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Effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus: a pooled analysis of six randomized, placebo-controlled clinical trials.

ABSTRACT: Our aim was to examine the effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus (T2DM). We conducted a pooled analysis of double-blind trials of Japanese T2DM patients, randomized to 50 mg ipragliflozin or placebo, with patient-level data for the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline to end of treatment (12-24 weeks). Data from six trials were analyzed: ipragliflozin was administered as monotherapy in two; in combination with metformin, pioglitazone, or sulfonylurea in one each; and in combination with prior therapy in patients with renal impairment in one. Overall, 628 and 368 patients were treated with ipragliflozin and placebo, respectively. The placebo-adjusted mean changes (95 % confidence interval) in SBP and DBP (mmHg) were -2.8 (-4.4, -1.3, P < 0.001) and -1.6 (-2.7, -0.6, P < 0.002), respectively, in all patients. The reductions in SBP and DBP were significantly greater in patients with baseline SBP ?140 mmHg [-5.5 (-9.1, -1.8) and -2.9 (-5.3, -0.5), respectively] than in patients with SBP <140 mmHg [-2.1 (-3.8, -0.4) and -1.3 (-2.5, -0.1), respectively]. The reductions in SBP and DBP were also significantly greater in the ipragliflozin group than in the placebo group in patients treated with [-2.8 (-5.1, -0.4) and -2.4 (-4.0, -0.8), respectively] or without [-3.0 (-5.0, -1.0) and -1.0 (-2.4, 0.4), respectively] concomitant antihypertensive therapy. In conclusion, this pooled analysis showed that ipragliflozin was associated with significant reductions in SBP and DBP compared with placebo.

SUBMITTER: Kashiwagi A

PROVIDER: S-EPMC6224932 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus: a pooled analysis of six randomized, placebo-controlled clinical trials.

Kashiwagi Atsunori A Yoshida Satoshi S Kawamuki Kosei K Nakamura Ichiro I Kazuta Kenichi K Ueyama Eiji E Takahashi Hideyuki H Akiyama Noriko N Kondo Yoshinori Y Ogihara Toshio T

Diabetology international 20160909 1

Our aim was to examine the effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus (T2DM). We conducted a pooled analysis of double-blind trials of Japanese T2DM patients, randomized to 50 mg ipragliflozin or placebo, with patient-level data for the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline to end of treatment (12-24 weeks). Data from six trials were analyz ...[more]

PMID: 30603310

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Project description:IntroductionSodium-dependent glucose cotransporter 2 (SGLT2) inhibitors inhibit the reabsorption of glucose from the kidneys and increase urinary glucose excretion (UGE), thereby lowering the blood glucose concentration in people suffering from type 1 and type 2 diabetes mellitus (T2DM). In a previous study, we reported a pharmacokinetics/pharmacodynamics model to estimate individual change in UGE (ΔUGE), which is a direct pharmacological effect of SGLT2 inhibitors. In this study, we report our enhancement of the previous model to predict the long-term effects of ipragliflozin on clinical outcomes in patients with T2DM.MethodsThe time course of fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) in patients with T2DM following ipragliflozin treatment that had been observed in earlier clinical trials was modeled using empirical models combined with the maximum drug effect (Emax) model and disease progression model. As a predictive factor of drug effect, estimated ΔUGE was introduced into the Emax model, instead of ipragliflozin exposure. The developed models were used to simulate the time course of FPG and HbA1c following once-daily treatment with placebo or ipragliflozin at doses of 12.5, 25, 50 and 100 mg, and the changes at 52 weeks at the approved dose of 50 mg were summarized by renal function category.ResultsThe developed models that included UGE as a dependent variable of response were found to well describe observed time courses in FPG and HbA1c. Baseline blood glucose level and renal function had significant effects on the glucose-lowering effect of ipragliflozin, and these models enabled quantification of these impacts on clinical outcomes. Simulated median changes in HbA1c in T2DM patients with mild and moderate renal impairment were 25 and 63% lower, respectively, than those in T2DM patients with normal renal function. These results are consistent with the observed clinical data from a previous renal impairment study.ConclusionsEmpirical models established based on the effect of UGE well predicted the renal function-dependent long-term glucose-lowering effects of ipragliflozin in patients with T2DM.

Dataset Information

Effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus: a pooled analysis of six randomized, placebo-controlled clinical trials.

Publications

Effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus: a pooled analysis of six randomized, placebo-controlled clinical trials.

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