Dipeptidyl Peptidase-4 Inhibitors In Patients Research Articles

Anticipatory guidance and systematic review of prescribing combination incretin therapy in the treatment of type 2 diabetes.

Few studies have evaluated the efficacy and safety of combining a glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus. Clinicians may frequently encounter this drug therapy combination in practice and should be aware of clinical evidence and risks associated with its use. A literature search was conducted in Embase (1947-April 20, 2020), Medline - Ovid (1946-April 21, 2020), Medline - PubMed (1946-April 21, 2020), Cochrane Library CENTRAL Register of Controlled Trials (1991-April 20, 2020) and Web of Science (1900-April 17, 2020). Databases were searched using keywords and subject headings to identify studies assessing efficacy and safety of combination incretin therapy. The search identified 1255 studies. Of these, 383 were excluded for duplicate citations. Articles were then excluded based on title and abstract screen. Six studies were included. A small reduction in haemoglobin A1c and weight loss was found by combining incretin therapy. Adverse effects such as hypoglycaemia, gastrointestinal upset and pancreatitis were infrequent. On current evidence, the small benefit in glycaemic control that may be realized by using combination incretin therapy is unlikely to be offset by the potential increased risk of pancreatitis or additional cost. Additional long-term prospectively designed studies are needed to better understand the efficacy and safety of combination incretin therapy.

Lower cardiorenal risk with sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes without cardiovascular and renal diseases: A large multinational observational study.

AimsWe compared the new use of sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) versus dipeptidyl peptidase‐4 inhibitor (DPP4i) and the risk of cardiorenal disease, heart failure (HF) or chronic kidney disease (CKD), in patients with type 2 diabetes without a history of prevalent cardiovascular and renal disease, defined as cardiovascular and renal disease (CVRD) free, managed in routine clinical practice.Materials and methodsIn this observational cohort study, patients were identified from electronic health records from England, Germany, Japan, Norway, South Korea and Sweden, during 2012‐2018. In total, 1 006 577 CVRD‐free new users of SGLT2i or DPP4i were propensity score matched 1:1. Unadjusted Cox regression was used to estimate hazard ratios (HRs) for outcomes: cardiorenal disease, HF, CKD, stroke, myocardial infarction (MI), cardiovascular and all‐cause mortality.ResultsBaseline characteristics were well balanced between the treatment groups (n = 105 130 in each group) with total follow‐up of 187 955 patient years. Patients had a mean age of 56 years, 43% were women and they were indexed between 2013 and 2018. The most commonly used agents were dapagliflozin (91.7% of exposure time) and sitagliptin/linagliptin (55.0%), in the SGLT2i and DPP4i, groups, respectively. SGLT2i was associated with lower risk of cardiorenal disease, HF, CKD, all‐cause and cardiovascular mortality; HR (95% confidence interval), 0.56 (0.42‐0.74), 0.71 (0.59‐0.86), 0.44 (0.28‐0.69), 0.67 (0.59‐0.77), and 0.61 (0.44‐0.85), respectively. No differences were observed for stroke [0.87 (0.69‐1.09)] and MI [0.94 (0.80‐1.11)].ConclusionIn this multinational observational study, SGLT2i was associated with a lower risk of HF and CKD versus DPP4i in patients with type 2 diabetes otherwise free from both cardiovascular and renal disease.

Role of dipeptidyl peptidase-4 inhibitors in patients with diabetes infected with coronavirus-19.

The pandemic infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is widely increasing the patients affiliated with coronavirus disease 2019 (COVID-19) from last December of 2019. It is reported that the entry receptor of SARS-CoV-2 has been confirmed to be angiotensin-converting enzyme 2 (ACE2). Notably, whether the ACE-related inhibitors or drugs modulated ACE2 activity in affecting the viral activity and disease severity of SARS-CoV-2 is still an open question. Dipeptidyl peptidase-4 (DDP-4), a well-known anti-diabetic drug, has been widely used to control the glycemic condition in patients with diabetes. In this article, we are focusing on the impact of ACE inhibitors (ACEI) and DPP4 inhibitors used on SARS-CoV-2 activity and discussions about those drugs that may be related to infectious condition of COVID-19 diseases.

