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Linagliptin for type 2 diabetes mellitus: a review of the pivotal clinical trials.

ABSTRACT: Patients with type 2 diabetes mellitus (T2DM) frequently require multiple therapies to effectively control hyperglycemia, and many new agents for glucose control have been developed over the past few decades. Linagliptin is a recently approved oral antidiabetic drug that acts by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4). Unlike other DPP-4 inhibitors, linagliptin is excreted chiefly via the enterohepatic system, and can be used without dose adjustment in patients with renal or hepatic impairment. Linagliptin was approved by the US Food and Drug Administration based on a large development program, including four pivotal trials in patients with T2DM, assessing the efficacy and safety of linagliptin when used as monotherapy or in combination with other oral antidiabetes drugs. Linagliptin was associated with significant improvements in glycosylated hemoglobin, fasting plasma glucose and postprandial glucose, and more patients receiving linagliptin showed meaningful improvements and achieved targets for glycosylated hemoglobin. Linagliptin was well tolerated, with an adverse event profile similar to that of placebo, and low rates of hypoglycemic events. Taken together, the pivotal trials confirm linagliptin is effective and safe in patients with T2DM: the convenience of oral dosing with no requirement for dose adjustment in patients with renal or hepatic impairment make linagliptin a valuable option when considering therapies for patients with T2DM.

SUBMITTER: McGill JB

PROVIDER: S-EPMC3498850 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Linagliptin for type 2 diabetes mellitus: a review of the pivotal clinical trials.

McGill Janet B JB

Therapeutic advances in endocrinology and metabolism 20120801 4

Patients with type 2 diabetes mellitus (T2DM) frequently require multiple therapies to effectively control hyperglycemia, and many new agents for glucose control have been developed over the past few decades. Linagliptin is a recently approved oral antidiabetic drug that acts by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4). Unlike other DPP-4 inhibitors, linagliptin is excreted chiefly via the enterohepatic system, and can be used without dose adjustment in patients with renal or hepatic ...[more]

PMID: 23185685

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Project description:Sodium glucose cotransporter 2 (SGLT2) inhibitors have a unique mechanism of action leading to excretion of glucose in the urine and subsequent lowering of plasma glucose. This mechanism is independent of ?-cell function; thus, these agents are effective treatment for type 2 diabetes mellitus (T2DM) at theoretically any disease stage. This class should not confer an additional risk of hypoglycemia (unless combined with insulin or an insulin secretagogue) and has the potential to be combined with other classes of glucose-lowering agents. Empagliflozin is one of three currently approved SGLT2 inhibitors in the United States, and has shown a favorable benefit-risk ratio in phase 3 clinical trials as monotherapy and as add-on to other glucose-lowering therapy in broad patient populations. In addition to its glucose-lowering effects, empagliflozin has been shown to reduce body weight and blood pressure without a compensatory increase in heart rate. Moreover, on top of standard of care, empagliflozin is the first glucoselowering agent to demonstrate cardiovascular risk reduction in patients at high risk of cardiovascular disease in a prospective outcomes trial: a 14% reduction in risk of the 3-point composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Like other SGLT2 inhibitors, empagliflozin is associated with a higher rate of genital mycotic infections than placebo and has the potential for volume depletion-associated events.This review summarizes the empagliflozin phase 3 clinical trials program and its potential significance in the treatment of patients with T2DM. Evidence from these clinical trials show reductions in glycated hemoglobin (-0.59 to -0.82%) with a low risk of hypoglycemia except when used with insulin or insulin secretagogues, and moderate reductions in body weight (-2.1 to - 2.5 kg) and systolic blood pressure (-2.9 to -5.2 mm Hg), thus supporting the use of empagliflozin as monotherapy or in addition to other glucose-lowering agents. In addition, evidence from the recent EMPA-REG OUTCOME study, which demonstrated relative risk reductions in major adverse cardiac events (14%), cardiovascular mortality (38%) and all-cause mortality (32%), as well as hospitalization for heart failure (36%), supports use of empagliflozin in patients with T2DM and increased cardiovascular risk.

Project description:IntroductionLinagliptin is a xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor that is now available in numerous countries worldwide for the treatment of type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate further the mechanisms underlying the improvements in glycemic control observed with linagliptin. The effects of linagliptin on DPP-4, pharmacodynamic parameters, and glycemic control versus placebo were assessed in patients with inadequately controlled T2DM.MethodsPatients in this phase 2a, multicenter, randomized, double-blind, placebo-controlled study received placebo (n = 40) or linagliptin 5 mg (n = 40). Sitagliptin 100 mg (n = 41) once daily for 4 weeks was included for exploratory purposes. Primary endpoints for linagliptin versus placebo: change from baseline to day 28 in 24-h weighted mean glucose (WMG) and intact glucagon-like peptide (GLP)-1 area under the time-effect curve between 0 and 2 h (AUEC(0-2h)) following meal tolerance test on day 28.ResultsLinagliptin increased intact GLP-1 AUEC(0-2h) (+18.1 pmol/h/L) and lowered 24-h WMG (-1.1 mmol/L) versus placebo (both P < 0.0001) after 28 days. Intact glucose-dependent insulinotropic polypeptide increased in line with GLP-1 (+91.4 pmol/h/L increase vs. placebo; P < 0.0001). Glycated hemoglobin (-0.22%; P = 0.0021), fasting plasma glucose (-0.6 mmol/L; P = 0.0283), and glucose (AUEC(0-3h)) (-5.9 mmol/h/L; P < 0.0001) improved significantly with linagliptin versus placebo. Most adverse events were mild; hypoglycemia or serious adverse events were not reported. Sustained DPP-4 inhibition (≥80%) throughout the treatment period was accompanied by significant reductions in glucagon starting at day 1 of linagliptin administration.ConclusionLinagliptin was well tolerated and effectively inhibited plasma DPP-4 activity in patients with T2DM, producing immediate improvements in incretin levels, glucagon suppression, and glycemic control that were maintained throughout the study period.

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Linagliptin for type 2 diabetes mellitus: a review of the pivotal clinical trials.

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Linagliptin for type 2 diabetes mellitus: a review of the pivotal clinical trials.

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