Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative.

BACKGROUND: Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications. METHODS: We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication. RESULTS: Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation. CONCLUSIONS: Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.

Antidiabetic medications and the risk of prostate cancer in patients with diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Antidiabetic medications (ADMs) may modify prostate cancer (PCa) risk in patients with diabetes mellitus (DM). Accordingly, the current study assessed the possible associations between ADMs and the risk of PCa in diabetics. METHODS: A systematic literature search (PubMed, Embase and Cochrane Library) identified studies evaluating the associations between ADMs and incidence of PCa. A meta-analysis followed PRISMA was performed using odds ratio (OR) with 95% confidence interval (CI) as effect measures. RESULTS: In total of 47 studies involving 3094,152 patients with diabetes were included. Results of meta-analysis of the observational studies suggested no significant association between metformin, thiazolidinediones, sulfonylureas, insulin or dipeptidyl peptidase-4 inhibitors administration and the risk of PCa (All p-values > 0.05). Separate analysis of randomized controlled trials (RCTs) revealed a significant reduction in PCa risk with thiazolidinediones (OR = 0.55, p = 0.04) or glucagon-like peptide-1 receptor agonists (GLP-1RA) administration (OR = 0.53, p = 0.006), whereas no significant association was found in SGLT2 inhibitors (p = 0.3). CONCLUSION: Thiazolidinediones or GLP-1RA administration may have benefits in PCa based on RCTs, however, further research is needed to confirm these findings.

Discovery, synthesis and in combo studies of Schiff's bases as promising dipeptidyl peptidase-IV inhibitors.

Diabetes mellitus is a main global health apprehension. Macrovascular illnesses, neuropathy, retinopathy, and nephropathy are considered some of its severe hitches. Gliptins are a group of hypoglycemic agents that inhibit dipeptidyl peptidase-IV (DPP-IV) enzyme and support blood glucose-lowering effect of incretins. In the current research, synthesis, characterization, docking, and biological evaluation of fourteen Schiff's bases 5a-f and 9a-h were carried out. Compound 9f revealed the best in vitro anti-DPP-IV activity of 35.7% inhibition at a concentration of 100 µM. Compounds 9c and 9f with the highest in vitro DPP-IV inhibition were subjected to the in vivo glucose-lowering test using vildagliptin as a positive inhibitor. Vildagliptin, 9c, and 9f showed significant reduction in the blood glucose levels of the treated mice after 30 min of glucose administration. Moreover, induced fit docking showed that these derivatives accommodated the enzyme binding site with comparable docking scores. Schiff's bases can serve as promising lead for the development of new DPP-IV inhibitors.

Health Beneficial Bioactivities of Faba Bean Gastrointestinal (In Vitro) Digestate in Comparison to Soybean and Pea.

Faba beans are a promising emerging plant-based protein source to be used as a quality alternative to peas and soy. In this study, the potential health beneficial activities of three Canadian faba bean varieties (Fabelle, Malik and Snowbird) were investigated after in vitro gastrointestinal digestion and compared to two commonly used legumes (peas and soy). The results revealed that the faba beans had a higher antioxidant activity than peas when assessed with the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assays, except for the Fabelle variety. In the oxygen radical absorbance capacity (ORAC) and the iron chelating assays, the faba beans had a lower antioxidant activity than soy. Interestingly, Fabelle and Snowbird showed a higher antioxidant effect than the peas and soy at the cellular level. The antihypertensive properties of Fabelle and Malik varieties were significantly higher than peas but lower than soy. The in vitro antidiabetic activity was higher for soy, but no differences were found at the cellular level. The faba bean peptides were further fractionated and sequenced by mass spectrometry. Eleven peptides with in silico predicted bioactivities were successfully identified in the faba bean digestate and support validating the health-promoting properties of peptides. The results demonstrate the bioactive potential of faba beans as a health-promoting food ingredient against non-communicable diseases.

The roles of dipeptidyl peptidase-4 inhibitors in prognosis of COVID-19 infection in patients with type 2 diabetes mellitus.