Comparative effect of dipeptidyl-peptidase 4 inhibitors on laboratory parameters in patients with diabetes mellitus

BackgroundThe purpose of this study was to evaluate and compare the effects on laboratory parameters among monotherapy with five DPP-4 inhibitors in patients with type 2 diabetes mellitus (DM).MethodsWe identified cohorts of new sitagliptin users (n = 879), vildagliptin users (n = 253), teneligliptin users (n = 260), alogliptin users (n = 237), and linagliptin users (n = 180) in patients with type 2 DM. We used a multivariate regression model to evaluate and compare the effects of the drugs on laboratory parameters including HbA1c concentration and serum concentrations of creatinine, estimated glomerular filtration rate, high density lipoprotein, total cholesterol, triglyceride, aspartate aminotransferase, and alanine aminotransferase among the five DPP-4 inhibitors up to 12 months.ResultsOur study showed a favorable effect on HbA1c concentration and a slightly unfavorable effect on serum creatinine concentration in users of the five DPP-4 inhibitors, a favorable effect on lipid metabolism in sitagliptin, vildagliptin, and alogliptin users, and a favorable effect on hepatic parameters in sitagliptin, alogliptin, and linagliptin users, in comparison of the baseline and exposure periods. However, there was no significant difference in mean change in the concentration of any laboratory parameter among the five groups of DPP-4 inhibitor users.ConclusionsIn this study, we showed the effect of five DPP-4 inhibitors on glycemic, renal, and lipid metabolism, and hepatic parameters. DPP-4 inhibitors are well-tolerated hypoglycemic drugs.

Effect of Dipeptidyl Peptidase 4 Inhibitors on Cardiovascular Events in Type-2 Diabetes Patients with Renal Impairment: A Systematic Review and Meta-analysis.

Background:Recent studies suggested that the increased risk of heart failure by DPP-4 inhibitors may have an interconnection with patients' baseline eGFR. We decided to investigate the effect of DPP-4 inhibitors and the degree of renal function on cardiovascular (CV) safety in type 2 diabetes (T2D) patients.Materials and Methods:Systemic search of literature that examined the DPP-4 inhibitors and reported cardiovascular outcomes in diabetes patients with renal impairment were performed. Studies were examined for inclusion criteria: Randomized controlled trials with reduced renal function taking DPP-4 inhibitors alone or in combination with other anti-diabetes agents reporting evaluable CV events for at least 24 weeks.Result:Analysis of four CV outcome studies (11,789 patients with eGFR ≤60 ml/min/1.73m2) did not find any increase in primary composite endpoints with DPP-4 inhibitors in patients stratified by baseline renal function. Rate of hospitalization due to heart failure (hHF) is found to be non-inferior to placebo group in patients with renal insufficiency (RR 1.07; 95% CI, 0.96-1.20 P = 0.26). In moderate renal dysfunction, there is a significant increase in heart failure risk compared to placebo. (RR 1.27; 95% CI, 1.033 -1.5 8; P = 0.024).Conclusion:Treatment with DPP-4 inhibitors did not affect the risk of cardiovascular events regardless of baseline renal function, however, an increase in the risk of hHF in moderate renal function in T2D patients with high CV risk merits careful consideration. Further research would be necessitated to reach definitive conclusion to understand the effect of declining renal function on CV safety of DPP-4 inhibitors.

Combination therapy with once-weekly glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a case series.

