Dipeptidyl Peptidase-4 Inhibitors In Combination Research Articles

Comparison of SGLT2 inhibitors with DPP-4 inhibitors combined with metformin in patients with acute myocardial infarction and diabetes mellitus

BackgroundAlthough sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular benefits in patients with type 2 diabetes mellitus, real-world evidence regarding their benefits to diabetic patients with acute myocardial infarction (AMI) is insufficient. This study evaluated cardiovascular outcomes by comparing SGLT2i with dipeptidyl peptidase-4 inhibitors (DPP-4i) in combination with metformin in diabetic patients with AMI.MethodsThis study involved 779 diabetic participants with AMI from a Korean nationwide multicenter observational cohort, who were divided into two groups: (1) metformin plus SGLT2i group (SGLT2i group, n = 186) and (2) metformin plus DPP-4i (DPP-4i group, n = 593). The primary endpoint was one year of major adverse composite events (MACEs), a composite outcome of all-cause mortality, non-fatal myocardial infarction, any revascularization, cerebrovascular accident, and stent thrombosis. To balance the baseline differences, inverse probability of treatment weighting (IPTW) was performed.ResultsAfter IPTW, the rate of MACEs in the SGLT2i group was not significantly lower than that in the DPP-4i group (hazard ratio [HR], 0.99; 95% confidence interval [Cl], 0.46 to 2.14, p = 0.983). In the unadjusted and adjusted analyses, all items for clinical outcomes were comparable between the two groups. In our exploratory analysis, the left ventricular ejection fraction showed a significant improvement in the SGLT2i group than in the DPP-4i group before achieving statistical balancing (6.10 ± 8.30 versus 2.95 ± 10.34, p = 0.007) and after IPTW adjustment (6.91 ± 8.91 versus 3.13 ± 10.41, p = 0.027).ConclusionsOur findings demonstrated that SGLT2i did not influence the rate of MACEs compared with DPP-4i in combination with metformin in diabetic patients with AMI but did improve left ventricular ejection fraction.Trial registrationNot applicable (retrospectively registered).

Correction to: "Cardiovascular Outcomes Comparison of Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylurea as Add-on Therapy for Type 2 Diabetes Mellitus: A Meta-Analysis".

ObjectiveRecent studies have raised concerns about the cardiovascular safety of dipeptidyl peptidase-4 (DPP4) inhibitors. We performed a systematic review and meta-analysis to compare the cardiovascular outcomes of sulfonylureas (SUs) versus DPP4 inhibitors in combination with metformin.MethodsAfter searching for trials using combination therapy of metformin with an SU or DPP4 inhibitor in PubMed, Cochrane Library, and Embase, 1 prospective observational study and 15 randomized controlled studies were selected.ResultsRegarding the primary analysis endpoint, no significant differences were found in the risk of all-cause mortality between SUs and DPP4 inhibitors as add-on therapies to metformin (random-effect relative risk [RR], 1.14; 95% confidence interval [CI], 0.98–1.33; I2=0%; p=0.097). Cardiovascular death was also similar between SUs and DPP4 inhibitors in the 5 studies that reported outcomes (random-effect RR, 1.03; 95% CI, 0.83–1.27; I2=0%; p=0.817). Furthermore, there were no significant differences in major adverse cardiac events, coronary heart disease, myocardial infarction, and heart failure. However, the SU group showed a higher risk of ischemic stroke, more hypoglycemic events, and more weight gain than the DPP4 inhibitor group (ischemic stroke, random-effect RR, 2.78; 95% CI, 1.06–7.30; I2=51.9%; p=0.039; hypoglycemia, random-effect RR, 3.79; 95% CI, 1.53–9.39; I2=98.2; p=0.004; weight gain, weighted mean difference, 1.68; 95% CI, 1.07–2.29; I2=94.7; p<0.001).ConclusionAs add-on therapies to metformin, SUs and DPP4 inhibitors showed no significant differences in all-cause mortality and cardiovascular mortality. However, some of the favorable results of DPP4 inhibitors suggest good safety and feasibility of the drugs.

DPP-4 Inhibitors in Combination with Lipid-Lowering Agents and Risk of Serious Muscular Injury: A Nested Case-Control Study in a Nationwide Cohort of Patients with Type 2 Diabetes Mellitus.

