Long‐term efficacy and safety of canagliflozin over 104 weeks in patients aged 55–80 years with type 2 diabetes

Bode, Bruce W.; Stenlöf, Kaj; Harris, Stewart B.; Sullivan, Daniel J.; Fung, Albert; Usiskin, Keith; Meininger, Gary

doi:10.1111/dom.12428

Cited by 191 publications

(229 citation statements)

References 37 publications

(61 reference statements)

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“…Reductions from baseline in alanine aminotransferase and serum urate were observed in the CANA groups compared with MET. Consistent with previous studies of CANA (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), all CANA groups experienced early reductions in eGFR and commensurate increases in serum creatinine that attenuated over 26 weeks (Supplementary Fig. 3).…”

Section: Safety and Tolerabilitysupporting

confidence: 89%

“…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.…”

mentioning

confidence: 99%

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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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Section: Safety and Tolerabilitysupporting

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…11, 12, 22, 23, 24, 25, 26, 27, 28, 29, 30 For cardiovascular outcomes analysis, 3 RCTs11, 12, 22 and 2 observational studies23, 24 were included with 351 476 patients and median follow‐up of 3.1 years. Nine RCTs contributed to the analysis of long‐term noncardiovascular safety and efficacy of SGLT2 inhibitors, with a medium follow‐up of 2 years 11, 12, 22, 25, 26, 27, 28, 29, 30. All trials were carried out with patients who had type 2 DM.…”

Section: Resultsmentioning

confidence: 99%

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Zhang

Zhu

Chen

et al. 2018

JAHA

105

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BackgroundThe cardiovascular and long‐term noncardiovascular safety and efficacy of SGLT2 (sodium–glucose cotransporter 2) inhibitors have not been well documented.Methods and ResultsFor cardiovascular outcomes, we performed a meta‐analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26 weeks and 2000 patient‐years of follow‐up. For long‐term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2 years and 1000 patient‐years of follow‐up. Five studies with 351 476 patients were included in cardiovascular outcomes analysis. Meta‐analyses showed that SGLT2 inhibitors significantly reduced the risks of major adverse cardiac events (hazard ratio [HR]: 0.80; 95% confidence interval [CI], 0.69–0.92; P=0.002), all‐cause mortality (HR: 0.67; 95% CI, 0.54–0.84; P<0.001), cardiovascular mortality (HR: 0.77; 95% CI, 0.60–0.98; P=0.03), nonfatal myocardial infarction (HR: 0.86; 95% CI, 0.76–0.98; P=0.02), hospitalization for heart failure (HR: 0.62; 95% CI, 0.55–0.69; P<0.001), and progression of albuminuria (HR: 0.68; 95% CI, 0.58–0.81; P<0.001). No significant difference in nonfatal stroke was found. Analyses limited to randomized controlled trials showed similar findings. Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all‐cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long‐term noncardiovascular and efficacy analyses. SGLT2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections.Conclusions SGLT2 inhibitors showed remarkable cardiovascular‐ and renal‐protective effects and good long‐term noncardiovascular safety with sustained efficacy.

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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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Long‐term efficacy and safety of canagliflozin over 104 weeks in patients aged 55–80 years with type 2 diabetes

Abstract: Canagliflozin improved glycaemic control, reduced body weight and systolic blood pressure, and was generally well tolerated in patients aged 55-80 years with T2DM over 104 weeks.

Cited by 191 publications

References 37 publications

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

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

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

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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