Safety Of Dipeptidyl Peptidase-4 Inhibitors Research Articles

Effects of newer anti-hyperglycemic agents on cardiovascular outcomes in older adults: Systematic review and meta-analysis

AimTo demonstrate cardiovascular safety of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and sodium/glucose cotransporter 2 inhibitors (SGLT-2i) across age-groups. MethodsPubMed, Embase and Cochrane were searched for cardiovascular outcome trials (CVOTs) testing newer agents until August 31, 2022 (PROSPERO ID CRD42021260167). Studies with ≥1000 T2D participants enrolled for ≥12 months were included. Random effect models were used to report relative-risk (RR) for three-point major adverse cardiovascular events (3P-MACE) and its components by age subgroups (65 years; 75 years). ResultsFor SGLT-2is, five CVOTs (46,969 patients, 45–50 % ≥65 years) were included. SGLT-2is reduced risk of MACE (RR; 0.91 [CI, 0.85–0.98]); cardiovascular death (CV-death) (RR; 0.84 [CI, 0.73–0.96]); and all-cause mortality (ACM) (RR; 0.86 [CI, 0.79–0.93]) with no difference in subgroups <65 or ≥65 years.For GLP-1RAs, nine CVOTs (n = 64,236, 34–75 % ≥65 years) were included. GLP-1RAs reduced risk of MACE (RR; 0.89 [CI, 0.83–0.95]), stroke (RR; 0.86 [CI, 0.76–0.97]) and ACM (RR; 0.90 [CI, 0.83–0.97]) with no significant difference in subgroups <65 or ≥65 years. Additionally, GLP-1RAs reduced risk of MACE (10 %), ACM (12 %) and CV-death (12 %) with no significant difference in subgroups <75 or ≥75 years.Four CVOTs (n = 33,063; 35–58 % ≥65 years) with DPP-4is were included. There were no significant differences in risk for CV outcomes with DPP-4is compared to placebo in any of the age subgroups. ConclusionThe overall cardiovascular safety profile of newer anti-hyperglycemic agents is consistent in older and younger individuals.

Overall Efficacy and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Luseogliflozin Versus Dipeptidyl-Peptidase 4 Inhibitors: Multicenter, Open-Label, Randomized-Controlled Trial (J-SELECT study).

Evidence of a direct comparison between dipeptidyl-peptidase 4 inhibitors (DPP-4is) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) remains lacking, and no clear treatment strategy or rationale has been established using these drugs. This study aimed to compare the overall efficacy and safety of DPP-4is and the SGLT2i luseogliflozin in patients with type 2 diabetes mellitus (T2DM). Patients with T2DM who had not used antidiabetic agents or who had used antidiabetic agents other than SGLT2is and DPP-4is were enrolled in the study after written informed consent had been obtained. The enrolled patients were subsequently randomly assigned to either the luseogliflozin or DPP-4i group and followed up for 52weeks. The primary (composite) endpoint was the proportion of patients who showed improvement in ≥ 3 endpoints among the following five endpoints from baseline to week 52: glycated hemoglobin (HbA1c), weight, estimated glomerular filtration rate (eGFR), systolic blood pressure, and pulse rate. A total of 623 patients were enrolled in the study and subsequently randomized to either the luseogliflozin or DPP-4i groups. The proportion of patients who showed improvement in ≥ 3 endpoints at week 52 was significantly higher in the luseogliflozin group (58.9%) than in the DPP-4i group (35.0%) (p < 0.001). When stratified by body mass index (BMI) (< 25 or ≥ 25kg/m2) or age (< 65 or ≥ 65years), regardless of BMI or age, the proportion of patients who achieved the composite endpoint was significantly higher in the luseogliflozin group than in the DPP-4i group. Hepatic function and high-density lipoprotein-cholesterol were also significantly improved in the luseogliflozin group compared with the DPP-4i group. The frequency of non-serious/serious adverse events did not differ between the groups. This study showed the overall efficacy of luseogliflozin compared with DPP-4is over the mid/long term, regardless of BMI or age. The results suggest the importance of assessing multiple aspects regarding the effects of diabetes management. jRCTs031180241.

Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitor Compared to Sulphonylurea in Type II Diabetes Patients Inadequately Controlled with Metformin Alone

INTRODUCTIONDiabetes is a metabolic disorder marked by high blood glucose levels, and treatment often requires multiple drugs to achieve adequate glycemic control. In individuals with type 2 diabetes mellitus who do not respond to Metformin, doctors may prescribe a Dipeptidyl Peptidase-4 inhibitor or a Sulphonylurea as potential add-on therapy. The study was conducted to compare the efficacy and safety of the Dipeptidyl Peptidase-4 inhibitor with Sulphonylurea. MATERIAL AND METHODSThis was an interventional, comparative study involving 100 type 2 diabetic patients who visited the Medicine department at Universal college of Medical Sciences. All the eligible patients were randomly divided into two treatment groups (50 each): Group A (Sulphonylurea + Metformin) and Group B (Dipeptidyl Peptidase-4 inhibitor + Metformin). Treatment was provided for 18 weeks, and patients were investigated for blood glucose parameters like glycosylated hemoglobin, fasting blood glucose, postprandial glucose at baseline and after 18 weeks of follow-up, and questions regarding adverse reactions. The efficacy of the drugs between the two treatment groups was compared using an independent t-test. RESULTSDipeptidyl Peptidase-4 inhibitor plus Metformin was found to be superior to Sulphonylurea plus Metformin in terms of HbA1c-lowering efficacy (p=0.030). A total of 26% of patients in the Sulphonylurea group reported unpleasant hypoglycemic events, compared to 6% in the Dipeptidyl Peptidase-4 inhibitor group (p=0.006). Patients treated with Sulphonylurea gained weight over 18 weeks, but those on Dipeptidyl Peptidase-4 inhibitor lost weight (p=0.043). CONCLUSIONCompared to Sulphonylurea, adding a Dipeptidyl Peptidase-4 inhibitor to a Metformin therapy significantly improves glycaemic control in type 2 diabetic patients who are not well controlled with Metformin monotherapy, without producing hypoglycemia or weight gain.

Safety of dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

Registration:PROSPERO: CRD42020210645Introduction:We aimed to assess the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in older patients with type 2 diabetes with inadequate glycaemic control.Methods:We included randomized controlled trials (RCTs) in older (⩾65 years) patients with type 2 diabetes. The intervention group was randomized to treatment with any DPP-4 inhibitors. A systematic search in MEDLINE and Embase was performed in December 2020. For assessing the risk of bias, RoB 2 tool was applied. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We pooled outcomes using random effects meta-analyses.Results:We identified 16 RCTs that included 19,317 patients with a mean age of greater than 70 years. The mean HbA1c level ranged between 7.1 and 10.0 g/dl. Adding DPP-4 inhibitors to standard care alone may increase mortality slightly [risk ratio (RR) 1.04; 95% confidence interval (CI) 0.89–1.21]. Adding DPP-4 inhibitors to standard care increases the risk for hypoglycaemia (RR 1.08; 95% CI 1.01–1.16), but difference in overall adverse events is negligible. DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas (RR 0.88; 95% CI 0.75–1.04). DPP-4 inhibitors probably reduce the risk for hypoglycaemia compared with sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible. There is insufficient evidence on hospitalizations, falls, fractures, renal impairment and pancreatitis.Conclusion:There is no evidence that DPP-4 inhibitors in addition to standard care decrease mortality but DPP-4 inhibitors increase hypoglycaemia risk. Second-line therapy in older patients should be considered cautiously even in drugs with a good safety profile such as DPP-4 inhibitors. In case second-line treatment is necessary, DPP-4 inhibitors appear to be preferable to sulfonylureas.Plain language summarySafety of dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetesIntroduction:We performed the review to assess the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in older type 2 diabetes patients with blood sugar outside the normal level.Methods:To answer the question, we searched various electronic databases. We included studies in older (⩾65 years) patients with type 2 diabetes that assessed the safety of DPP-4 inhibitors. The data from the different studies were quantitatively summarized using statistical methods. We assessed the quality of the data to judge the certainty of the findings.Results:We identified 16 studies that included 19,317 patients with a mean age greater than 70 years. The average blood sugar level of patients in the included studies was slightly or moderately increased. Adding DPP-4 inhibitors to standard care alone may increase mortality slightly. Adding DPP-4 inhibitors to standard care increases the risk for hypoglycaemia, but difference in overall adverse events is negligible. DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas. DPP-4s probably reduce the risk of hypoglycaemia compared with sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible. There is insufficient evidence on hospitalizations, falls, fractures, renal impairment and pancreatitis.Conclusion:There is no evidence that DPP-4 inhibitors in addition to standard care decrease mortality but DPP-4 inhibitors increase the risk that blood sugar falls below normal. Adding DPP-4 inhibitorss to standard care in older patients should be considered cautiously even in drugs with a good safety profile such as DPP-4 inhibitors. In case additional treatment is necessary, DPP-4 inhibitors appear to be preferable to sulfonylureas.

Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of cardiovascular outcome trials.