Background:National treatment guidelines recommend glucagon-like peptide receptor agonists (GLP-1 RAs) as add-on therapy to oral agents. However, GLP-1 RAs in combination with dipeptidyl peptidase-4 (DPP-4) inhibitors is not recommended due to a lack of evidence.Objective:This case series aims to describe the efficacy and safety of once-weekly GLP-1 RAs administered concomitantly with DPP-4 inhibitors in patients with type 2 diabetes.Methods:A retrospective chart review of electronic medical records at a free health clinic was conducted between July 2014 and September 2016. Patients 18 years and older with type 2 diabetes were included if they received concomitant DPP-4 inhibitor and once-weekly GLP-1 RA therapy with at least one glycated hemoglobin A1c (HbA1c) measurement within three to six months of starting the combination. The primary and secondary outcomes included change in HbA1c and weight, and patient reported adverse events.Results:Out of forty-three patients that received combination DPP-4 inhibitor plus GLP-1 RA therapy, only eighteen received once-weekly GLP-1 RA. At 3 months, the median (IQR) HbA1c and weight change was -0.8% (-4.3 to 2%) and -0.4kg (-4.2 to 5.8 kg) respectively. No patients reached an HbA1c below 7% and only three patients (17%) reached a HbA1c less than 8%. Patient reported adverse effects included gastrointestinal disturbances (28%), hypoglycemic symptoms (17%), and injection site reactions (0.6%).Conclusions:Concomitant use of once-weekly GLP-1 RAs and DPP-4 inhibitors provides only modest improvement in glycemic control with minimal weight loss benefits, which is similar to monotherapy with either agent. The combination is unlikely to provide synergistic effects and is not cost effective. These data support the current recommendations against use of combined incretin therapy.

Outcomes for Inappropriate Renal Dose Adjustment of Dipeptidyl Peptidase-4 Inhibitors in Patients With Type 2 Diabetes Mellitus: Population-Based Study

ObjectivesTo estimate inappropriate dosing of dipeptidyl peptidase-4 (DPP-4) inhibitors and to assess the risk of emergency department visits, hypoglycemia, and mortality in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) prescribed inappropriate DPP-4 inhibitor doses because limited real-world information is available regarding rates of DPP-4 inhibitor dose adjustment and its safety in patients with T2DM and CKD. Patients and MethodsWe performed a retrospective observational cohort study of 82,332 patients aged 30 to 75 years with T2DM and CKD being treated with DPP-4 inhibitors from January 1, 2012, through December 31, 2014, using the Korean National Health Information Database. We divided the patients according to the prescription of DPP-4 inhibitor with or without dose adjustment according to estimated glomerular filtration rate. The incidences of emergency department visits, hypoglycemia, and mortality were assessed using hazard ratios estimated using Cox proportional hazards regression modeling. ResultsApproximately 40% of patients with T2DM and CKD were prescribed an inappropriate dose of DPP-4 inhibitor from 2009 through 2011; this proportion decreased to 24.4% in 2015. Hazard ratios (95% CIs) for inappropriate vs appropriate dosing of DPP-4 inhibitors were 1.115 (1.005-1.237) for mortality, 1.074 (1.018-1.133) for emergency department visits, and 1.192 (1.054-1.349) for severe hypoglycemia after multivariable adjustment for confounding factors. ConclusionOne of every 3 patients with T2DM and CKD received inappropriate dosing of DPP-4 inhibitor, which was associated with high risk of emergency department visits, severe hypoglycemia, and mortality.

The observational, cross-sectional study of drug utilization 90% and use of dipeptidyl peptidase-4 inhibitor in the patients with type 2 diabetes mellitus

Background: Diabetes is a chronic metabolic disease which affects the quality of life. It leads to multiple complications due to metabolic involvement. Out of multiple drugs used to treat diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors are comparatively new drugs used for type-2-diabetes mellitus (DM) treatment. This study aimed to find out the drug utilization (DU) 90% and use of DPP-4 inhibitors in patients with type-2-DM.Methods: A prospective, cross-sectional, observational study was conducted at a private healthcare clinic of an endocrinologist in Nashik. Type-2-DM patients of both sexes were selected and a total of 199 patients were enrolled in the study. The consented patients were interviewed and prescription copies were collected. After studying them; statistical analysis was done and results and conclusions were drawn.Results: Out of total prescribed drugs, 58.77% of drugs were anti-diabetics. It was observed that the biguanides were most frequently (25.32%) prescribed while the least prescribed drugs were meglitinide analogues (0.08%). Most commonly utilized anti-diabetic found to be metformin. Vildagliptin 50 mg is the most commonly prescribed drug from DPP-4 inhibitors. Most of the drugs from the DPP-4 inhibitor group came under DU90%.Conclusions:DPP-4 inhibitors are showing wide acceptability by endocrinologists for type-2-DM management, according to this study. Performing repetitive drug utilization pattern study and circulation of standard treatment guidelines to practising physicians can be required. To emphasize the point on generic prescription, more awareness should be created. So that these can responses to further cost-effective and rational prescribing practices.

