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Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes.

ABSTRACT: Metformin is typically the first pharmacologic treatment recommended for type 2 diabetes mellitus (T2DM), but many patients do not achieve glycemic control with metformin alone and eventually require combination therapy with other agents. Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was assessed in a comprehensive Phase 3 clinical development program consisting of ~10,000 participants, of which ~80% were on background therapy that consisted of metformin alone or in combination with other antihyperglycemic agents (AHAs; e.g., pioglitazone, sulfonylurea, and insulin). In addition, the efficacy and safety of canagliflozin and metformin as the initial combination therapy and canagliflozin monotherapy were assessed versus metformin in treatment-naïve patients with T2DM. Across studies in patients with T2DM who were on metformin alone or in combination with other AHAs, canagliflozin 100 and 300 mg provided improvements in glycated hemoglobin for up to 104 weeks. Canagliflozin was also associated with reductions in body weight and systolic blood pressure when added to background therapy consisting of metformin alone or with other AHAs. Canagliflozin was generally well tolerated, with increased incidence of adverse events (AEs) related to the mechanism of SGLT2 inhibition (i.e., genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs). Consistent with its insulin-independent mechanism of action, canagliflozin was associated with low rates of hypoglycemia when background therapy did not include sulfonylurea or insulin. Due to its favorable efficacy and safety profile, these results suggest that adding canagliflozin to a background regimen consisting of metformin or implementing treatment with a fixed-dose regimen of canagliflozin and metformin would provide an effective and safe treatment regimen for T2DM management.

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Janssen Global Services, LLC.

SUBMITTER: Qiu R

PROVIDER: S-EPMC5118239 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionCurrent guidelines recommend adding an oral antihyperglycemic agent (AHA) to metformin in patients with type 2 diabetes mellitus (T2DM) uncontrolled on metformin. Recent randomized clinical trials (RCTs) have demonstrated that adding dual AHAs instead of a single AHA provided more effective glycemic control. However, the comparative efficacy of approved single and dual initiation strategies is unknown. Therefore, we conducted a Bayesian network meta-analysis to compare the efficacy of dual and single add-on oral AHAs in patients uncontrolled on metformin.MethodsA systematic literature review of RCTs was conducted following Cochrane and ISPOR guidelines. MEDLINE, Embase, and CENTRAL were searched from inception to November 19, 2019. Approved oral doses of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists in single or dual initiation therapies were indirectly compared. Outcomes focused on efficacy and included mean change from baseline in hemoglobin A1c (HbA1c), weight, systolic blood pressure (SBP), diastolic blood pressure, and achieving HbA1c target < 7% at 24-26 weeks. Fixed and random effects models with Markov chain Monte Carlo simulations were used.ResultsOf 1955 unique records screened, 25 RCTs (14,264 participants) were included. In patients uncontrolled on metformin, dual AHA added to metformin had statistically significant or a trend of greater reduction in HbA1c compared to single AHAs, with ertugliflozin + sitagliptin showing the greatest improvement. Statistically significant reductions in weight and SBP were observed with ertugliflozin + sitagliptin, ertugliflozin, or canagliflozin compared to single initiation DPP-4 inhibitors.ConclusionFor reduction of HbA1c, weight, and SBP in patients uncontrolled on metformin, add-on dual AHAs showed greater improvement compared to single AHAs. These findings can further inform the treatment of T2DM patients uncontrolled on metformin.

Project description:Metformin is recommended as a first-line therapy for patients with type 2 diabetes mellitus (T2DM). However, many patients do not achieve glycemic goals with metformin monotherapy and require subsequent combination therapy with other antihyperglycemic agents (AHAs). For newly diagnosed patients with high blood glucose, initial combination therapy may be required to achieve glycemic control. The American Association for Clinical Endocrinologists algorithm for the treatment of T2DM recommends metformin plus a sodium glucose co-transporter 2 (SGLT2) inhibitor as the first oral combination in patients who present with HbA1c ≥7.5%. Canagliflozin, an SGLT2 inhibitor, lowers the renal threshold for glucose and increases urinary glucose excretion leading to a mild osmotic diuresis and a net caloric loss. The effect of canagliflozin is insulin-independent and complementary to other AHAs, including metformin. A fixed-dose combination (FDC) of canagliflozin and metformin is also available with variable dosing, which may be attractive to some patients owing to the potential for reduced pill burden and costs. This article reviews the efficacy and safety of canagliflozin in combination with metformin based on data from the canagliflozin phase 3 clinical program. As initial combination therapy in drug-naïve patients or as dual therapy with metformin or triple therapy in combination with metformin and other AHAs, canagliflozin 100 and 300 mg improved glycemic control and provided reductions in body weight and systolic blood pressure that were sustained for up to 104 weeks. Canagliflozin was generally well tolerated across studies in combination with metformin. An increased incidence of adverse events (AEs) related to the mechanism of SGLT2 inhibition (i.e., genital mycotic infections, urinary tract infections, osmotic diuresis-related AEs) was observed with canagliflozin. Canagliflozin was associated with a low incidence of hypoglycemia when not used in conjunction with AHAs associated with hypoglycemia (i.e., insulin or sulfonylurea). Together, these results support the use of a canagliflozin and metformin FDC as a treatment approach for a broad range of patients with T2DM.FundingJanssen Scientific Affairs, LLC.

Project description:The aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin.This randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants (N?=?1,284) with type 2 diabetes aged ? 18 and ? 80 years who had inadequate glycaemic control (HbA1c ? 7.0% [53 mmol/mol] and ?10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo (n?=?368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA1c at week 26; secondary endpoints included changes in HbA1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study.At week 26, canagliflozin 100 mg and 300 mg reduced HbA1c vs placebo (-0.79%, -0.94%, -0.17%, respectively; p?<?0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA1c (-0.73%, -0.88%,-0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (-0.12, 0.12) and -0.15% (-0.27, -0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: -3.7%, -4.2%, -1.2%, respectively; p?<?0.001) and sitagliptin (week 52: -3.8%, -4.2%, -1.3%, respectively; p?<?0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) (p?<?0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin.Canagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin.ClinicalTrials.gov NCT01106677 FUNDING: This study was supported by Janssen Research & Development, LLC.

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Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes.

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