Dapagliflozin Is Effective as Add-on Therapy to Sitagliptin With or Without Metformin: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

Jabbour, Serge; Hardy, Elise; Sugg, Jennifer; Parikh, Shamik

doi:10.2337/dc13-0467

Cited by 257 publications

(231 citation statements)

References 26 publications

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“…Glycaemic and weight benefits observed at week 24 were maintained through week 48 and fewer patients receiving dapagliflozin were discontinued or rescued for failing to achieve glycaemic targets compared with placebo. Combined therapy was well tolerated except an increase in genital infections (9.8% with dapagliflozin versus 0.4% with placebo [48].…”

Section: Dapagliflozin Added To Sitagliptinmentioning

confidence: 95%

“…versus placebo (n=226) as add-on therapy to sitagliptin 100 mg with or without metformin in patients with inadequately controlled T2D (mean baseline HbA1c 7.9%) [48]. At 24 week add-on treatment with dapagliflozin provided additional clinical benefit with a significant reduction in HbA1c (-0.5% versus 0% with placebo) and body weight (-2.1kg versus -0.3 kg).…”

Section: Dapagliflozin Added To Sitagliptinmentioning

confidence: 99%

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DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

Scheen

2016

Expert Opinion on Drug Metabolism & Toxicology

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SUMMARYIntroduction : Type 2 diabetes (T2D) is a complex disease with multiple defects, which generally require a combination of several pharmacological approaches to control hyperglycemia. Combining a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGT2i) appears to be an attractive approach.Area covered: An extensive literature search was performed to analyze the pharmacokinetics, pharmacodynamics and clinical experience of different gliptin-gliflozin combinations.Expert opinion: There is a strong rationale for combining a DPP-4i and a SGLT2i in patients with T2D because the two drugs exert different and complementary glucose-lowering effects.Dual therapy (initial combination or stepwise approach) is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin.Combining the two pharmacological options is safe and does not induce hypoglycemia. The additional glucose-lowering effect is more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Two fixed-dose combinations (FDCs) are already available (saxagliptin-dapagliflozin and linagliptin-empagliflozin) and others are in current development. Bioequivalence of the two compounds given as FDC tablets was demonstrated when compared with coadministration of the individual tablets. FDCs could simplify the antihyperglycaemic therapy and improve drug compliance. Article highlights box -Type 2 diabetes (T2D) often requires the combination of several medications with complementary actions to reach glucose control targets while limiting side effects -The combination of a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGLT2i) is an attractive approach for the management of T2D. Keywords-Both saxagliptin plus dapagliflozin and linagliptin plus empagliflozin combined therapies have been tested as separate tablets (no clinically relevant pharmacokinetic drug-drug interactions) and as fixed-dose combination (FDC : bioequivalence studies).-DPP-4i -SGLT2i combined therapies are more efficacious than either monotherapy to control blood glucose, without worsening of the safety profile.-Initial DPP-4i -SGLT2i combination may be considered or one compound may the added to the other. However, which one should be used in first place remains an open question.

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Section: Dapagliflozin Added To Sitagliptinmentioning

confidence: 95%

Section: Dapagliflozin Added To Sitagliptinmentioning

confidence: 99%

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

Scheen

2016

Expert Opinion on Drug Metabolism & Toxicology

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“…Although combination injectable therapy with insulin with or without glucagon-like peptide 1 receptor agonist is recommended in patients with severe hyperglycemia (HbA 1c level $10%) (7), for patients with less severe disease, the recently introduced class of SGLT2 inhibitors offers the advantage of reducing hyperglycemia independent of b-cell function and circulating insulin levels (22) and can thus, theoretically, be combined with all other glucose-lowering agents. In addition, adding an SGLT2 inhibitor to a combination therapy with metformin and a DPP-4 inhibitor results in a combination that works complementarily to address several of the pathologic defects of type 2 diabetes (11), leading to clinically relevant reductions in hyperglycemia in patients whose glycemic control has not been maintained with two oral agents and without the burden of hypoglycemia or weight gain that one would expect with sulfonylureas or insulins (23,24). Moreover, a DPP-4 inhibitor may reduce the increase in glucagon secretion induced by SGLT2 inhibitors (25).…”