After a safety warning was issued for a risk of muscular injury associated with dipeptidyl peptidase-4 (DPP-4) inhibitor use, especially when co-prescribed with statins, spontaneous reporting analyses provided conflicting results. The aim of this study was to investigate the association between DPP-4 inhibitor use and the risk of muscular injury in individuals with type 2 diabetes mellitus using statins or fibrates. We conducted a nested case-control study amongst a cohort of individuals with type 2 diabetes using statins or fibrates, identified from a nationwide French health insurance database (2009-2014). Cases of serious muscular injury were defined as subjects hospitalized for rhabdomyolysis or myopathy, or for whom testing for myoglobin or creatine phosphokinase followed by a change in statin or fibrate prescription (dose decrease, treatment switch, or stop) was identified. Up to ten controls were matched to each case according to sex, age, and type of lipid-lowering agent. Associations between DPP-4 inhibitor use and serious muscular injury were estimated using a multivariate conditional logistic regression model, providing odds ratios (ORs) adjusted for alcoholism, chronic renal failure, hypothyroidism, and number of concomitant drugs. Within the 35,117 individuals with type 2 diabetes mellitus constituting the source cohort, 437 statin-user cases were identified who were matched to 4358 statin-user controls. Similarly, 54 fibrate-user cases were identified who were matched to 540 fibrate-user controls. The adjusted OR for DPP-4 inhibitor use and serious muscular injury was estimated at 1.0 (95% confidence interval [CI] 0.7-1.2) in statin users and 0.8 (95% CI 0.4-1.9) in fibrate users. In this study, DPP-4 inhibitor use was not associated with an increased risk of serious muscular injury among patients with type 2 diabetes mellitus using statins or fibrates.

Myopathy with DPP-4 inhibitors and statins in the real world: investigating the likelihood of drug-drug interactions through the FDA adverse event reporting system.

To investigate the occurrence of myopathy with oral glucose-lowering drugs (OGLDs) and statins, with a focus on dipeptidyl peptidase-4 inhibitors (DPP4-is). The FDA adverse event reporting system (FAERS) was queried (2004-2016) to compare the proportion of adverse events with OGLDs, alone and in combination with statins, using the reporting odds ratio (ROR) with relevant 95% confidence interval (95%Cl), adjusted for sex, age and concomitant presence of other OGLDs/lipid-lowering drugs. Drug-drug interaction is claimed whenever the frequency of an event is enhanced by combination treatment. Consistency/robustness of findings was tested by applying additive/multiplicative models and accounting for competition bias (i.e., adverse events previously known to be associated with OGLDs were removed). Over a 13-year period, we retrieved 142,888 cases of myopathy. The use of DPP4-is alone was not associated with higher reporting of myopathy (no. of cases = 4898; adjusted ROR = 1.00; 95%CI = 0.96-1.04), with the notable exclusion of vildagliptin (262; 1.64; 1.42-1.88). No increased occurrence emerged when used in combination with statins, with consistent findings from additive/multiplicative models for all DPP4-is. Likewise, no increased reporting was found for other OGLDs (28,964; 0.64; 0.62-0.67); data on the interaction with statins were consistent/robust across analyses only for sulfonylureas (the interaction is likely and biologically plausible) and sodium glucose cotransporter-2 inhibitors. Real-world FAERS data do not raise concern for muscular toxicity with DPP4-is in combination with statins, making a drug interaction very unlikely.

A safety and tolerability profile comparison between dipeptidyl peptidase-4 inhibitors and sulfonylureas in diabetic patients: A systematic review and meta-analysis

