Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease

Yale, Jean-François; Bakris, G.; Cariou, Bertrand; Nieto, Javier; David‐Neto, Elias; Yue, Dennis K.; Wajs, Ewa; Figueroa, K.; Jiang, Joel; Law, Gordon; Usiskin, Keith; Meininger, Gary

doi:10.1111/dom.12348

Cited by 229 publications

(253 citation statements)

References 28 publications

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“…Available data on the impact of SGLT2 inhibitors on CKD have derived from an analysis of RCTs conducted with efficacy and safety end points in a diabetic population where SGLT2 inhibitors slowed renal function decline and reduced albuminuria independently of glycemic control (129) Mellitus Patients] trial, empagliflozin added to standard care was associated with a lower rate of the primary composite outcome of cardiovascular and allcause mortality (130).…”

Section: Targeting the Renal Tubule To Improve Ckd And Nafldmentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferatoractivated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium. EPIDEMIOLOGICAL EVIDENCE LINKING NAFLD AND CKDChronic kidney disease (CKD) affects up to 8% of the world's adult population, with its prevalence increasing in an aging population beset by lifestyle-associated diseases such as obesity, the metabolic syndrome, diabetes, hypertension, and smoking (1). CKD may progress to end-stage renal disease (ESRD) and is an important cardiovascular disease (CVD) risk factor. Importantly, most patients with CKD die as a result of CVD before renal replacement therapy is initiated (1).There is potential for improving recognition and treatment of CKD. In the Third National Health and Nutrition Survey, awareness among patients with stage 3 CKD was ,8% (1). Furthermore, ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and all-cause mortality remains unchanged in the CKD population (2). These data suggest that key pathogenetic mechanisms underlying

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Section: Targeting the Renal Tubule To Improve Ckd And Nafldmentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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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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“…Canagliflozin (CANA) is an SGLT2 inhibitor developed for the treatment of adults with type 2 diabetes (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). CANA lowers the renal threshold for glucose, thereby increasing urinary glucose excretion (UGE); increased UGE results in insulinindependent glucose-lowering effects, as well as a mild osmotic diuresis and net caloric loss that can lead to weight loss and blood pressure (BP) reductions (24,25).…”

mentioning

confidence: 99%

“…CANA lowers the renal threshold for glucose, thereby increasing urinary glucose excretion (UGE); increased UGE results in insulinindependent glucose-lowering effects, as well as a mild osmotic diuresis and net caloric loss that can lead to weight loss and blood pressure (BP) reductions (24,25). Across phase 3 studies in a broad range of patients with type 2 diabetes, CANA provided reductions in HbA 1c , body weight, and BP and was generally well tolerated as monotherapy and in combination with other AHAs, including MET (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). This study evaluated the efficacy and safety of initial combination therapy with CANA 100 mg (CANA100) or CANA 300 mg (CANA300) plus MET in drug-naïve patients with type 2 diabetes over 26 weeks.…”

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confidence: 99%

Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes

et al. 2016

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OBJECTIVE This study assessed the efficacy/safety of canagliflozin (CANA), a sodium–glucose cotransporter 2 (SGLT2) inhibitor, plus metformin extended-release (MET) initial therapy in drug-naïve type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, phase 3 study randomized 1,186 patients to CANA 100 mg (CANA100)/MET, CANA 300 mg (CANA300)/MET, CANA100, CANA300, or MET. Primary end point was change in HbA1c at week 26 for combinations versus monotherapies. Secondary end points included noninferiority in HbA1c lowering with CANA monotherapy versus MET; changes in fasting plasma glucose, body weight, and blood pressure; and proportion of patients achieving HbA1c <7.0% (<53 mmol/mol). RESULTS From mean baseline HbA1c of 8.8% (73 mmol/mol), CANA100/MET and CANA300/MET significantly lowered HbA1c versus MET (median dose, 2,000 mg/day) by –1.77%, –1.78%, and –1.30% (–19.3, –19.5, and –14.2 mmol/mol; differences of −0.46% and –0.48% [–5.0 and –5.2 mmol/mol]; P = 0.001) and versus CANA100 and CANA300 by –1.37% and –1.42% (–15.0 and –15.5 mmol/mol; differences of –0.40% and –0.36% [–4.4 and –3.9 mmol/mol]; P = 0.001). CANA100 and CANA300 monotherapy met noninferiority for HbA1c lowering and had significantly more weight loss versus MET (–2.8, –3.7, and –1.9 kg [–3.0%, –3.9%, and –2.1%]; P = 0.016 and P = 0.002). Greater attainment of HbA1c <7.0% (50%, 57%, and 43%) and significantly more weight loss (–3.2, –3.9, and –1.9 kg [–3.5%, –4.2%, and –2.1%]; P = 0.001) occurred with CANA100/MET and CANA300/MET versus MET. The incidence of adverse events (AEs) related to SGLT2 inhibition (genital mycotic infections, osmotic diuresis– and volume depletion–related AEs) was higher in the CANA arms (0.4–4.4%) versus MET (0–0.8%). AE-related discontinuation rates were 1.3–3.0% across groups. The incidence of hypoglycemia was 3.0–5.5% in the CANA arms and 4.6% with MET. CONCLUSIONS Initial therapy with CANA plus MET was more effective and generally well tolerated versus each monotherapy in drug-naïve type 2 diabetes. CANA monotherapy demonstrated noninferior HbA1c lowering versus MET.

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Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease

Abstract: Canagliflozin improved glycaemic control and was generally well tolerated in patients with T2DM and within a subset of Stage 3 CKD over 52 weeks.

Cited by 229 publications

References 28 publications

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

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

Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes

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