Clinical analysis of pre-existing diabetes mellitus and dipeptidyl peptidase-4 inhibitors in patients with remitting seronegative symmetrical synovitis and pitting edema syndrome

Objectives: To analyze the association among remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome, diabetes mellitus (DM), and antidiabetic drugs.Methods: We retrospectively analyzed the clinical and serologic manifestations of patients who had RS3PE syndrome with and without pre-existing DM. Then we performed a subanalysis in which patients with pre-existing DM were classified into two groups according to whether they were or were not taking a dipeptidyl peptidase 4 inhibitor (DPP4i), an antidiabetic drug that was suggested to have an association with the pathogenesis of RS3PE syndrome.Results: Pre-existing DM was found in 13 (35.1%) of 37 patients with RS3PE syndrome. No significant differences in age, gender, physical manifestations, and laboratory findings were observed between the patients with DM and those without DM. DPP4i had been administered to 6 of 13 patients with RS3PE and pre-existing DM. We observed no significant differences in manifestations of RS3PE syndrome before treatment; however, one relapse occurred in a patient with poorly controlled DM who had been continuing DPP4i therapy.Conclusion: This study revealed no evidence suggesting an association among RS3PE syndrome, DM, and antidiabetic drugs. DPP4i would be safe for use by most of patients with RS3PE syndrome. However, elderly patients and patients with poorly controlled DM might require careful observation.

Clinical effectiveness of switching between DPP-4 inhibitors in patients with type 2 diabetes mellitus .

Dipeptidyl peptidase-4 inhibitors (DPP-4Is) can be classified into three categories according to their binding subsites. We wished to clarify the efficacy of switching between DPP-4Is according to their binding subsites. We undertook a retrospective study of the medical records of patients who switched from one DPP-4I to another. Among 62 patients eligible for study inclusion, the mean change in the glycated hemoglobin (HbA1c) level between different categories of DPP-4I was -0.35 (95% CI, -0.12 to -0.58; n = 59). The mean change in the HbA1c level between each class of DPP-4I was calculated. From class 3 to class 2 it was -0.45 (n = 25); from class 3 to class 1 it was -0.36 (n = 17); from class 1 to class 2 it was -0.24 (n = 7); from class 1 to class 3 it was 0.33 (n = 4); from class 2 to class 1 it was -0.30 (n = 5); from class 2 to class 3 it was -1.30 (n = 1). When switching DPP-4Is because of insufficient efficacy, consideration of their DPP-4 binding site may be beneficial.

Cardiovascular outcomes in trials of new antidiabetic drug classes: a network meta-analysis

BackgroundRecent trials suggested that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduced cardiovascular events. Comparative effectiveness of these new antidiabetic drug classes remains unclear. We therefore performed a network meta-analysis to compare the effect on cardiovascular outcomes among GLP-1 RAs, SGLT-2 and dipeptidyl peptidase-4 (DPP-4) inhibitors.MethodsMEDLINE, EMBASE, Cochrane database, ClinicalTrials.gov, and congress proceedings from recent cardiology conferences were searched up to April 20, 2019. Cardiovascular outcome trials and renal outcome trials reporting cardiovascular outcomes on GLP-1 RAs, SGLT-2 and DPP-4 inhibitors in patients with type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality, all-cause mortality, hospitalisation for heart failure (HF), and renal composite outcome. ORs and 95% CI were calculated using random-effects models.ResultsFourteen trials enrolling 121,047 patients were included. SGLT-2 inhibitors reduced cardiovascular deaths and all-cause deaths compared to placebo (OR 0.82, 95% CI 0.73–0.93 and OR 0.84, 95% CI 0.77–0.92) and DPP-4 inhibitors (OR 0.83, 95% CI 0.70–0.99 and OR 0.83, 95% CI 0.73–0.94), respectively. SGLT-2 inhibitors and GLP-1 RAs significantly reduced MACE (OR 0.88, 95% CI 0.82–0.95 and OR 0.87, 95% CI 0.82–0.93), hospitalisation for HF (OR 0.68, 95% CI 0.61–0.77 and OR 0.87, 95% CI 0.82–0.93), and renal composite outcome (OR 0.59, 95% CI 0.52–0.67 and OR 0.86, 95% CI 0.78–0.94) compared to placebo, but SGLT-2 inhibitors reduced hospitalisation for HF (OR 0.79, 95% CI 0.69–0.90) and renal composite outcome (OR 0.69, 95% CI 0.59–0.80) more than GLP-1 RAs. Only GLP-1 RAs reduced nonfatal stroke (OR 0.88, 95% CI 0.77–0.99). DPP-4 inhibitors did not lower the risk of these outcomes when compared to placebo and were associated with higher risks of MACE, hospitalisation for HF, and renal composite outcome when compared to the other two drug classes.ConclusionsSGLT-2 inhibitors show clear superiority in reducing cardiovascular and all-cause deaths, hospitalisation for HF, and renal events among new antidiabetic drug classes. GLP-1 RAs also have cardiovascular and renal protective effects. DPP-4 inhibitors have no beneficial cardiovascular effects and are therefore inferior to the other two drug classes. SGLT-2 inhibitors should now be the preferred treatment for type 2 diabetes mellitus.

