Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis

Wu, Dan; Li, L.; Liu, C.

doi:10.1111/dom.12174

Cited by 113 publications

(106 citation statements)

References 47 publications

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“…The incidence of pancreatic cancer was not assessable due to the short follow-up. In a recent meta-analysis it was demonstrated that DPP-4 inhibitors and metformin combination therapy has a better efficacy than metformin monotherapy, without an increase in any adverse effect, 17,18 confirming the good safety profile of these drugs. In keeping with this, in our study there was no suspension of therapy and the adverse events appeared minor and temporary.…”

Section: Discussionmentioning

confidence: 93%

Sitagliptin versus saxagliptin in decompensated type 2 diabetes mellitus patients

et al. 2016

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Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease, characterized by persistent hyperglycemia, due to both a decline of b-pancreatic insulin production and an increased peripheral insulin resistance. The incidence of this pathology is increasing rapidly, indeed, it was estimated that the number of diabetics will arise from 371 million (2012) to 552 million (2030), representing one of the major challenge to health care worldwide. 1Traditional therapies can be still considered suboptimal, since there are no treatments able to guarantee a perfect glycemic control and a stable prevention of diabetic complications, without the risk of hypoglycemia.2 For these reasons, the finding that particular hormones, called glucon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are able to induce a greater secretion of insulin only in the presence of high level of glucose, has quickly attracted the attention of scientists. 3,4 GLP-1 is a polypeptide, secreted by endocrine cells of small intestine during the digestive phase; the glucose in the intestinal lumen acts as a trigger and induces the release of this hormone. Through the circulation, GLP-1 reaches its receptor on bpancreatic cells, stimulating the secretion of insulin in relation to the amount of glucose concentration. Physiologically, the half-life of endogenous GLP-1 is around 2 min; this hormone, indeed, is quickly degraded by a specific peptidase, the dipeptdylpeptidase 4 (DPP-4). 5In addition to the stimulus of insulin secretion, the hypoglycemic effect of this substance is enhanced by the inhibition of glucagon release. Moreover, this hormone stimulates the transcription of insulin and ABSTRACTSitagliptin and saxagliptin are oral hypoglycemic agents inhibitors of DPP-4, indicated in the treatment of type 2 diabetes mellitus in combination with metformin, in patients who have not achieved adequate glycemic control. In our study we enrolled 128 decompensated type 2 diabetes patients while on metformin maximum dosage. At time 0' we have detected, body mass index (BMI), total cholesterol, high-and low-density lipoproteins (HDL and LDL), triglycerides, transaminases and pancreatic amylase; patients were randomized to receive sitagliptin or saxagliptin; follow-up was performed after 4 months with the revaluation of the same variables and adverse events. In both sitagliptin and saxagliptin groups we observed a significant reduction in fasting glucose, glycated hemoglobin, weighing, BMI, triglycerides, while the reduction in total cholesterol, LDL cholesterol did not reach statistical significance. There was no suspension of therapy, adverse events appeared minor and temporary. In conclusion, our observations highlight the almost identical efficacy of sitagliptin and saxagliptin. These data reinforce even more the idea that we should think about this class of drugs as the next step in patients failing therapy with metformin.

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Section: Discussionmentioning

confidence: 93%

Sitagliptin versus saxagliptin in decompensated type 2 diabetes mellitus patients

et al. 2016

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“…The results of the first CV trials with DPP-4 inhibitors (3-5) did not meet the expectations of many clinicians, who hoped for a demonstration of a CV benefit, as suggested by meta-analyses of previous, shorter-term studies (8)(9)(10)43). However, CV trials provided exactly the result that they had been designed for: noninferiority versus placebo.…”

Section: Discussionmentioning

confidence: 96%

Analyses of Results From Cardiovascular Safety Trials With DPP-4 Inhibitors: Cardiovascular Outcomes, Predefined Safety Outcomes, and Pooled Analysis and Meta-analysis