BackgroundThe first treatment approach for type 2 diabetes mellitus is lifestyle change and metformin, but it is usually not sufficient. For some time, the anti-hyperglycemic classes of sulfonylureas and dipeptidyl peptidase-4 (DPP-4) inhibitors were considered second-line of treatment, since they show similar efficacy effect. However, the recent ADA-EASD consensus gives the preference to DPP-4 inhibitors compared to sulfonylureas, except if cost is a major problem. We performed a meta-analysis for safety and tolerability profile to comprehend which treatment has less adverse events. MethodsPUBMED and EMBASE databases were searched from inception until July 2017 to retrieve RCT studies comparing DPP-4 inhibitors and sulfonylureas treatments in adult type 2 diabetes patients. There was no language restriction. We extracted and combined data from studies comparison that reported safety profile and weight change. A random effect, meta-analytic model was applied to all calculations. Cochrane collaboration tool was used to assess quality and bias of the included studies. Trial registered with PROSPERO (CRD42017075823). FindingsOut of 1472 articles identified in our search and screened for eligibility, 36 studies comparing DPP-4 inhibitors and sulfonylureas were identified. DPP-4 inhibitors in combination with metformin had less overall adverse events (RR: 0·90; 95% CI, 0·86–0·94; p < 0·0001; I2 = 83%; 17 studies), cardiovascular events (RR: 0·54; 95% CI, 0·37–0·79; p = 0·002; I2 = 0%; 6 studies), hypoglycemia (RR: 0·17; 95% CI, 0·13–0·22; p < 0·00001; I2 = 76%; 17 studies) and severe hypoglycemic events (RR: 0·10; 95% CI, 0·05–0·19; p < 0·00001; I2 = 0%; 12 studies). The mean difference of the weight change was 1·92 kg in favor of DPP-4 inhibitors in combination with metformin in relation to sulfonylureas in combination with metformin. Monotherapy with DPP-4 inhibitors also had less rates of hypoglycemia (RR: 0·31; 95% CI, 0·24–0·41; p < 0·00001; I2 = 0%; 8 studies) and severe hypoglycemic events (RR: 0·26; 95% CI, 0·10–0·66; p = 0·004; I2 = 0%; 8 studies) and patients did not gain 1·19 kg. InterpretationThese results suggest better safety profile for DPP-4 inhibitors than sulfonylureas for both comparisons, and it is more notable when the treatment regimen includes metformin. FundingThis study was funded by Takeda Pharmaceuticals, Brazil.

Renoprotection Provided by Dipeptidyl Peptidase-4 Inhibitors in Combination with Angiotensin Receptor Blockers in Patients with Type 2 Diabetic Nephropathy.

Background:Treatment with the dipeptidyl peptidase-4 inhibitors (DPP4i) and angiotensin receptor blockers (ARBs) in patients with type 2 diabetic nephropathy (DN) has not been well characterized. This study aimed to assess the renoprotection of this combined treatment in DN patients.Methods:A total of 159 type 2 DN patients from 2013 to 2015 were enrolled retrospectively from a prospective DN cohort at the National Clinical Research Center of Kidney Diseases, Jinling Hospital (China). Fifty-seven patients received DPP4i and ARB treatment, and 102 patients were treated with ARBs alone. All patients were followed up for at least 12 months. Statistical analyses were performed using Stata version 12.0.Results:There were no significant differences at baseline for age, sex, body mass index, duration of diabetes, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and estimated glomerular filtration rate (eGFR) between the two groups. Antihypertensive and antidiabetic medication use was similar in each group except calcium channel antagonists (P = 0.032). No significant changes in FBG and HbA1c were observed in the two groups after treatment. The eGFR decreased slower in the DPP4i + ARB group than in the ARB group at 12 months (Δ12 months: −2.48 ± 13.86 vs. −6.81 ± 12.52 ml·min–1·1.73m–2, P = 0.044). In addition, proteinuria was decreased further in the DPP4i + ARB group than in the ARB group after 24 months of treatment (Δ24 months: −0.18 [−1.00, 0.17] vs. 0.32 [−0.35, 0.88], P = 0.031). There were 36 patients with an eGFR decrease of more than 30% over 24 months. After adjusting for FBG, HbA1c, and other risk factors, DPP4i + ARB treatment was still associated with a reduced incidence of an eGFR decrease of 20% or 30%.Conclusions:The combined treatment of DPP4i and ARBs is superior to ARBs alone, as evidenced by the greater proteinuria reduction and lower eGFR decline. In addition, the renoprotection of DPP4i combined with ARBs was independent of glycemic control.