Treatment preference for weekly versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: outcomes from the TRINITY trial

Objective: To examine patient preference for treatment with the oral once-weekly dipeptidyl peptidase-4 inhibitor (DPP-4i), trelagliptin, and oral once-daily DPP-4i, alogliptin, administered for 8 weeks each in patients with type 2 diabetes mellitus prescribed a daily DPP-4i.Methods: In this randomized, open-label, two-way crossover study, patients received trelagliptin followed by alogliptin (T-A group) or alogliptin followed by trelagliptin (A-T group), for 8 weeks each (NCT03231709, JapicCTI-173662). Treatment preference was assessed using a standardized questionnaire in the overall population and by baseline characteristics. Other outcomes included patient satisfaction with diabetes treatment (assessed using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), hemoglobin A1c (HbA1c) levels after 8 weeks of treatment with each agent, and safety.Results: Sixty patients from two clinical sites were randomized 1:1 to T-A and A-T groups (each n = 30); baseline characteristics were similar between groups. After 16 weeks of treatment, 51.7% of patients preferred treatment with alogliptin compared with 30.0% selecting trelagliptin (p = .014); preference for alogliptin was consistently greater than for trelagliptin in the secondary analyses by baseline characteristics. DTSQ score and HbA1c levels were similar between treatments after 8 weeks of therapy. Both treatments demonstrated favorable safety and tolerability profiles.Conclusions: Patients expressed a significantly greater treatment preference for once-daily alogliptin than once-weekly trelagliptin, although patient satisfaction and HbA1c levels were similar across treatments. The decision to administer a once-weekly or once-daily DPP-4i is likely to depend on patient preference, patient-physician discussions, and treatment practices of the prescribing physician.Trial registration: ClinicalTrials.gov identifier: NCT03231709.

Risk of cardiovascular events associated with dipeptidyl peptidase-4 inhibitors in patients with diabetes with and without chronic kidney disease: A nationwide cohort study.