BACKGROUNDDipeptidyl peptidase-4 (DPP-4) inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus (T2DM). Recently, a series of large, randomized controlled trials (RCTs) addressing cardiovascular outcomes with DPP-4 inhibitors have been published. AIMTo pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias. METHODSWe searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020. We extracted data concerning the following “hard” efficacy outcomes: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospitalization for heart failure, hospitalization for unstable angina, hospitalization for coronary revascularization and cardiovascular death. We also extracted data regarding the risk for major cardiac arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia.RESULTSWe pooled data from 6 trials in a total of 52520 patients with T2DM assigned either to DPP-4 inhibitor or placebo. DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction [risk ratio (RR) = 1.02, 95%CI: 0.94-1.11, I2 = 0%], hospitalization for heart failure (RR = 1.09, 95%CI: 0.92-1.29, I2 = 65%) and cardiovascular death (RR = 1.02, 95%CI: 0.93-1.11, I2 = 0%). DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke (RR = 0.96, 95%CI: 0.85-1.08, I2 = 0%) and coronary revascularization (RR = 0.99, 95%CI: 0.90-1.09, I2 = 0%), Finally, DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina (RR = 1.00, 95%CI: 0.85-1.18, I2 = 0%). As far as cardiac arrhythmias are concerned, DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation (RR = 0.95, 95%CI: 0.78-1.17, I2 = 0%), while they were associated with a significant increase in the risk for atrial flutter, equal to 52% (RR = 1.52, 95%CI: 1.03-2.24, I2 = 0%). DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias. CONCLUSIONDPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2DM, while they do not seem to be associated with a significant risk for any major cardiac arrhythmias, except for atrial flutter. Therefore, this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors, except for those cases when newer antidiabetics (glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) are not tolerated, contraindicated or not affordable for the patient.

Dipeptidyl peptidase-4 inhibitor and insulin combination treatment in type 2 diabetes and chronic kidney disease: A meta-analysis.

ABSTRACTAims/IntroductionThe union of dipeptidyl peptidase‐4 inhibitors and insulin in patients with type 2 diabetes and chronic kidney disease provides satisfactory glucose management without increasing adverse events (AEs). This research appraised the therapeutic effect and safety of combination therapy in patients with type 2 diabetes and chronic kidney disease.Materials and MethodsWe carried out a meta‐analysis of randomized controlled trials to analyze AEs, hypoglycemia, serious AEs, severe hypoglycemia, estimated glomerular filtration rate, fasting plasma glucose, glycated hemoglobin, insulin dose, low‐density lipoprotein cholesterol, uric acid and weight between combination treatment groups and control groups by searching the Cochrane Library, Excerpta Medica Database (Embase), PubMed and Web of Science databanks until October 2020.ResultsFive studies (6 trials, 1,278 participants) met the inclusion criteria. The evidence quality ranged from moderate to high. Glycated hemoglobin (standardized mean difference −0.29, 95% confidence interval −0.44 to −0.14) and insulin dose (standardized mean difference −0.16, 95% confidence interval −0.29 to −0.02) were obviously smaller in the combination cure patients than in the control patients. Compared with the control groups, combination treatment did not increase AEs, hypoglycemia, serious AEs or severe hypoglycemia.ConclusionsThis study showed the effectiveness and safety of dipeptidyl peptidase‐4 inhibitors bonded with insulin in patients with type 2 diabetes and chronic kidney disease, but the protective actions of this cure on kidney and cardiovascular outcomes, as well as the functions of other dipeptidyl peptidase‐4 inhibitors, need to be affirmed by more good‐quality randomized controlled trials.

Meta-analysis of cardiovascular outcome trials assessing the cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus

Abstract Background Type 2 diabetes mellitus (T2DM) represents an independent risk factor for the development of cardiovascular disease, which accounts for half of deaths among the affected patients. Patients with T2DM experience higher incidence of vascular interventions compared to high-risk patients without T2DM or cardiovascular disease at baseline, underscoring the necessity for targeted therapeutic interventions. Dipeptidyl peptidase-4 (DPP-4) inhibitors constitute a safe treatment option with fair glycemic efficacy in T2DM whose cardiovascular efficacy has been doubted over recent years. A series of randomized controlled trials (RCTs) addressing cardiovascular outcomes with DPP-4 inhibitors have been recently published, while previous meta-analyses failed to show any cardiovascular benefit with their use in patients with T2DM. Purpose The purpose of our analysis was to report the impact of antidiabetic treatment with DPP-4 inhibitors on different cardiovascular efficacy outcomes. Methods We searched PubMed for all published RCTs assessing cardiovascular outcomes after antidiabetic treatment with DPP-4 inhibitors. We extracted data related to the following efficacy outcomes: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospitalization for heart failure, hospitalization for unstable angina, hospitalization for coronary revascularization and cardiovascular death. Results We pooled data from a total of 6 trials in a total of 52,520 patients. Antidiabetic treatment with DPP-4 inhibitors did not significantly affect any of the prespecified cardiovascular efficacy outcomes. More specifically, DPP-4 inhibitors compared to control led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction (RR=1.02, 95% CI: 0.94–1.11, I2=0%), hospitalization for heart failure (RR=1.09, 95% CI: 0.92–1.29, I2=65%) and cardiovascular death (RR=1.02, 95% CI: 0.93–1.11, I2=0%), as shown in figures 1a, 1c and 1f. In addition, DPP-4 inhibitors produced a non-significant decrease in the risk for fatal and non-fatal stroke (RR=0.96, 95% CI: 0.85–1.08, I2=0%) and coronary revascularization (RR=0.99, 95% CI: 0.90–1.09, I2=0%), as depicted in figures 1b and 1e. Finally, DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina (RR=1.00, 95% CI: 0.85–1.18, I2=0%), as shown in figure 1d. Conclusions Antidiabetic treatment with DPP-4 inhibitors does not seem to confer any significant cardiovascular benefit for patients with T2DM. Funding Acknowledgement Type of funding sources: None. Figure 1