Background: COVID-19 is responsible for the latest pandemic. Dipeptidyl peptidase-4 (DPP-4) is one of the cellular receptors of interest for coronavirus. The aim of this study was to assess the roles of DPP-4 inhibitors in prognosis of COVID-19 infection in patients with type 2 diabetes mellitus. Materials and Methods: retrospective cohort study was performed in 2020 in military medical centers affiliated to AJA University of Medical Sciences in Tehran on 220 patients with type 2 diabetes mellitus who were admitted in medical centers with COVID-19 infection. We collected demographic data of patients including age, gender, drug history, usage of DPP-4 inhibitors, clinical presentations at the time of the first visit, and the disease outcome including hospitalization duration and need for respiratory assist. Results: The study population consisted of 133 males (60.5%) and 87 females (39.5%), with a mean age of 66.13 ± 12.3 years. Forty-four patients (20%) consumed DPP-4 inhibitors (sitagliptin and linagliptin). Patients who were treated with DPP-4 inhibitors required less oxygen (O2) therapies compared to other cases (76.7% vs. 88.6%, P = 0.04). Patients who were treated with DPP-4 inhibitors had significantly lower hospitalization duration compared to other cases (6.57 ± 2.3 days vs. 8.03 ± 4.4 days, respectively, P = 0.01). There were no significant differences between the two groups of patients regarding survival rates (P = 0.55). Age was a predictive factor for survival (odds ratio, 1.13; 95% confidence interval, 1.04-1.23; P = 0.004). Conclusion: DPP-4 inhibitors could significantly decrease hospitalization days in patients with type 2 diabetes mellitus who were hospitalized for COVID-19. However, DPP-4 inhibitor usage showed no statistically significant impact on survival. Age was the important prognostic factor.

Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes.

BACKGROUND: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. METHODS: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. RESULTS: Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (P=0.061) to 0.85 (P=0.008) and the ACM HR from 0.86 (P=0.016) to 0.81 (P=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. CONCLUSIONS: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01144338.

Effect of dipeptidyl peptidase IV inhibitors, thiazolidinedione, and sulfonylurea on osteoporosis in patients with type 2 diabetes: population-based cohort study.

The population-based cohort study used the Korean National Health Insurance claims database to evaluate the effect of anti-diabetic drugs on osteoporosis. The use of DPP-IV inhibitors does not increase the risk of osteoporosis compared with the use of sulfonylureas in patients with type 2 diabetes mellitus, while a weak association was found between thiazolidinediones and increased risk of osteoporosis. PURPOSE: The current study aimed to evaluate the effect of dipeptidyl peptidase IV inhibitors (DPP-IVi), thiazolidinedione (TZD), and sulfonylurea (SU) on osteoporosis in patients with type 2 diabetes. METHODS: A population-based cohort study was conducted in the Republic of Korea using the Korean National Health Insurance claims database. Data from 2012 to 2017 for patients of 50-99 years of age who were prescribed DPP-IVi, TZD, or SU during 2013-2015 were extracted from the database. Based on pre-defined criteria, a total of 381,404 patients were analyzed after inverse probability of treatment weighting. The association between the study drugs and osteoporosis was estimated using Cox proportional hazards models. Data of 220,166 patients who were prescribed DPP-IVi, 18,630 who were prescribed TZD, and 142,608 patients who were prescribed SU were set. RESULTS: In the multivariate-adjusted analysis, the hazard ratio (HR) of osteoporosis in the DPP-IVi group was not significantly different from that of the SU group (HR: 0.97; 95% confidence interval (CI) 0.94-1.00), whereas the HR of osteoporosis in the TZD group was higher (HR: 1.13; 95% CI 1.06-1.20). In the subgroup analysis, the HRs of osteoporosis were higher with pioglitazone (HR: 1.14; 95% CI 1.06-1.23) in the TZD group and with glibenclamides (HR: 1.39; 95% CI 1.09-1.77) in the SU group, whereas drugs with lower HR in the DPP-IVi group were saxagliptin (HR: 0.93; 95% CI 0.87-0.99) and sitagliptin (HR: 0.93; 95% CI 0.89-0.97). CONCLUSION: DPP-IV inhibitors do not increase the risk of osteoporosis compared with sulfonylureas in patients with type 2 diabetes mellitus, while a weak association was found between thiazolidinediones and increased risk of osteoporosis.

Defining dipeptidyl peptidase-4 inhibitors-related bullous pemphigoid: A single-centre retrospective study.