The Safety Profile Comparison Between Dipeptidyl Peptidase-4 Inhibitors and Sulfonylureas in Diabetic Patients: A Systematic Review and Meta-Analysis

Background: The first treatment approach for type 2 diabetes mellitus is lifestyle change and metformin, but it is usually not enough. The anti-hyperglycemic classes of sulfonylureas and dipeptidyl peptidase-4 (DPP-4) inhibitors are considered second-line of treatment, since they show similar efficacy effect. Due to this fact, we performed a meta-analysis for safety profile to comprehend which treatment has lower adverse events. Methods: PUBMED and EMBASE databases were searched from inception until July 2017 to retrieve RCT studies comparing DPP-4 inhibitors and sulfonylureas treatments in adult type 2 diabetes patients. There was no language restriction. We extracted and combined data from studies comparison that reported safety profile and weight change. A random effect, meta-analytic model was applied in all calculations. Cochrane collaboration tool was used to assess quality and bias of the included studies. Findings: Of 1,472 articles identified in our search and screened for eligibility, 36 studies comparing DPP-4 inhibitors and sulfonylureas were identified. DPP-4 inhibitors in combination with metformin had less overall adverse events (RR: 0*90; 95% CI, 0*86-0*94; p<0*0001; I2=83%; 17 studies), cardiovascular events (RR: 0*54; 95% CI, 0*37-0*79; p=0*002; I2=0%; 6 studies), hypoglycemia (RR: 0*17; 95% CI, 0*13-0*22; p≤0*00001; I2=76%; 17 studies) and severe hypoglycemia events (RR: 0*10; 95% CI, 0*05-0*19; p≤0*00001; I2=0%; 12 studies). The mean difference of the weight change was 1*92 kg in favor of DPP-4 inhibitors in combination with metformin in relation to sulfonylureas in combination with metformin. Monotherapy with DPP-4 inhibitors also had less rates of hypoglycemia (RR: 0*31; 95% CI, 0*24-0*41; p≤0*00001; I2=0%; 8 studies) and severe hypoglycemia events (RR: 0*26; 95% CI, 0*10-0*66; p=0*004; I2=0%; 8 studies) and patients did not gain 1*19 kg. Interpretation: These results suggest better safety profile for DPP-4 inhibitors than sulfonylureas for both comparisons, and it is more notable when the treatment regimen includes metformin. Trial Registration for Meta-Analysis: Trial registered in PROSPERO (CRD42017075823). Funding Statement: This study was funded by Takeda Pharmaceuticals, Brazil. Declaration of Interests: DF reports grants from Takeda Distribuidora Ltda., during the conduct of the study. MCMF reports grants from Takeda Distribuidora Ltda. during the conduct of the study; he is scientific director from AxiaBio Life Sciences International, a consultancy company that provides various work to distinct healthcare stakeholders, including Takeda Distribuidora Ltda; and he is employed by Sao Paulo Federal University as professor, outside the submitted work. GML has nothing to discosure. FGE has nothing to disclosure. Ethics Approval Statement: We conducted the systematic review and meta-analysis in accordance with recommendations from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study protocol was registered in PROSPERO (CRD42017075823).

Safety and Efficacy of DPP4 Inhibitor and Basal Insulin in Type 2 Diabetes: An Updated Review and Challenging Clinical Scenarios.

The safety and efficacy of dipeptidyl peptidase-4 (DPP4) inhibitors as monotherapy or in combination with other oral antidiabetic agents or basal insulin are well established. DPP4 inhibitors stimulate glucose-dependent insulin secretion and inhibit glucagon production. As monotherapy, they reduce the hemoglobin A1c level by about 0.6–0.8%. The addition of a DPP4 inhibitor to basal insulin is an attractive option, because they lower both postprandial and fasting plasma glucose concentrations without increasing the risk of hypoglycemia or weight gain. The present review summarizes the extensive evidence on the combination therapy of DPP4 inhibitors and insulin-based regimens in patients with type 2 diabetes. We focus our discussion on challenging clinical scenarios including patients with chronic renal impairment, elderly persons and hospitalized patients. The evidence indicates that these drugs are highly effective and safe in the elderly and in the presence of mild, moderate and severe renal failure improving glycemic control with low risk of hypoglycemia. In addition, several randomized-controlled trials have shown that the use of DPP4 inhibitors in combination with basal insulin represents an alternative to the basal-bolus insulin regimen in hospitalized patients with type 2 diabetes.