Antidiabetic Agent DPP-4i Facilitates Murine Breast Cancer Metastasis by Oncogenic ROS-NRF2-HO-1 Axis via a Positive NRF2-HO-1 Feedback Loop.

Cancer has been as one of common comorbidities of diabetes. Long-term antidiabetic treatment may potentially exert uncertain impacts on diabetic patients with cancer including breast cancer (BC). Dipeptidyl peptidase-4 inhibitors (DPP-4i) are currently recommended by the AACE as first-line hypoglycemic drugs in type 2 diabetes mellitus (T2DM). Although the safety of DPP-4i has been widely evaluated, the potential side-effects of DPP-4i in cancer metastasis were also reported and remain controversial. Here, we revealed that Saxagliptin (Sax) and Sitagliptin (Sit), two common DPP-4i compounds, potentially promoted murine BC 4T1 metastasis in vitro and in vivo under immune-deficient status. Mechanically, we observed that DPP-4i treatment induced aberrant oxidative stress by triggering ROS overproduction, as well as ROS-dependent NRF2 and HO-1 activations in BC cells, while specific inhibition of ROS, NRF2 or HO-1 activations abrogated DPP-4i-driven BC metastasis and metastasis-associated gene expression in vitro. Furthermore, ALA, a NRF2 activator significantly promoted BC metastasis in vitro and in vivo, which can be abrogated by specific HO-1 inhibition in vitro. Moreover, specific HO-1 inhibition not only reversed DPP-4i-induced NRF2 activation but also abrogated ALA-induced NRF2 activation, resulting in a decrease of metastasis-associated genes, indicating a positive-feedback NRF2-HO-1 loop. Our findings suggest that DPP-4i accelerates murine BC metastasis through an oncogenic ROS-NRF2-HO-1 axis via a positive-feedback NRF2-HO-1 loop. Therefore, this study not only offers novel insights into an oncogenic role of DPP-4i in BC progression but also provides new strategies to alleviate the dark side of DPP-4i by targeting HO-1.

Safety of Dipeptidyl Peptidase-4 Inhibitors in COVID-19: An Update

Background: Safety of use of dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes and coronavirus disease 2019 (COVID-19) is unclear. Objective: To review the most recent data regarding safety of use of DPP-4 inhibitors before and during hospitalization of patients with type 2 diabetes and COVID-19

Therapeutic Role of Dipeptidyl Peptidase-4 Inhibitors in COVID-19

Background: Limited retrospective data suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin may decrease mortality in patients with type 2 diabetes hospitalized with coronavirus disease 2019 (COVID-19). Objective: To review the strength of evidence that supports possible therapeutic role of DPP-4 inhibitors in COVID-19. Methods: PUBMED search until October 10, 2020. Search terms included COVID-19, DPP-4 inhibitors, sitagliptin, CD26, mortality, diabetes. Retrospective studies, pertinent animal investigations and pre-print studies are reviewed. Results: Three retrospective studies have shown that use of DPP-4 inhibitors was associated with significant mortality reduction of approximately 56- 87% in patients with diabetes admitted with COVID-19. In addition, in one of these studies, the use of sitagliptin before hospitalization was associated with greater number of hospital discharges, improvement of clinical status, reduced risk of transfer to intensive care unit (ICU) and need for mechanical ventilation compared with patients who were not receiving sitagliptin. Moreover, there was significant decrease in some pro-inflammatory markers in the sitagliptin group. A small retrospective study of 9 patients who were taking a DPP-4 inhibitor prior to admission did not find any significant effect of DPP-4 inhibitors on mortality and clinical outcomes after hospitalization. Results of another small study suggested increase susceptibility to COVID-19, but not to its severity, in patients taking DPP-4 inhibitors. Conclusions: Weak evidence derived from observational studies suggests possible beneficial effects of DPP-4 inhibitors use in patients with type 2 diabetes and COVID-19. Randomized trials are urgently needed to clarify the efficacy and safety of DPP-4 inhibitors in patients with COVID-19 with and without type 2 diabetes