BACKGROUND: Many studies have corroborated the association of dipeptidyl peptidase-4 inhibitors (DPP4i) use with bullous pemphigoid (BP). It has been speculated that this drug-induced variant presents with a different clinical spectrum than conventional BP. OBJECTIVE: To determine the prevalence of DPP4i-induced cases of BP and to evaluate whether gliptin-related BP has specific clinicopathological and immunological features. METHODS: We conducted a retrospective, observational study of BP cases attended at our centre between January 2000 and June 2020. Epidemiological, clinical, histopathological and laboratory data were collected. RESULTS: A total of 257 cases of BP were collected; 51 (24.3%) were on treatment with DPP4i. When analysing DPP4i-induced BP cases, generalized BP was the predominant pattern and scalp/mucosal involvement was found in 13 patients. Gliptin-related BP cases were associated to a decrease in the eosinophilic infiltrate (p = 0.000) and both the detection rate and concentration of anti-BP180 IgG were lower (p = 0.004, p = 0.001, respectively) than non-DPP4i cases. LIMITATIONS: Retrospective, single-centre study. CONCLUSION: Our large DPP4i-induced BP case series has highlighted that DPP4i-induced BP is characterized by generalized lesions and scalp involvement. Lower titres of anti-BP180 antibodies and a decrease in eosinophils infiltrating into the skin may be distinct features of DPP4i-related BP.

Angioedema associated with dipeptidyl peptidase-IV inhibitors.

BACKGROUND: Dipeptidyl peptidase-IV (DPP-IV) inhibitors, also known as gliptins, are a class of oral antidiabetic agents. Postmarketing reports have documented the occurrence of angioedema in patients treated with gliptins and it was found that these drugs increased the risk of angioedema in patients concurrently treated with angiotensin-converting enzyme inhibitors (ACEIs). The aim of this manuscript is to provide an overview of the risk of angioedema associated with gliptins. METHODS: The keywords used for the literature search in the PubMed database included "angioedema" and "dipeptidyl peptidase", "gliptins", or the name of each DPP-IV inhibitor. Articles in English published up to December 2020 were taken into consideration. RESULTS: The available data appear to rule out a higher risk of angioedema associated with gliptin monotherapy and have revealed an increased susceptibility in patients simultaneously treated with gliptins and ACEIs. However, one single multicenter phase IV trial and case reports, even if very limited in number, have shown that angioedema can also occur during treatment with DPP-IV inhibitors without the concomitant use of ACEIs. The involvement of other drugs and drug interactions has occasionally been suggested. In a few patients, deficiency of enzymes involved in bradykinin catabolism was detected and this finding can constitute a risk factor for angioedema exacerbated by treatment with DPP-IV inhibitors. CONCLUSIONS: This risk of angioedema associated with the use of gliptins has mostly been related to the concurrent administration of ACEIs, and has been considered rare, but it might be underestimated and underreported. The role of additional risk factors or drug interactions deserves further investigations. Caution should be taken when considering the use of DPP-IV inhibitors in patients treated with ACEIs or presenting with other known risk factors for angioedema.

The treament of hyperglycemia in acute ischemic stroke with incretin-based drugs.

Stroke is a major cause of mortality and morbidity worldwide. Considerable experimental and clinical evidence suggests that both diabetes mellitus (DM) and post-stroke hyperglycemia are associated with increased mortality rate and worsened clinical conditions in acute ischemic stroke (AIS) patients. Insulin treatment does not seem to provide convincing benefits for these patients, therefore prompting a change of strategy. The selective agonists of Glucagon-Like Peptide-1 Receptors (GLP-1Ras) and the Inhibitors of Dipeptidyl Peptidase-IV (DPP-IVIs, gliptins) are two newer classes of glucose-lowering drugs used for the treatment of DM. This review examines in detail the rationale for their development and the physicochemical, pharmacokinetic and pharmacodynamic properties and clinical activities. Emphasis will be placed on their neuroprotective effects at cellular and molecular levels in experimental models of acute cerebral ischemia. In perspective, an adequate basis does exist for a novel therapeutic approach to hyperglycemia in AIS patients through the additive treatment with GLP-1Ras plus DPP-IVIs.

Dipeptidyl-peptidase IV inhibitors (DPP4i)-associated bullous pemphigoid: Estimating the clinical profile and exploring intraclass differences.