2016

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The U.S. Food and Drug Administration requires that the cardiovascular (CV) safety of all new drugs for diabetes be demonstrated through pooled analyses of phase III studies or specifically designed trials. This requirement prompted several placebo-controlled, noninferiority CV safety trials in high-risk patients; to date, all completed trials showed that dipeptidyl peptidase (DPP)-4 inhibitors do not increase or reduce the risk of major CV events. These results apparently contrast with those of pooled analyses and meta-analyses of previous, smaller trials with metabolic end points, which had suggested a reduction of risk. However, the design of CV trials, which were required to demonstrate safety, is not adequate (for duration, management of concurrent therapies, etc.) for the assessment of potential therapeutic benefits. In addition, CV safety trials enroll patients at high risk of CV events, who are different from those included in earlier trials with metabolic end points. Differences in characteristics of patients enrolled probably account for most of the discrepancy in CV outcomes between CV safety studies and earlier trials. The availability of several large-scale trials with longer duration provides the unique opportunity for assessment of the safety of DPP-4 inhibitors not only with respect to major CV events but also with reference to other safety issues. For example, CV safety trials can be a source of information for pancreatitis, cancer, or hypoglycemia.In December 2008, the U.S. Food and Drug Administration (FDA) published guidance prompting pooled analyses and meta-analyses of cardiovascular (CV) events (sometimes with post hoc adjudication) observed in trials with metabolic outcomes (1). A shift of emphasis occurred from short-term, HbA 1c -centered phase II-III trials in "healthy" patients with type 2 diabetes to CV safety studies in a more vulnerable population (2). Results from the first trials according to the FDA guidance were

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“…Recently, it was shown that the combination of metformin and a DPP-4 inhibitor is more beneficial than either alone for optimizing glycemic control in type 2 diabetes (24). Metformin augments GLP-1 concentrations by uncertain means (25,26) and in mice, can increase expression of GLP-1 and GIP receptors in pancreatic islets (25).…”

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confidence: 99%

Effects of Sitagliptin on Glycemia, Incretin Hormones, and Antropyloroduodenal Motility in Response to Intraduodenal Glucose Infusion in Healthy Lean and Obese Humans and Patients With Type 2 Diabetes Treated With or Without Metformin

Bound

et al. 2014

Diabetes

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The impact of variations in gastric emptying, which influence the magnitude of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) secretion, on glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60 g over 120 min [i.e., 2 kcal/min], a rate that predominantly stimulates GIP but not GLP-1) after sitagliptin versus control in 12 healthy lean, 12 obese, and 12 type 2 diabetic subjects taking metformin 850 mg b.i.d. versus placebo. As expected, sitagliptin augmented plasma-intact GIP substantially and intact GLP-1 modestly. Sitagliptin attenuated glycemic excursions in healthy lean and obese but not type 2 diabetic subjects, without affecting glucagon or energy intake. In contrast, metformin reduced fasting and glucose-stimulated glycemia, suppressed energy intake, and augmented total and intact GLP-1, total GIP, and glucagon in type 2 diabetic subjects, with no additional glucose lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes, 1) the capacity of endogenous GIP to lower blood glucose is impaired; 2) the effect of DPP-4 inhibition on glycemia is likely to depend on adequate endogenous GLP-1 release, requiring gastric emptying >2 kcal/min; and 3) the action of metformin to lower blood glucose is not predominantly by way of the incretin axis.Inhibition of dipeptidyl peptidase-4 (DPP-4) lowers glycemia by increasing intact glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) concentrations (1). In type 2 diabetes, the insulinotropic effects of GIP and GLP-1 are diminished, although the effect of GLP-1 is better preserved (2,3). GLP-1 also suppresses glucagon secretion (4), appetite, and energy intake (5) and slows gastric emptying (6,7). Therefore, the glucoselowering effect of DPP-4 inhibitors in this disorder is likely to depend primarily on the actions of GLP-1 rather than of GIP.Postprandial incretin secretion is regulated by the rate of nutrient delivery to the small intestine (8,9); GIP

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Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis

Cited by 113 publications

References 47 publications

Sitagliptin versus saxagliptin in decompensated type 2 diabetes mellitus patients

Sitagliptin versus saxagliptin in decompensated type 2 diabetes mellitus patients

Analyses of Results From Cardiovascular Safety Trials With DPP-4 Inhibitors: Cardiovascular Outcomes, Predefined Safety Outcomes, and Pooled Analysis and Meta-analysis

Effects of Sitagliptin on Glycemia, Incretin Hormones, and Antropyloroduodenal Motility in Response to Intraduodenal Glucose Infusion in Healthy Lean and Obese Humans and Patients With Type 2 Diabetes Treated With or Without Metformin

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