The efficacy and safety of dipeptidyl peptidase-4 inhibitors compared to other oral glucose-lowering medications in the treatment of type 2 diabetes

The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong to the class of incretin-based medications, are recommended as second or third-line therapies in guidelines for the management of type 2 diabetes mellitus. They have a favorable drug tolerability and safety profile compared to other glucose-lowering agents. This review discusses data concerning the use of DPP-4is and their cardiovascular profile, and gives an updated comparison with the other oral glucose-lowering medications with regards to safety and efficacy. Currently available original studies, abstracts, reviews articles, systematic reviews and meta-analyses were included in the review. DPP4is are moderately efficient in decreasing the HbA1c by an average of 0.5% as monotherapy, and 1.0% in combination therapy with other drugs. They have a good tolerability and safety profile compared to other glucose-lowering drugs. However, there are possible risks pertaining to acute pancreatitis and pancreatic cancer. Cardiovascular outcome trials thus far have proven the cardiovascular safety for ischemic events in patients treated with sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin. Data showing increased rate of hospitalisation in the case of saxagliptin did not seem to be a class effect.

Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitors in Kidney Transplant Recipients with Post-transplant Diabetes Mellitus (PTDM)- a Systematic Review and Meta-Analysis.

Kidney transplant recipients may develop post-transplant diabetes mellitus (PTDM). Dipeptidyl peptidase 4(DPP-4) inhibitors are evolving agents in the management of patients with diabetes mellitus. To evaluate the efficacy and safety of DPP-4 inhibitors in the management of post-transplant diabetes mellitus (PTDM) in renal transplant recipients. We performed a systematic search of the electronic databases using keys words and Mesh terms. Data were extracted and reviewed using structured proforma. A comprehensive review of the eligible studies was performed independently by each of two reviewers; conflicts were resolved by the third reviewer. The primary efficacy endpoint was the difference in glycosylated hemoglobin (HbA1c) comparing any of the DPP-4 inhibitors to either placebo or other hypoglycaemic agent. The primary safety endpoints were the worsening of graft functions and change in Tacrolimus trough level. We performed the Random effect model using standardised mean difference. We identified seven studies that were eligible for the systematic review; only one study compared Sitagliptin to insulin Glargine. One study involved head to head comparison of three DPP-4 inhibitors. The other five studies were pooled in the meta-analysis. DPP-4 inhibitors had a favourable glycemic effect as measured by HbA1c when compared to either placebo or oral anti-hyperglycemic medications (standardised mean difference in HbA1c = -0.993, 95% CI= -1.303 to -0.683, P=0.001). DPP-4 inhibitors use did not result in significant change in eGFR ((standardised mean difference = 0.147, 95% CI= -0.139 - 0.433, p=0.312).) nor Tacrolimus level (standardised Mean Difference= 0.152, 95% CI= -0.172 to 0.477, P=0.354). Current evidence supports the short term efficacy and safety of DDP-4 inhibitor agents in the management of post transplantation diabetes mellitus (PTDM) in kidney transplant recipients. However, more RCTs are required to investigate the long-term safety and efficacy of these agents in kidney transplant recipients.