Data regarding the clinical characteristics of patients with dipeptidyl-peptidase IV inhibitors (DPP4i)-associated BP is inconclusive. We aimed to characterize the clinical features of patients with DPP4i-associated BP, and to assess whether there are phenotypic differences associated with different agents belonging to the DPP4i class. A retrospective prevalence study was performed, including all consecutive patients diagnosed with BP throughout the years 2000 to 2019. The study included 397 patients with BP, of whom 58 (14.6%) were DPP4i-associated. Compared to other patients with BP, patients with DPP4i-associated BP had a more prominent male preponderance (60.3% vs 41.0%; P = .006), presented more frequently with extensive disease (60.3% vs 46.3%; P = .049), had greater truncal (96.6% vs 85.5%; P = .019) and cephalic (51.7% vs 33.6%; P = .008) involvement, and had less frequent peripheral eosinophilia (25.9% vs 51.9%; P < .001). Compared to patients with vildagliptin-associated BP, those with linagliptin-associated BP were managed by higher dosage of systemic corticosteroids in order to achieve disease control (prednisone > 1 mg/kg: 68.2% vs 40.0%; P = .046). In conclusion, DPP4i-associated BP seems to have a unique clinical profile characterized by male predominance, extensive disease, truncal and cephalic involvement, and less peripheral eosinophilia. Linagliptin may be associated with a harder course necessitating more aggressive therapy.

Dipeptidyl peptidase-4 inhibitors lower the risk of autoimmune disease in patients with type 2 diabetes mellitus: A nationwide population-based cohort study.

AIMS: To evaluate the real-world effect of dipeptidyl peptidase-4 inhibitor (DPP4i) on the incidence of autoimmune diseases (AD), including rheumatoid arthritis (RA), inflammatory bowel diseases, multiple sclerosis and systemic lupus erythematosus. METHODS: We identified new users of DPP4i (n = 497 619) or non-DPP4i (n = 643 165) oral combination therapy between 1 January 2011 and 30 June 2015 among patients with type 2 diabetes mellitus in the Korean national health insurance claims database. Patients were followed from the date of initiation of combination therapy until AD outcome, censoring for treatment discontinuation or switching, death or end of study (31 August 2016). Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for RA, inflammatory bowel diseases, other AD (multiple sclerosis and systemic lupus erythematosus), and the composite of all outcomes were estimated using propensity score (PS)-adjusted Cox model. RESULTS: In the PS-weighted and PS-matched analysis, the risk of incident RA was decreased for DPP4i initiators compared with non-DPP4i initiators (aHR 0.67 [95% CI 0.49-0.92] and aHR 0.72 [95% CI 0.51-1.01], respectively). In both analyses, the risk of incident composite AD was also decreased for DPP4i initiators compared with non-DPP4i initiators (aHR 0.82 [95% CI 0.68-0.99] and aHR 0.76 [95% CI 0.62-0.93], respectively). CONCLUSIONS: In this large population-based cohort study, upfront DPP4i combination therapy was associated with a lower risk of composite AD compared with initial non-DPP4i combination therapy.

Cardiovascular risks associated with dipeptidyl peptidase-4 inhibitors monotherapy compared with other antidiabetes drugs in the Japanese population: A nationwide cohort study.

PURPOSE: We evaluated the cardiovascular risk associated with dipeptidyl peptidase-4 inhibitors (DPP-4Is) as monotherapy compared with other antidiabetic drugs in Japan. METHODS: We conducted a nationwide cohort study involving 2 716 000 diabetes patients in Japan. New users of any antidiabetic drug as monotherapy between 1 April 2010 and 31 October 2014 were identified. Occurrences of myocardial infarction (MI), heart failure (HF), and stroke requiring hospitalization associated with DPP-4Is were compared with those associated with biguanides (BGs), sulfonylureas (SUs), or α-glucosidase inhibitors (α-GIs). Adjusted hazard ratios (aHRs) for these outcomes were estimated by Cox proportional hazards model. Propensity score standardization was used to control for confounding. RESULTS: We identified 1 105 103 patients using DPP-4Is, 278 280 patients using BGs, 273 449 patients using SUs, and 217 026 patients using α-GIs. The risks of MI and HF for DPP-4I users were significantly higher than those for BG users (MI: aHR, 1.48 [95%CI, 1.20-1.82], HF: aHR, 1.46 [95%CI, 1.31-1.62]), while significantly lower than those for SU users (MI: aHR, 0.84 [95%CI, 0.72-0.98], HF: aHR, 0.86 [95%CI, 0.81-0.92]). The risk of MI for DPP-4I users was similar to that for α-GI users, while the risk of HF for DPP-4I users was slightly higher than for α-GI users (MI: aHR, 0.98 [95%CI, 0.82-1.17], HF: aHR, 1.12[95%CI, 1.04-1.21]). CONCLUSIONS: Risk of MI and HF requiring hospitalization associated with DPP-4Is as monotherapy was significantly higher than BGs, significantly lower than SUs, and similar to α-GIs.