Meta-analysis of HbA1c-Lowering Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Combination with Insulin in T2DM Patients

Randomized controlled trials (RCTs) have evaluated the efficacy of dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy to insulin compared to insulin alone in T2DM patients, while there have been differences in the magnitude of the outcome effect across studies. This updated systematic review and meta-analysis aimed to evaluate the effect of DPP-4i in combination with insulin on HbA1c in T2DM patients. MEDLINE, EMBASE, and Cochrane databases were searched for RCTs that compared DPP-4i plus insulin to insulin alone for T2DM patients, with or without background therapy with other oral agents. The primary endpoint was the absolute change of HbA1c from baseline. Weighted mean difference (WMD) with 95% confidence intervals (CI) was calculated using a random effect model. The methodological quality of included RCTs was evaluated using the Cochrane risk of bias tool. Eighteen RCTs involving 6,493 patients with average follow-up of 32 weeks were identified and analyzed. DPP-4i plus insulin showed greater reduction in HbA1c than insulin alone (WMD -0.52%, 95% CI -0.61 to -0.43; P&amp;lt;0.0001) (Figure 1). In conclusion, compared with use of insulin alone, DPP-4i in combination with insulin can significantly lower HbA1c levels in T2DM patients. Further analysis is needed to better understand effects of this combination therapy on other outcomes, such as hypoglycemia and insulin. Disclosure J. Yang: None. Q. Tian: None. Y. Tang: Employee; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Self; Merck &amp; Co., Inc.. Employee; Spouse/Partner; GlaxoSmithKline plc.. Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc. A.K. Shah: Employee; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Self; Merck &amp; Co., Inc. R. Zhang: Employee; Self; Merck Sharp &amp; Dohme Corp. G. Chen: Employee; Self; Merck Sharp &amp; Dohme Corp.. Y. Zhang: None. S. Rajpathak: Employee; Self; Merck &amp; Co., Inc. T. Hong: Advisory Panel; Self; Novo Nordisk A/S, AstraZeneca.

Efficacy and Safety of a Single-Pill Combination of Vildagliptin and Metformin in Japanese Patients with Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Placebo-Controlled Trial

IntroductionThe use of dipeptidyl peptidase-4 inhibitors in combination with metformin is increasing in Japanese patients with type 2 diabetes mellitus (T2DM), but no single-pill combination (SPC) is currently available in Japan. The objective of this study was to assess the efficacy and safety of vildagliptin/metformin SPC in Japanese patients with T2DM inadequately controlled with vildagliptin monotherapy.MethodsThis was a 14-week, randomized, double-blind, parallel-group, placebo-controlled trial. 171 patients with T2DM inadequately controlled [HbA1c (glycosylated hemoglobin) 7.0–10.0%] with vildagliptin 50 mg twice daily (bid) were randomized (2:1) to receive either a vildagliptin/metformin SPC (n = 115) or matching vildagliptin/placebo SPC (n = 56).ResultsBaseline demographics and background characteristics were generally comparable between the treatment groups. The change in HbA1c [mean ± standard error (SE)] was −0.8 ± 0.1% in the vildagliptin/metformin SPC (baseline HbA1c, 7.9 ± 0.1%) group and 0.1 ± 0.1% in the vildagliptin/placebo SPC (baseline HbA1c, 8.0 ± 0.1%) group, with a between-treatment difference of −1.0 ± 0.1% (P <0.001) in favor of the vildagliptin/metformin SPC group. The proportion of patients achieving target HbA1c <7.0% was significantly higher with vildagliptin/metformin SPC compared with vildagliptin/placebo SPC (45.8% vs. 13.5%, P <0.001). The overall incidences of adverse events (AEs) were 43.5% in the vildagliptin/metformin SPC and 67.9% in the vildagliptin/placebo SPC group. The incidences of serious AEs were low in both the treatment groups (0.9% vs. 3.6%, respectively). Body weight remained constant throughout the study in both the treatment groups. There were no deaths or hypoglycemic events during the study.ConclusionsSwitching Japanese patients with T2DM requiring treatment intensification, from vildagliptin monotherapy to a vildagliptin/metformin SPC (50/250 or 50/500 mg) was efficacious and safe, eliciting significant reduction in HbA1c without increased risk of hypoglycemia and weight gain.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-015-0099-x) contains supplementary material, which is available to authorized users.