GLP-1 Analogs and DPP-4 Inhibitors in Type 2 Diabetes Therapy: Review of Head-to-Head Clinical Trials.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in response to the presence of nutrients in the small intestines. These homones facilitate glucose regulation by stimulating insulin secretion in a glucose dependent manner while suppressing glucagon secretion. In patients with type 2 diabetes (T2DM), an impaired insulin response to GLP-1 and GIP contributes to hyperglycemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors block the breakdown of GLP-1 and GIP to increase levels of the active hormones. In clinical trials, DPP-4 inhibitors have a modest impact on glycemic control. They are generally well-tolerated, weight neutral and do not increase the risk of hypoglycemia. GLP-1 receptor agonists (GLP-1 RA) are peptide derivatives of either exendin-4 or human GLP-1 designed to resist the activity of DPP-4 and therefore, have a prolonged half-life. In clinical trials, they have demonstrated superior efficacy to many oral antihyperglycemic drugs, improved weight loss and a low risk of hypoglycemia. However, GI adverse events, particularly nausea, vomiting, and diarrhea are seen. Both DPP-4 inhibitors and GLP-1 RAs have demonstrated safety in robust cardiovascular outcome trials, while several GLP-1 RAs have been shown to significantly reduce the risk of major adverse cardiovascular events in persons with T2DM with pre-existing cardiovascular disease (CVD). Several clinical trials have directly compared the efficacy and safety of DPP-4 inhibitors and GLP-1 RAs. These studies have generally demonstrated that the GLP-1 RA provided superior glycemic control and weight loss relative to the DPP-4 inhibitor. Both treatments were associated with a low and comparable incidence of hypoglycemia, but treatment with GLP-1 RAs were invariably associated with a higher incidence of GI adverse events. A few studies have evaluated switching patients from DPP-4 inhibitors to a GLP-1RA and, as expected, improved glycemic control and weight loss are seen following the switch. According to current clinical guidelines, GLP-1RA and DPP-4 inhibitors are both indicated for the glycemic management of patients with T2DM across the spectrum of disease. GLP-1RA may be preferred over DPP- 4 inhibitors for many patients because of the greater reductions in hemoglobin A1c and weight loss observed in the clinical trials. Among patients with preexisting CVD, GLP-1 receptor agonists with a proven cardiovascular benefit are indicated as add-on to metformin therapy.

Evaluation of Dipeptidyl Peptidase-4 Inhibitors versus Thiazolidinediones or Insulin in Patients with Type 2 Diabetes Uncontrolled with Metformin and a Sulfonylurea in a Real-World Setting.

Guidelines do not make clear recommendations for third add-on agents to metformin plus a sulfonylurea. This study compared the effectiveness and safety of dipeptidyl peptidase-4 inhibitors (DPP4is) to thiazolidinedione (TZD) or insulin as a third add-on agent to metformin plus a sulfonylurea in an integrated health care setting. This retrospective database cohort study included adults with type 2 diabetes not at goal hemoglobin A1C (HbA1C) who initiated DPP4i, TZD, or insulin as a third add-on agent to metformin plus a sulfonylurea from January 2006 to June 2016. Primary outcomes were the proportion of patients who achieved goal HbA1C after starting the third add-on agent and change in HbA1C. Subgroup analysis was performed for patients with baseline HbA1C greater than 9%. In this study, 2080 patients started on a DPP4i were matched to 8320 patients started on TZD and to 8320 patients taking insulin. A significantly higher percentage of patients taking TZD reached goal HbA1C (31.0% versus 23.6%; p < 0.05) and had a significantly larger HbA1C reduction (-0.94% ± 1.34% versus -0.79% ± 1.23%; p < 0.01) compared to patients taking a DPP4i. No difference in the percentage of patients meeting goal HbA1C nor in change in HbA1C was demonstrated between insulin versus DPP4i regimens. For patients with baseline HbA1C greater than 9%, insulin or TZD resulted in a significantly higher proportion of patients achieving goal HbA1C compared to DPP4i (17.3% and 19.0% versus 12.4%, respectively; p < 0.01). TZD was more effective than DPP4i but DPP4i was as effective as insulin as a third add-on agent in the overall study population. Insulin was more effective than DPP4i only in the subgroup analysis of patients with baseline HbA1C greater than 9%.

Evaluation of Dipeptidyl Peptidase-4 Inhibitors versus Thiazolidinediones or Insulin in Patients with Type 2 Diabetes Uncontrolled with Metformin and a Sulfonylurea in a Real-World Setting

BACKGROUND Guidelines do not make clear recommendations for third add-on agents to metformin plus a sulfonylurea. This study compared the effectiveness and safety of dipeptidyl peptidase-4 inhibitors (DPP4is) to thiazolidinedione (TZD) or insulin as a third add-on agent to metformin plus a sulfonylurea in an integrated health care setting. METHODS This retrospective database cohort study included adults with type 2 diabetes not at goal hemoglobin A1C (HbA1C) who initiated DPP4i, TZD, or insulin as a third add-on agent to metformin plus a sulfonylurea from January 2006 to June 2016. Primary outcomes were the proportion of patients who achieved goal HbA1C after starting the third add-on agent and change in HbA1C. Subgroup analysis was performed for patients with baseline HbA1C greater than 9%. RESULTS In this study, 2080 patients started on a DPP4i were matched to 8320 patients started on TZD and to 8320 patients taking insulin. A significantly higher percentage of patients taking TZD reached goal HbA1C (31.0% versus 23.6%; p < 0.05) and had a significantly larger HbA1C reduction (-0.94% ± 1.34% versus -0.79% ± 1.23%; p < 0.01) compared to patients taking a DPP4i. No difference in the percentage of patients meeting goal HbA1C nor in change in HbA1C was demonstrated between insulin versus DPP4i regimens. For patients with baseline HbA1C greater than 9%, insulin or TZD resulted in a significantly higher proportion of patients achieving goal HbA1C compared to DPP4i (17.3% and 19.0% versus 12.4%, respectively; p < 0.01). CONCLUSION TZD was more effective than DPP4i but DPP4i was as effective as insulin as a third add-on agent in the overall study population. Insulin was more effective than DPP4i only in the subgroup analysis of patients with baseline HbA1C greater than 9%.