Effect of Dipeptidyl Peptidase-4 Inhibitors on the Risk of Bone Fractures in a Korean Population.

BACKGROUND: There have been equivocal results in studies of the effects of dipeptidyl peptidase-4 inhibitors (DPP-4i) on fractures. In this study, we analyzed the effect of DPP-4i on bone fracture risk in a Korean population. METHODS: We extracted subjects (n = 11,164) aged 50 years or older from the National Health Insurance Service-National Sample Cohort 2.0 from 2009 to 2014. Our control group included subjects without diabetes (n = 5,582), and our treatment groups with diabetes included DPP-4i users (n = 1,410) and DPP-4i non-users (n = 4,172). The primary endpoint was the incidence of a composite outcome consisting of osteoporosis diagnosis, osteoporotic fractures, vertebral fractures, non-vertebral fractures, and femoral fractures. The secondary endpoint was the incidence of each individual component of the composite outcome. Survival analysis was performed with adjustment for age, gender, diabetes complications severity index, Charlson comorbidity index, hypertension medication, and dyslipidemia treatment. RESULTS: The incidence of the composite outcome per 1,000 person-years was 0.089 in DPP-4i users, 0.099 in DPP-4i non-users, and 0.095 in controls. There was no significant difference in fracture risk between DPP-4i users and DPP-4i non-users or controls after the adjustments (P > 0.05). The incidences of osteoporosis diagnosis, osteoporotic fractures, vertebral fractures, non-vertebral fractures, and femoral fractures were not significantly different between DPP-4i users and non-users. The results of subgroup analyses by gender and age were consistent. CONCLUSION: DPP-4i had no significant effect on the risk of fractures in a Korean population.

Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk.

BACKGROUND: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. METHODS: CARMELINA® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. RESULTS: Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m2, and eGFR 55 ± 25 mL/min/1.73 m2. A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m2 or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. CONCLUSIONS: CARMELINA® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier-NCT01897532; registered July 9, 2013.

Cardiovascular safety signals with dipeptidyl peptidase-4 inhibitors: A disproportionality analysis among high-risk patients.

PURPOSE: In 2008, the US Food and Drug Administration (FDA) issued Draft Guidance on investigating cardiovascular risk with oral diabetic drugs, including dipeptidyl peptidase-4 inhibitors (DPP-4i). In 2014, underpowered, post hoc analyses of clinical trials suggested an increased risk of heart failure with the use of these products. As such, we assessed disproportionate reporting of major adverse cardiac events (MACE) among reports for DPP-4i submitted to the FDA Adverse Event Reporting System (FAERS) from 2006 to 2015. METHODS: We assessed the empirical Bayes geometric mean (EBGM) and its lower bound (EB05) of the relative reporting ratio for MACE among DPP-4i reports in the full FAERS database and in a subset of reports limited to cardiovascular and diabetic drugs. We then compared the EB05 in these 2 analyses and calculated the percent positive agreement for signals of disproportional reporting (SDRs) involving MACE. RESULTS: Of 180.3 million adverse event reports, 13.4 million were for diabetic and cardiovascular drugs. In the cardiovascular subset, there was an SDR for heart failure with linagliptin (EB05 = 2782.47) and saxagliptin (EB05 = 2.40), myocardial infarction with alogliptin (EB05 = 290.11), and cerebral infarction with sitagliptin (EB05 = 2.80). Of the 14 MACE, 8 had a percent positive agreement ≥50% for an SDR in both analyses. Overall, the cardiovascular subset elicited 11 more SDRs for DPP-4i than the full dataset. CONCLUSIONS: Postmarketing surveillance of DPP-4i through FAERS suggest increased reporting of MACE, supporting the current FDA warning of heart failure risk. This suggests the need for additional longitudinal, observational research into the association of DPP-4i and other MACE.

Effectiveness and safety of dipeptidyl peptidase 4 inhibitors in the management of type 2 diabetes in older adults: a systematic review and development of recommendations to reduce inappropriate prescribing.