Section: Discussionmentioning

confidence: 99%

Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes

et al. 2015

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OBJECTIVETo compare the efficacy and safety of treatment with dapagliflozin versus that with placebo add-on to saxagliptin plus metformin in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin treatment. RESEARCH DESIGN AND METHODS Patients RESULTSTreatment with dapagliflozin add-on to saxagliptin plus metformin resulted in a greater mean HbA 1c reduction than placebo (20.82 vs. 20.10% [29 vs. 21.1 mmol/mol], P < 0.0001). Significantly greater reductions in FPG level, 2-h PPG level, and body weight were observed, and more patients achieved an HbA 1c level of <7% (53 mmol/mol) with treatment with dapagliflozin versus placebo. Adverse events were similar across treatment groups, with a low overall risk of hypoglycemia (∼1%). Genital infections developed in more patients with dapagliflozin treatment (5%) than with placebo (0.6%). CONCLUSIONSTriple therapy with dapagliflozin add-on to saxagliptin plus metformin improves glycemic control and is well tolerated in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin therapy.

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“…The sample size was calculated based on results from three previous studies: (1) dapagliflozin add‐on to sitagliptin and metformin19; (2) dapagliflozin add‐on to metformin20; and (3) ipragliflozin add‐on to metformin 15. Assuming the difference for changes in HbA1c from baseline to EOT between the ipragliflozin and placebo groups would be −0.45% with an SD of 0.80, approximately 67 patients per treatment group would be required to detect superiority of ipragliflozin to placebo with 90% power and a significance level of 5% for a two‐sided test.…”

Section: Methodsmentioning

confidence: 99%

Efficacy and safety of ipragliflozin as an add‐on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial

Han

Chon

Chung

et al. 2018

Diabetes Obesity Metabolism

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AimTo evaluate the efficacy and safety of ipragliflozin vs placebo as add‐on therapy to metformin and sitagliptin in Korean patients with type 2 diabetes mellitus (T2DM).MethodsThis double‐blind, placebo‐controlled, multi‐centre, phase III study was conducted in Korea in 2015 to 2017. Patients were randomized to receive either ipragliflozin 50 mg/day or placebo once daily for 24 weeks in addition to metformin and sitagliptin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT).ResultsIn total, 143 patients were randomized and 139 were included in efficacy analyses (ipragliflozin: 73, placebo: 66). Baseline mean (SD) HbA1c levels were 7.90 (0.69)% for ipragliflozin add‐on and 7.92 (0.79)% for placebo. The corresponding mean (SD) changes from baseline to EOT were −0.79 (0.59)% and 0.03 (0.84)%, respectively, in favour of ipragliflozin (adjusted mean difference −0.83% [95% CI −1.07 to −0.59]; P < .0001). More ipragliflozin‐treated patients than placebo‐treated patients achieved HbA1c target levels of <7.0% (44.4% vs 12.1%) and < 6.5% (12.5% vs 1.5%) at EOT (P < .05 for both). Fasting plasma glucose, fasting serum insulin, body weight and homeostatic model assessment of insulin resistance decreased significantly at EOT, in favour of ipragliflozin (adjusted mean difference −1.64 mmol/L, −1.50 μU/mL, −1.72 kg, and −0.99, respectively; P < .05 for all). Adverse event rates were similar between groups (ipragliflozin: 51.4%; placebo: 50.0%). No previously unreported safety concerns were noted.ConclusionsIpragliflozin as add‐on to metformin and sitagliptin significantly improved glycaemic variables and demonstrated a good safety profile in Korean patients with inadequately controlled T2DM.

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Dapagliflozin Is Effective as Add-on Therapy to Sitagliptin With or Without Metformin: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

Cited by 257 publications

References 26 publications

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes

Efficacy and safety of ipragliflozin as an add‐on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial

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