BackgroundCardiovascular events associated with oral hypoglycemic agents (OHAs) have raised significant safety concerns. This study assessed the association between dipeptidyl peptidase-4 inhibitors (DPP-4i) and the risk of cardiovascular events in patients with type 2 diabetes mellitus with or without chronic kidney disease (CKD).Study designA retrospective cohort study using Taiwan’s National Health Insurance Research Database.Settings and participantsOur study included patients with type 2 diabetes who received OHAs between March 1, 2009, and December 31, 2012. All eligible subjects were classified into CKD and non-CKD cohorts and further categorized as the DPP-4i and non-DPP-4i users in each cohort.MethodsThe DPP-4i and non-DPP-4i groups were matched 1:1 by propensity score to attenuate potential selection bias. Propensity score was estimated by logistic regression, using demographics, co-medications, comorbidities. and adapted diabetic complication severity index at baseline.OutcomesOutcomes of interest included a composite endpoint of ischemic stroke, myocardial infarction, cardiovascular death (major adverse cardiac events [MACE]), and hospitalization for heart failure (hHF). COX proportional hazard models were applied to examine the association between DPP-4i and outcomes of interest.ResultsWe identified 37,641 and 87,604 patients with type 2 diabetes with and without CKD, respectively. After propensity score matching, 8,213 pairs of CKD patients and 12,313 pairs of non-CKD patients were included for analysis. In the CKD cohort, DPP-4i were associated with a 25% increased risk of hHF (DPP-4i vs. non-DPP-4i incidence/1,000 person-years: 15.0 vs. 9.9, HR = 1.25; 95% CI 1.01–1.54, p = 0.037) but not with the risk of MACE (HR = 0.89, p = 0.144). In the non-CKD cohort, DPP-4i were associated with a lower risk of MACE (DPP-4i vs. non-DPP-4i incidence/1,000 person-years: 9.8 vs. 12.6 HR = 0.73; 95% CI 0.61–0.87, p = 0.0007), but not the risk of hHF (HR = 1.09, p = 0.631).ConclusionsDPP-4i were found to be associated with decreased risk of MACE in the non-CKD cohort in our study. However, DPP-4i were associated with increased risk of hHF in the CKD cohort. DPP-4i in the CKD cohort should be used cautiously.

DPP (Dipeptidyl Peptidase)-4 Inhibition Potentiates the Vasoconstrictor Response to NPY (Neuropeptide Y) in Humans During Renin-Angiotensin-Aldosterone System Inhibition.

DPP (dipeptidyl peptidase)-4 inhibitors are antidiabetic drugs that may increase heart failure in high-risk patients. NPY (neuropeptide Y) is coreleased with norepinephrine, causes vasoconstriction via the Y1 receptor, and is degraded by DPP4 to NPY (3-36) in vitro. NPY (3-36) decreases release of norepinephrine via the Y2 receptor. We tested the hypothesis that DPP4 inhibition would potentiate the vasoconstrictor effect of NPY. Eighteen nonsmokers (12 healthy controls and 6 with type 2 diabetes mellitus) participated in 1 of 2 randomized, double-blind, placebo-controlled crossover studies. First, subjects were randomized to order of treatment with sitagliptin 100 mg/d versus placebo for 7 days separated by 4-week washout. On the last day of treatment, NPY was infused by brachial artery and forearm blood flow was measured using plethysmography. Blood samples were collected after each dose. NPY infusions were repeated after 90-minute washout and intra-arterial enalaprilat. Second, 5 healthy subjects were randomized to crossover treatment with sitagliptin 100 mg/d plus valsartan 160 mg/d versus placebo plus valsartan. NPY infusions were performed on the seventh day of treatment. NPY caused dose-dependent vasoconstriction. During enalaprilat, sitagliptin significantly potentiated NPY-induced vasoconstriction in controls and diabetics ( P≤0.02 for forearm blood flow in either group). Baseline norepinephrine release was increased during sitagliptin and enalaprilat, but not further by NPY. Sitagliptin increased the ratio of NPY to NPY (3-36). During valsartan, sitagliptin also significantly potentiated NPY-induced vasoconstriction ( P=0.009 for forearm blood flow). Potentiation of endogenous NPY could contribute to cardiovascular effects of DPP4 inhibitors in patients taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

Sodium-glucose co-transporter-2 inhibitors and the risk of fractures of the upper or lower limbs in patients with type 2 diabetes: A nested case-control study.

