Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial

BackgroundThe sodium‐glucose cotransporter 2 (SGLT2) inhibitors are a class of oral hypoglycemic agents. We undertake a systematic review and meta‐analysis of prospective studies to determine the effect of SGLT2 on blood pressure (BP) among individuals with type 2 diabetes mellitus.Methods and ResultsPubMed‐Medline, Web of Science, Cochrane Database, and Google Scholar databases were searched to identify trial registries evaluating the impact of SGLT2 on BP. Random‐effects models meta‐analysis was used for quantitative data synthesis. The meta‐analysis indicated a significant reduction in systolic BP following treatment with SGLT2 (weighted mean difference −2.46 mm Hg [95% CI −2.86 to −2.06]). The weighted mean differences for the effect on diastolic BP was −1.46 mm Hg (95% CI −1.82 to −1.09). In these subjects the weighted mean difference effects on serum triglycerides and total cholesterol were −2.08 mg/dL (95% CI −2.51 to −1.64) and 0.77 mg/dL (95% CI 0.33‐1.21), respectively. The weighted mean differences for the effect of SGLT2 on body weight was −1.88 kg (95% CI −2.11 to −1.66) across all studies. These findings were robust in sensitivity analyses.ConclusionsTreatment with SGLT2 glucose cotransporter inhibitors therefore has beneficial off‐target effects on BP in patients with type 2 diabetes mellitus and may also be of value in improving other cardiometabolic parameters including lipid profile and body weight in addition to their expected effects on glycemic control. However, our findings should be interpreted with consideration for the moderate statistical heterogeneity across the included studies.

SummaryAimsThere is a large population of people with type 2 diabetes mellitus (T2DM) who are Muslim and fast during Ramadan. Changes in the pattern and amount of meal and fluid intake during Ramadan, in addition to the long fasting hours, may increase the risk of hypoglycaemia, hyperglycaemia, and dehydration. The Canagliflozin in Ramadan Tolerance Observational Study (CRATOS) evaluated the tolerability of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, compared with sulphonylureas among patients with T2DM who fast during Ramadan.MethodsThis non‐randomised, parallel‐cohort, prospective, comparative, observational study was conducted in the Middle East during Ramadan and enrolled patients who were taking canagliflozin (n=162) or any sulphonylurea (n=159) added to metformin±dipeptidyl peptidase‐4 inhibitor. The proportion of patients who experienced hypoglycaemia events was assessed as the primary end‐point. Between‐cohort comparisons were adjusted using propensity score analysis.ResultsDuring Ramadan, fewer patients experienced symptomatic hypoglycaemia with canagliflozin vs sulphonylurea (adjusted odds ratio: 0.273 [95% CI: 0.104, 0.719]). Of hypoglycaemia events for which blood glucose was measured, two of six with canagliflozin and 27 of 37 with sulphonylurea were confirmed by blood glucose <3.9 mmol/L. More patients treated with canagliflozin experienced volume depletion events compared with sulphonylurea (adjusted odds ratio: 3.5 [95% CI: 1.3, 9.2]). Missed fasting days were few and medication adherence was high in both groups. No patients treated with canagliflozin and 9.4% treated with sulphonylurea adjusted their medication dose near the beginning of Ramadan. Both treatments were generally well tolerated, with low rates of adverse events and no serious adverse events in either group.ConclusionsOverall, these findings support the use of canagliflozin for the treatment of adults with T2DM who fast during Ramadan.ClinicalTrials.gov Identifier: NCT02737657

Canagliflozin (Invokana ® ) is a sodium-glucose co-transporter-2 (SGLT2) inhibitor indicated in various countries worldwide for the once-daily oral treatment of type 2 diabetes (T2D). Unlike many T2D therapies, canagliflozin lowers blood glucose levels independently of insulin, with the inhibition of SGLT2 reducing renal reabsorption of glucose and increasing excretion of glucose in the urine. In well-designed clinical trials, canagliflozin (as first-line monotherapy or add-on therapy to other antihyperglycaemic agents) improved glycaemic control in adults with T2D, including those of older age and/or at high cardiovascular (CV) risk, and also had beneficial effects on their bodyweight and BP; whether the drug impacts the CV risk profile of T2D is currently being evaluated in the large CV outcomes study CANVAS. Canagliflozin was generally well tolerated, had a low risk of hypoglycaemia and was most commonly associated with adverse events such as genital and urinary tract infections and increased urination, consistent with its mechanism of action. Thus, canagliflozin is a useful monotherapy and add-on therapy option for the management of T2D in adults, and its CV profile is eagerly awaited.