Testing the Therapeutic Equivalence of Alogliptin, Linagliptin, Saxagliptin, Sitagliptin or Vildagliptin as Monotherapy or in Combination with Metformin in Patients with Type 2 Diabetes

BackgroundIn studying the therapeutic evidence of innovative drug treatments, increasing attention is being devoted to differentiating between results that indicate no significant differences among the treatments under examination (“no proof of difference”) and results that demonstrate the therapeutic equivalence among the treatments (“proof of no difference”).AimOur analysis was aimed at evaluating the degree of therapeutic equivalence for dipeptidylpeptidase-4 (DPP-4) inhibitors given in type 2 diabetes as monotherapy or in combination with metformin.MethodsEquivalence was determined by developing a standard Forest plot that incorporated the information on margins previously reported in randomized trials on these agents. The end point was HbA1c change from baseline; the equivalence margin was set at ±0.25% change in HbA1c. The clinical material was obtained from a systematic review on this topic.ResultsGiven as monotherapy, linagliptin, sitagliptin, and vildagliptin (but not saxagliptin) met the equivalence criterion when compared with one another. Given in combination with metformin, linagliptin, saxagliptin, sitagliptin, and vildagliptin showed an equivalent effect whereas alogliptin did not satisfy the equivalence criterion.ConclusionsConsidering the most recent therapeutic guidelines, our results are of interest particularly as regards the information on DPP-4 inhibitors in combination with metformin. Four of the five DPP-4 inhibitors under examination clearly showed to have the same effectiveness; the fifth agent—alogliptin—failed to meet the equivalence criterion, but only because its superiority could not be excluded.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-014-0066-y) contains supplementary material, which is available to authorized users.

Managing hyperglycemia in patients with type 2 diabetes mellitus: rationale for the use of dipeptidyl peptidase-4 inhibitors in combination with other oral antidiabetic drugs.

Type 2 diabetes mellitus is a chronic, progressive disease that necessitates comprehensive and individualized patient treatment strategies. Daily glycemic measures, including measures of postprandial glucose and fasting plasma glucose levels, in combination with measures of glycated hemoglobin (HbA(1c)) levels may be a more reliable indicator of blood glucose control and the long-term risk of complications than measures of HbA(1c) levels alone. Emerging treatment strategies for type 2 diabetes support the rationale for using dipeptidyl peptidase-4 (DPP-4) inhibitors in combination with other oral antidiabetic drugs for early and aggressive management of type 2 diabetes. Information was gathered through a search of MEDLINE, Derwent Drug File, BIOSIS, and EMBASE databases for DPP-4 inhibitors and postprandial hyperglycemia in patients with type 2 diabetes. Studies published from 2003 to the present and in any language were included. Additional sources were relevant conference poster presentations. Early in the disease process, more intensive glucose-lowering intervention prior to the onset of advanced disease and cardiovascular events may be necessary to demonstrate effective reduction in macrovascular risk. Recent advances in pharmacotherapy allow physicians to target glucose excursions and variability. Data support the use of a combination of drugs with a complementary mechanism of action; to achieve an HbA(1c) level of less than 7% of total hemoglobin, use a drug with a primary mechanism of action that targets postprandial glucose levels in combination with a drug that primarily lowers fasting plasma glucose levels. Based on the glucose-dependent action of incretins, DPP-4 inhibitors demonstrate a low propensity for hypoglycemia, are generally weight neutral, and have a low risk of interactions with other drugs, which makes them appropriate candidates for combination therapy, particularly with other oral antidiabetic drugs including metformin, thiazolidinediones, and sulfonylureas. The complementary mechanism of action of DPP-4 inhibitors with other oral antidiabetic drugs affords clinicians an effective and well-tolerated treatment option for early and more aggressive management of hyperglycemia in patients with type 2 diabetes.

Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitors in Combination with Metformin