European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose-lowering drugs in patients with heart failure.

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose-lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose co-transporter type 2 (SGLT-2) inhibitors]. Regarding safety of DPP-4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF hospitalisation. There is no compelling evidence of excess HF risk with the other DPP-4 inhibitors. GLP-1 RAs have an overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT-2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT-2 inhibitors could be recommended to prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors. The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess whether the results observed with dapagliflozin could be extended to other SGLT-2 inhibitors in the treatment of HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose-lowering therapies in patients with HF.

1635-P: Risk of Pancreatitis among Patients with Type 2 Diabetes Receiving DPP-4 Inhibitors: Nationwide Case-Control Study

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are widely used antidiabetic incretin-based drugs. There remain concerns about the pancreatic safety of DPP-4i due to its pleiotropic effects on the exocrine pancreas. We studied whether DPP-4i are associated with acute and chronic pancreatitis using nationwide population-based cohort study. This study included patients with newly diagnosed type 2 diabetes being treated with antidiabetic drugs (n = 33,208) from 2007 to 2013, from the sample cohort (n = 514,866) of the ***** National Health Insurance Service-Health Screening Cohort database. A Cox proportional hazards model with time-dependent covariates was used to calculate the risk. Lag time of 6 months was applied to reflect a cumulative effect of DPP-4i. Subgroup analyses were also performed according to various confounding factors. Of the 33,208 subjects, 10,210 new DPP-4i users and 22,998 new users of antidiabetic drugs other than DPP-4i were included. DPP-4i significantly increased the risk for pancreatitis (adjusted hazard ratio (aHR) 1.26, 95% CI 1.06-1.50) even after adjusting for age, sex, BMI, smoking and alcohol status, Charlson comorbidity index, and residential region. With a drug-use lag exposure of 6 months, aHR for pancreatitis was still statistically significant as similar (aHR 1.23, 95% CI 1.01-1.51) In subgroup analyses, the risk of pancreatitis was apparent only in subjects with a higher comorbidity score, suggesting a clinical factor which increases the risk of pancreatitis by DPP-4i use. In an analysis of data from a large nation-wide cohort database, we found that DPP-4i are associated with the increased risk of pancreatitis in patients with newly diagnosed type 2 diabetes. Disclosure M. Lee: None. J. Sun: None. M. Han: None. J. Kim: None. Y. Kim: None. I. Lee: None. S. Lee: None. J. Bae: None. Y. Cho: None. J. Lee: None. C. Kim: None. C. Nam: None. E. Kang: None.

Review of the cardiovascular safety of dipeptidyl peptidase-4 inhibitors and the clinical relevance of the CAROLINA trial

BackgroundCardiovascular (CV) disease (CVD) is a well-recognized complication of type 2 diabetes mellitus (T2DM) and there is a clinical need for glucose-lowering therapies that do not further increase CV risk in this population. Although sulfonylureas (SUs) may be used as second-line therapy for patients requiring additional therapy after first-line metformin to improve glycemic control, their long-term effects on CV outcomes remain uncertain, and a wide range of alternative agents exist including dipeptidyl peptidase-4 (DPP-4) inhibitors.MethodsLiterature searches in PubMed (2013–2018) were conducted with terms for DPP-4 inhibitors combined with CV terms, with preference given to cardiovascular outcomes trials (CVOTs). Reference lists from retrieved articles and diabetes guidelines were also considered.ResultsThis narrative review discusses current evidence for the CV safety of these agents, describes the long-term CV effects of DPP-4 inhibitors, including effects on CV events, mortality, the risk for heart failure hospitalization, and highlights the need for further research into the CV effects of SU therapy. Although SUs remain a treatment option for T2DM, the long-term effects of these agents on CV outcomes are unclear, and further long-term studies are required. For DPP-4 inhibitors, uncertainties have been raised about their long-term effect on hospitalization for heart failure in light of the results of SAVOR-TIMI 53, although the findings of other DPP-4 inhibitor CVOTs in T2DM and data analyses have suggested these agents do not increase the occurrence of adverse CV outcomes.ConclusionsBased on recent CVOTs and guideline updates, the choice of add-on to metformin therapy for patients with T2DM and established CV disease should be a sodium-glucose co-transporter-2 inhibitor or a glucagon-like peptide-1 agonist with proven CV benefit. Additional treatment options for those individuals who require therapy intensification, as well as in patients with T2DM and without established CVD include DPP-4 inhibitors and SUs. Since few head-to-head trials have compared the effects of different oral glucose-lowering agents on CV outcomes in T2DM, with most CVOTs using placebo as a comparator, the CAROLINA trial will provide important information on the comparative CV safety of a commonly prescribed SU and a DPP-4 inhibitor.