To investigate whether the use of SGLT-2 inhibitors is associated with an increased risk of fractures. We conducted a cohort study with nested case-control analysis based on the InGef database between November 2011 and December 2016 among patients with type 2 diabetes who were initiating treatment with, switching to, or adding a new class of non-insulin antidiabetic drug. Patients with a hospital or ambulatory diagnosis of fractures of the upper or lower limbs were included and were matched to up to 40 randomly sampled control subjects. Conditional logistic regression was used to estimate confounder adjusted odds ratios (ORs) of fractures, comparing current use of metformin plus SGLT-2 inhibitor or metformin plus another antidiabetic drug class to metformin plus DPP-4 inhibitor as reference. The cohort comprised 210 042 new users of non-insulin antidiabetic drugs. For the nested case-control analysis, 7522 patients with fractures were matched to 296 845 control subjects. In the crude and confounder adjusted analyses, current use of metformin plus SGLT-2 inhibitor compared to current use of metformin plus DPP-4 inhibitor was not associated with fractures (OR: 1.00; 95% CI: 0.72-1.39 and OR: 0.99; 95% CI: 0.71-1.37, respectively). Similarly, no statistically significant association was found for current use of metformin plus another antidiabetic drug class. No treatment effect modification was observed after stratification by number of documented risk factors for falls and fractures (< 4 vs ≥ 4) and age (< 75 vs ≥ 75 years). Our study suggests that use of SGLT-2 inhibitors and other antidiabetic drug classes are not associated with an increased risk of fractures of the upper or lower limbs compared to use of DPP-4 inhibitors in patients with type 2 diabetes.

Dose adjustment of metformin and dipeptidyl-peptidase IV inhibitors in diabetic patients with renal dysfunction

Objectives: This analysis of real-world data aimed to (a) determine the proportion of Type II diabetes (T2DM) patients treated with metformin or dipeptidyl peptidase-4 inhibitors (DPP-4i) that require dose adjustment or therapy discontinuation due to chronic kidney disease (CKD), and (b) to assess the time required to dose adjustment from the time of worsening of CKD.Methods: In this retrospective study, two study populations were defined in a large healthcare organization. In the cross-sectional analysis, the distribution of CKD stages and the appropriate dosage of metformin and DPP-4i in 2013 was examined according to renal function among T2DM patients. In the longitudinal analysis, a cohort was defined to assess the time elapsed from first indication worsening of CKD to dose adjustment, among patients treated with those medications during years 2006–2013.Results: Among patients treated with metformin or DPP-4i, one third of patients with CKD failed to adjust the dosage or to discontinue metformin or DPP-4i as indicated. Median time for dose adjustment or discontinuation was significantly longer for DPP-4i than for metformin (9.8 compared to 16.8 months for metformin and DPP-4i, respectively; p-value <.001).Conclusions: This real-world data analysis showed that adjustment of dose or discontinuation of metformin or DPP-4i in patients with worsening CKD occurred less often in DPP-4i users than metformin users and took a longer time.

Cardiovascular outcomes of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes on insulin therapy

AimsTo compare the hazard of cardiovascular diseases between DPP-4 inhibitor users and non-users who were on insulin therapy. MethodsWe conducted a population-based cohort study. 2652 patients with type 2 diabetes mellitus (T2DM) under insulin therapy were enrolled during 1997–2010. The incidence rates per 1000 person-years (PYs) of stroke, coronary heart disease (CAD) and heart failure were compared between 1326 DPP-4 inhibitor users and 1326 propensity score matched non-users. Multivariable Cox proportional hazards model was used to evaluate excess risk of the DPP-4 inhibitor non-users. ResultsAfter adjustment of age, gender, comorbidities, drugs used and diabetes duration; the incidence rate per 1000 PYs were 21.70 and 9.88 in DPP-4 inhibitor non-users and users; DPP-4 inhibitor users had lower hazard ratio (HR) of stroke (adjusted HR: 0.59, 95% CI: 0.42–0.83, p value: 0.002) compared with non-users. The incidence rates per 1000 PYs of CAD and heart failure of control versus users were 19.85 versus 13.54 and 5.56 versus 4.78; the adjusted HRs of CAD and heart failure were 0.86 and 1.11. Both were non-significant. ConclusionThis nationwide study demonstrated that insulin plus DPP-4 inhibitor users had significantly lower risk of stroke as compared with non-users.

