhibitor AHAs, respectively. For the comparative analysis, 63 845 new users of canagliflozin were matched with 63 845 new users of non-SGLT2 inhibitor AHAs, resulting in well-balanced baseline covariates. The incidence rates of BKLE amputation were 1.18 and 1.12 events per 1000 person-years with canagliflozin and non-SGLT2 inhibitor AHAs, respectively; the hazard ratio was 0.98 (95% confidence interval 0.68-1.41; P = .92, calibrated P = .95). CONCLUSIONS: This real-world study observed no evidence of increased risk of BKLE amputation for new users of canagliflozin compared with non-SGLT2 inhibitor AHAs in a broad population of patients with T2DM.

Optimizing the analysis strategy for the CANVAS Program: A prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials.

Two large cardiovascular outcome trials of canagliflozin, comprising the CANVAS Program, will complete in early 2017: the CANagliflozin cardioVascular Assessment Study (CANVAS) and the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R). Accruing data for the sodium glucose co-transporter 2 (SGLT2) inhibitor class has identified questions and opportunities that were not apparent when the trials were designed. Accordingly, a series of modifications have been made to the planned analyses. These updates will ensure that the data from the CANVAS Program will maximize advances in scientific knowledge and patient care. The specification of the analysis strategy prior to knowledge of the trial results, their design by the independent scientific trial Steering Committee, the detailed a priori definition of the analysis plans, and the external review provided by the US Food and Drug Administration all provide maximally efficient and robust utilization of the data. The CANVAS Program should significantly advance our understanding of the effects of canagliflozin, and the broader SGLT2 inhibitor class, on a range of important efficacy and safety outcomes.

Renal safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus.

The incidence of renal-related adverse events (AEs) with canagliflozin in patients with type 2 diabetes mellitus from a pooled population of patients in 7 active- and placebo-controlled trials (N = 5598) and in a 104-week study vs glimepiride (N = 1450) was low and similar in canagliflozin and non-canagliflozin groups. In the study vs glimepiride, canagliflozin was associated with an initial acute decrease in estimated glomerular filtration rate (eGFR) that attenuated over time, while eGFR declined progressively over 104 weeks with glimepiride. The incidence of renal-related AEs with canagliflozin was generally stable over time, while the incidence with glimepiride increased over 104 weeks. In the present analysis, based on postmarketing reports from the US Food and Drug Administration Adverse Event Reporting System, a potential signal was identified for acute kidney injury with all approved sodium glucose co-transporter 2 (SGLT2) inhibitors (ie, canagliflozin, dapagliflozin and empagliflozin). The early onset of acute kidney injury events with SGLT2 inhibitors in postmarketing reports probably reflects the acute changes in eGFR attibutable to the known renal haemodynamic effects of SGLT2 inhibition.

Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With Canagliflozin.

CONTEXT: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM). OBJECTIVE: Our objective is to describe the effects of canagliflozin on bone mineral density (BMD) and bone biomarkers in patients with T2DM. DESIGN: This was a randomized study, consisting of a 26-week, double-blind, placebo-controlled period and a 78-week, double-blind, placebo-controlled extension. SETTING: This study was undertaken in 90 centers in 17 countries. PATIENTS: Patients were aged 55-80 years (N = 716) and whose T2DM was inadequately controlled on a stable antihyperglycemic regimen. INTERVENTIONS: Canagliflozin 100 or 300 mg or placebo were administered once daily. OUTCOME AND MEASURES: BMD was assessed using dual-energy x-ray absorptiometry at weeks 26, 52, and 104. Bone strength was assessed using quantitative computed tomography and finite element analysis at week 52. Serum collagen type 1 ß-carboxy-telopeptide, osteocalcin, and estradiol were assessed at weeks 26 and 52. RESULTS: Canagliflozin doses of 100 and 300 mg were associated with a decrease in total hip BMD over 104 weeks, (placebo-subtracted changes: -0.9% and -1.2%, respectively), but not at other sites measured (femoral neck, lumbar spine, or distal forearm). No meaningful changes in bone strength were observed. At week 52, canagliflozin was associated with an increase in collagen type 1 ß-carboxy-telopeptide that was significantly correlated with a reduction in body weight, an increase in osteocalcin, and, in women, a decrease in estradiol. CONCLUSIONS: In older patients with T2DM, canagliflozin showed small but significant reductions in total hip BMD and increases in bone formation and resorption biomarkers, due at least in part to weight loss.

Canagliflozin: a sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus.

The sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin is a novel treatment option for adults with type 2 diabetes mellitus (T2DM). In patients with hyperglycemia, SGLT2 inhibition lowers plasma glucose levels by reducing the renal threshold for glucose (RTG ) and increasing urinary glucose excretion (UGE). Increased UGE is also associated with a mild osmotic diuresis and net caloric loss, which can lead to reductions in body weight and blood pressure (BP). After promising results from preclinical and phase I/II studies, the efficacy and safety of canagliflozin was evaluated in a comprehensive phase III development program in over 10,000 patients with T2DM on various background therapies. Canagliflozin improved glycemic control and provided reductions in body weight and BP versus placebo and active comparators in studies of up to 2 years' duration. Canagliflozin was generally well tolerated, with higher incidences of adverse events (AEs) related to the mechanism of action, including genital mycotic infections and AEs related to osmotic diuresis. Results from the preclinical and clinical studies led canagliflozin to be the first-in-class SGLT2 inhibitor approved in the United States, and support canagliflozin as a safe and effective therapeutic option across a broad range of patients with T2DM.