The efficacy and safety of dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a Bayesian network meta-analysis of 58 randomized controlled trials.

The aim is to evaluate the efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP4-I: sitagliptin, saxagliptin, linagliptin, vildagliptin and alogliptin) in patients with type 2 diabetes. We searched the Cochrane Library, PubMed, EMBASE, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), and the Wanfang Database from inception to April, 2018. Randomized controlled trials were included if they compared the different versions of DPP4-I with each other or with placebo in treatment of type 2 diabetes. Bayesian network meta-analysis and pairwise meta-analysis were performed to evaluate the efficacy and safety of the different kinds of DPP4-I and placebo. The data were analyzed using STATA 12.0 and WinBUGS1.4 software. We identified 58 eligible studies (with 31356 patients) involving 14 treatment arms. Indirect comparison results showed that except for alogliptin, a decrease was found for all DPP4-I versus the placebo for hemoglobin A1c (HbA1c) with vildagliptin50 twice daily (BID) showing the highest probability. Linagliptin5 once daily (QD) decreased the level of fasting plasma glucose (FPG) the most for all DPP4-I versus the placebo; when comparing them with each other, alogliptin25QD was more effective when compared with sitagliptin100QD and vildaglipti50BID; linagliptin5qd had the highest decrease impact on body mass index (BMI). Except for hypoglycemia and upper respiratory tract infection (URTI), there are no statistical significance on incidence of adverse events and the body weight when DPP4-I are compared with each other or with placebo. Our network meta-analysis presents the associations of DPP4-I versus placebos on HbA1c, FPG, 2h postprandial blood glucose (2HPPG), BMI, body weight and adverse events. DPP4-I have a lowering effect on the glycemic level (HbA1c, FPG), especially vildaglipti50BID and linagliptin10QD, respectively. Besides, linagliptin5QD has the greatest probabilities of reducing BMI. In addition, DPP4-I were associated with not increasing the incidence of adverse events. Among them, vildagliptin100QD and sitagliptin100QD have the lowest probability in reducing the incidence of hypoglycemia and URTI, respectively.

Efficacy and safety of dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes mellitus patients with moderate to severe renal impairment: a meta-analysis.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antidiabetic agents for type 2 diabetes mellitus (T2DM) patients. However, the effects and safety of DPP-4 inhibitors in T2DM patients with renal impairment (RI) remain controversial. Therefore, we conducted this meta-analysis to assess the efficacy and safety of DPP-4 inhibitors in T2DM patients with moderate to severe RI. The PubMed, Embase, and Web of Science database were searched for published randomized controlled trials (RCTs), which compared DPP-4 inhibitors with placebo or a control regimen. A fixed-model effect or random-effect model was used to assess the effects of DPP-4 inhibitors on T2DM patients with RI. Subgroup analysis or meta-regression analysis were performed to explore the potential sources of heterogeneity among the included studies. 13 RCTs with a total of 2,940 patients were included in this meta-analysis. Compared with other treatments, DPP-4 inhibitors were associated with a greater change in HbA1c level (weight mean difference (WMD)=-0.50, 95%CI: -0.61, -0.39; p<0.001), and a higher response rate of patients achieving the HbA1c goal of <7% (risk ratio (RR)=1.38, 95%CI: 1.12, 1.70; p=0.002). Subgroup analysis suggested that the reduced HbA1c was observed in all types of DPP-4 inhibitors, and in patients with moderate or severe RI, but not in those with end-stage renal disease. DPP-4 inhibitors did not significantly lower the FPG level (WMD=-0.36, 95%CI: -0.92, 0.20; p=0.204), and this was seen in all types of DPP-4 inhibitors except gemigliptin, which showed a significant reduction in FPG level. The prevalence of adverse events (RR=0.98, 95%CI: 0.94, 1.02; p=0.256) in the two groups was not significantly different, and DPP-4 inhibitors did not induce a higher rate of hypoglycemia (RR=1.31, 95%CI: 0.97, 1.77; p=0.075). DPP-4 inhibitors significantly lowered HbA1c levels in T2DM patients with moderate to severe RI. And the treatment of DPP-4 inhibitors did not increase the risk of hypoglycemia and adverse events. Considering the potential limitations in this meta-analysis, more large-scale, well-conducted RCTs are needed to identify our findings.