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors is prevalent for the treatment of type 2 diabetes since they have fewer adverse effects compared with other non-insulin medications currently available; however, as monotherapy, the glycosylated hemoglobin (HbA1c)-lowering power of these agents is moderate. The aim of this article is to evaluate the current literature regarding the safety and efficacy of DPP-4 inhibitors in combination with metformin. A literature search was conducted through MEDLINE (from 1950 to October 2012), PubMed (from 1966 to October 2012), EMBASE (from 1966 to October 2012), and International Pharmaceutical Abstracts (from 1970 to October 2012) using the search terms "sitagliptin," "linagliptin," "alogliptin," "vildagliptin," "saxagliptin," and "metformin." Studies that did not evaluate the DPP-4 inhibitors in combination with metformin and those that were not phase 3, were excluded. Many of the studies evaluated DPP-4 inhibitors in combination with metformin versus glucagon-like peptide-1 (GLP-1) agonists, placebo, DPP-4 inhibitors as monotherapy, thiazolidinediones, and sulfonylureas. The results of these noninferiority trials were that DPP-4 inhibitors as a whole are noninferior to either each other or other agents except for GLP-1 agonists. Also, in superiority studies, GLP-1 agonists proved to have greater HbA1c lowering. In summary, DPP-4 inhibitors play a vital role in the treatment of diabetes. They have relatively limited adverse effects, especially regarding hypoglycemia. DPP-4 inhibitors in combination with metformin are generally well tolerated and are available as combination products to reduce pill burden and enhance compliance. The limitations to DPP-4 inhibitors are the lack of outcomes data and more limited HbA1c lowering than other medications currently approved for the treatment of type 2 diabetes. However, as previously stated, thiazolidinediones, glinides, sulfonylureas, pramlinitide, and GLP-1 agonists are all quite beneficial in HbA1c lowering but are not without major adverse effects. Therefore, DPP-4 inhibitors have a vital role as an oral add-on agent for the treatment of type 2 diabetes.

The Effects of Dipeptidyl Peptidase-4 Inhibitors in Treatment of Obese Patients with Type 2 Diabetes

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antihyperglycemic drugs that block degradation ofincretin hormones. To assess the effects oftreatment with DPP-4 inhibitors on glucoregulation and body weight in obese patients with type 2 diabetes mellitus. The study included 9 females and 9 males with type 2 diabetes (n=18), BMI=31.24 +/- 2,26 kg/m2, mean age 58 +/- 6,8 years. The patients have been thoroughly evaluated before treatment, and 6 months after treatment with DPP-4 inhibitor (sitagliptin) in combination with metformin. After 6 months of treatment with DPP-4 inhibitors in combination with metformin HbAlc (-1,49%)., FBG (-3.75 mmol/L) and PBG (-5.79 mmol/L) significantly reduced (p=0.000). Mean body weight also significantly reduced (-12.5%; p=0.000). Reduction of mean fasting insulin was 5.46 mIU/L or 27% (p=0.000). Mean HOMA-IR change was -1.64 (p=0.000). Also there was significant decreasing of systolic blood pressure (p=0.001), cholesterol (p=0.004), triglycerides (p=0.001), LDL (p=0.002) and increasing of HDL (p=0.002). Hypoglycaemia was not registered in any of the patients. These results show that in obese patients with type 2 diabetes, DPP-4 inhibitors treatment in combination with metformin was associated with improvements in glycaemic control, and a reduction in body weight.

Les nouveaux traitements du diabète de type 2 : quelle place pour les incrétines et le rimonabant par rapport aux précédents ?

Treatment of type 2 diabetes (T2DM) is based on lifestyle changes and oral antidiabetic agents or insulin. The UKPDS study has confirmed metformin (Met) as the initial monotherapy. Accordingly, Met is widely regarded as the first drug of choice for most patients with T2DM. Safety and efficacy of sulphonylureas (SU) have been confirmed by several clinical trials. Recently, thiazolidinediones (TZD) have addressed some aspects of insulin-resistance that characterized several T2DM patients. However, SU and TZD are associated with various side effects that limit their use in many patients. New agents have been recently developed which potentiate the activity of the incretin (GLP1). GLP1, a gut hormone secreted in response to meal ingestion, is rapidly degraded by dipeptidylpeptidase-4 (DPP-4). GLP1 enhances insulin secretion and inhibits glucagon secretion in a glucose-dependent manner, delays gastric emptying and, in animal studies, preserves beta-cell mass by reducing apoptosis and stimulates of beta-cell proliferation. GLP1 levels are abnormally low in T2DM patients. Two classes of agents based on GLP1 have been launched: DPP-4 inhibitors and DPP-4 resistant GLP1 analogues. Randomized studies confirmed their efficacy to improve glycemic control in T2DM patients. Orally administered DPP-4 inhibitors reduce HbA1c by 0.5-1.1%, without hypoglycaemic events and no weight gain. The sub-cutaneous injected GLP1 analogues (exenatide and liraglutide) show larger reductions in HbA1c by 0.8-1.7% and weight loss but are associated with gastrointestinal side effects contributing to a significant treatment interruption. Several studies support the use of DPP-4 inhibitors in combination with Met as a promising second line treatment.