Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease

Yale, JF; Bakris, George L.; Cariou, Bertrand; Yue, Dennis K.; David‐Neto, Elias; Xi, Liwen; Figueroa, K.; Wajs, Ewa; Usiskin, Keith; Meininger, Gary

doi:10.1111/dom.12090

Cited by 443 publications

(591 citation statements)

References 17 publications

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“…SGLT2 inhibition has similar anti-albuminuric effects in animal models of type 2 diabetes [21], including recent evidence that empagliflozin reduced albuminuria, independent of effects on BP or hyperglycaemia, in BTBR ob/ob mouse models of type 2 diabetes [22]. Previous clinical studies in type 2 diabetes patients with and without CKD have shown that SGLT2 inhibition is associated with an acute but modest decline in eGFR within 3-6 weeks of treatment initiation, followed by a period of stable renal function for 52-104 weeks; this change is reversible after drug cessation for 2 weeks [17,23,24]. Notably, within this same treatment period, renal safety assessments of SGLT2 inhibitors have also reported a reduction in UACR or urinary albumin excretion in patients with type 2 diabetes and CKD [15,24].…”

Section: Discussionmentioning

confidence: 99%

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

et al. 2016

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Aims/hypothesis Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA 1c , systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA 1c , SBP, weight and intraglomerular pressure is associated with antialbuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent. Methods We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 3 0 -3 0 0 m g / g ; n = 6 3 6 ) o r m a c r o a l b u m i n u r i a (UACR > 300 mg/g; n = 215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24. Results After controlling for clinical confounders including baseline log-transformed UACR, HbA 1c , SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (−32% vs placebo; p < 0.001) or macroalbuminuria (−41% vs placebo; p < 0.001). Intriguingly, in regression models, most of the UACR-lowering effect with empagliflozin was not explained by SGLT2 inhibition-related improvements in HbA 1c , SBP or weight. Conclusions/interpretation In patients with type 2 diabetes and either micro-or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes.

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Section: Discussionmentioning

confidence: 99%

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

et al. 2016

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“…Data were sorted by first author, year of publication, country of the study, design, age range of the participants, total sample size, SGLT2 inhibitor, comparator, number of patients, dosage, and follow‐up duration (Table 1). 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 …”

Section: Methodsmentioning

confidence: 99%

Effect of Sodium‐Glucose Cotransport‐2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta‐Analysis of 43 Randomized Control Trials With 22 528 Patients

Mazidi

Rezaie

Gao

et al. 2017

JAHA

260

174

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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.

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“…While the insulin‐independent mechanism of canagliflozin leads to a low inherent risk of hypoglycaemia, the mild osmotic diuresis it causes may be associated with an increased risk of volume–depletion events, including dehydration. Across Phase 3 studies in a broad range of patients, canagliflozin provided reductions in HbA1c, body weight, and systolic blood pressure (BP) and was generally well tolerated, with a low risk of hypoglycaemia when not used in conjunction with insulin or sulphonylureas 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. An analysis of T2DM patients living in hot climates found that canagliflozin treatment was generally well tolerated, with a low incidence of volume depletion–related AEs 23…”

Section: Introductionmentioning

confidence: 99%

Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS)

Hassanein

Echtay

Hassoun³

et al. 2017

Int J Clin Pract

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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

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Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease

Cited by 443 publications

References 17 publications

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

Effect of Sodium‐Glucose Cotransport‐2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta‐Analysis of 43 Randomized Control Trials With 22 528 Patients

Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS)

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