DPP-4 Inhibitors as Treatments for Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Objective Several clinical studies have reported the application of dipeptidyl peptidase-4 (DPP-4) inhibitors as treatments for type 1 diabetes mellitus (T1DM). This study aims to review the outcomes of these existing studies and to discuss the therapeutic effects of DPP-4 inhibitors on T1DM. Methods We thoroughly searched the Medline, Embase, PubMed, and Cochrane Library databases and ClinicalTrials.gov for studies concerning the use of DPP-4 inhibitors in patients with T1DM. Results In preclinical trials, DPP-4 inhibitors improved the pathogenesis of T1DM. However, only a portion of the studies showed potential efficacy regarding clinical glycemic control and other clinical parameters. From this meta-analysis, pooled data from 5 randomized controlled trials revealed that the additional use of DPP-4 inhibitors resulted in a greater decrease in glycated hemoglobin A1c (HbA1c) levels (0.07%, 95% CI (−0.37%–0.23%)) than insulin monotherapy, although the decrease was not significant. A small decrease in postprandial glucose or insulin consumption was confirmed. Conclusion Although DPP-4 inhibitors may be beneficial for T1DM, existing studies do not strongly support these positive effects in clinical practice. Further optimized clinical trials are needed.

Renoprotective Effect of Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus.

Diabetic nephropathy is one of three major complications of diabetes mellitus, often leading to chronic renal failure requiring dialysis. Recently developed dipeptidyl peptidase-4 (DPP-4) inhibitors may exhibit renoprotective effects in addition to antihyperglycemic effects. In this study, we retrospectively investigated temporal changes in the renal function index of patients with type 2 diabetes mellitus (DM) and examined the influence of DPP-4 inhibitors on renal function. Patients with type 2 DM (>18 years old) prescribed hypoglycemic agents at Gifu Municipal Hospital for ≥3 months between March 2010 and April 2014 were included in the study. Renal function was evaluated as estimated the decline in 12-month glomerular filtration rate from the baseline in patients receiving and not receiving DPP-4 inhibitors. Patient data from the DPP-4 inhibitor-treated (501 patients, 58.6%) and untreated (354, 41.4%) groups were analyzed using multiple logistic regression analysis, as well as Cox proportional-hazards regression analysis (616, 55.6% and 491, 44.4%, for DPP-4 inhibitors-treated and untreated groups). Multiple logistic regression analysis indicated that DPP-4 inhibitors significantly lowered the estimated glomerular filtration rate (eGFR) decline [20% over 12 months; odds ratio (OR), 0.626; 95% confidence interval [CI], 0.409–0.958; P = 0.031]. Similar results were obtained using Cox proportional-hazards regression analysis (hazard ratio [HR], 0.707; 95% CI, 0.572–0.874; P = 0.001). These findings suggest that DPP-4 inhibitors suppress the decrease of estimated glomerular filtration rate in patients with type 2 DM and show a renoprotective effect.

Efficacy and safety of combination therapy with an α-glucosidase inhibitor and a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: A systematic review with meta-analysis.

Aims/IntroductionThe combination of dipeptidyl peptidase‐4 (DPP4) inhibitors and α‐glucosidase inhibitors (AGIs) might provide an additive or synergistic glucose‐lowering effect, as they have a complementary mode of action. In the present study, we examined the efficacy and safety of the addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI.Materials and MethodsWe carried out an electronic search of MEDLINE, EMBASE, the Cochrane Library and Clinicaltrials.gov through October 2016. Randomized controlled trials written in English that compared DPP4 inhibitors plus AGI (DPP4i/AGI) and placebo plus AGI (PCB/AGI) in patients with type 2 diabetes were selected. Data on the study characteristics, efficacy and safety outcomes were extracted, and the risk of potential biases was assessed. The efficacy and safety of DPP4i/AGI and PCB/AGI were compared.ResultsOf 756 potentially relevant published articles and 40 registered trials, five studies including 845 patients randomized to DPP4i/AGI and 832 patients randomized to PCB/AGI were included for meta‐analysis. Compared with PCB/AGI, DPP4i/AGI showed a greater reduction in glycated hemoglobin (weighted mean difference −1.2%, 95% confidence interval −1.6 to −0.8), fasting plasma glucose and 2‐h postprandial plasma glucose levels, with no increase in bodyweight. The risks of hypoglycemia and gastrointestinal adverse events were similar between DPP4i/AGI and PCB/AGI.ConclusionsThe addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI achieved better glycemic control without further increasing the risk of weight gain and hypoglycemia.