BACKGROUND: Preventable drug-related hospital admissions can be associated with drugs used in diabetes and the benefits of strict diabetes control may not outweigh the risks, especially in older populations. The aim of this study was to look for evidence on risks and benefits of DPP-4 inhibitors in older adults and to use this evidence to develop recommendations for the electronic decision support tool of the PRIMA-eDS project. METHODS: Systematic review using a staged approach which searches for systematic reviews and meta-analyses first, then individual studies only if prior searches were inconclusive. The target population were older people (≥65 years old) with type 2 diabetes. We included studies reporting on the efficacy and/or safety of DPP-4 inhibitors for the management of type 2 diabetes. Studies were included irrespective of DPP-4 inhibitors prescribed as monotherapy or in combination with any other drug for the treatment of type 2 diabetes. The target intervention was DPP-4 inhibitors compared to placebo, no treatment, other drugs to treat type 2 diabetes or a non-pharmacological intervention. RESULTS: Thirty studies (reported in 33 publications) were included: 1 meta-analysis, 17 intervention studies and 12 observational studies. Sixteen studies were focused on older adults and 14 studies reported subgroup analyses in participants ≥65, ≥70, or ≥75 years. Comorbidities were reported by 26 studies and frailty or functional status by one study. There were conflicting findings regarding the effectiveness of DPP-4 inhibitors in older adults. In general, DPP-4 inhibitors showed similar or better safety than placebo and other antidiabetic drugs. However, these safety data are mainly based on short-term outcomes like hypoglycaemia in studies with HbA1c control levels recommended for younger people. One recommendation was developed advising clinicians to reconsider the use of DPP-4 inhibitors for the management of type 2 diabetes in older adults with HbA1c <8.5% because of scarce data on clinically relevant benefits of their use. Twenty-two of the included studies were funded by pharmaceutical companies and authored or co-authored by employees of the sponsor. CONCLUSIONS: Other than the surrogate endpoint of improved glycaemic control, data on clinically relevant benefits of DPP-4 inhibitors in the treatment of type 2 diabetes mellitus in older adults is scarce. DPP-4 inhibitors might have a lower risk of hypoglycaemia compared to other antidiabetic drugs but data show conflicting findings for long-term benefits. Further studies are needed that evaluate the risks and benefits of DPP-4 inhibitors for the management of type 2 diabetes mellitus in older adults, using clinically relevant outcomes and including representative samples of older adults with information on their frailty status and comorbidities. Studies are also needed that are independent of pharmaceutical company involvement.

Two-Year Therapeutic Efficacy and Safety of Initial Triple Combination of Metformin, Sitagliptin, and Empagliflozin in Drug-Naïve Type 2 Diabetes Mellitus Patients.

BACKGRUOUND: We investigated the long-term efficacy and safety of initial triple therapy using metformin, a dipeptidyl peptidase-4 inhibitor, and a sodium-glucose cotransporter-2 inhibitor, in patients with type 2 diabetes mellitus. METHODS: We enrolled 170 drug-naïve patients with glycosylated hemoglobin (HbA1c) level >7.5% who had started triple therapy (metformin, sitagliptin, and empagliflozin). Glycemic, metabolic, and urinary parameters were measured for 24 months. RESULTS: After 24 months, HbA1c level decreased significantly from 11.0%±1.8% to 7.0%±1.7%. At 12 and 24 months, the rates of achievement of the glycemic target goal (HbA1c <7.0%) were 72.5% and 61.7%, respectively, and homeostasis model assessment of ß-cell function and insulin resistance indices improved. Whole-body fat percentage decreased by 1.08%, and whole-body muscle percentage increased by 0.97% after 24 months. Fatty liver indices and albuminuria improved significantly. The concentration of ketone bodies was elevated at the baseline but decreased after 24 months. There were no serious adverse events, including ketoacidosis. CONCLUSION: Initial triple combination therapy with metformin, sitagliptin, and empagliflozin led to achievement of the glycemic target goal, which was maintained for 24 months without severe hypoglycemia but with improved metabolic function and albuminuria. This combination therapy may be a good strategy for drug-naïve patients with type 2 diabetes mellitus.

Efficacy and safety of sitagliptin with basal-plus insulin regimen versus insulin alone in non-critically ill hospitalized patients with type 2 diabetes: SITA-PLUS hospital trial.

AIMS: To compare the efficacy and safety of basal-plus (BP) insulin regimen with or without sitagliptin in non-critically ill patients with type 2 diabetes (T2D). METHODS: This open-label, randomized clinical trial included inpatients with a previous diagnosis of T2D and blood glucose (BG) between 180 and 400 mg/dL. Participants received basal and correctional insulin doses (BP regimen) either with or without sitagliptin. The primary outcome was the difference in the mean daily BG among the groups. RESULTS: Seventy-six patients (mean age 60 years, 64 % men) were randomized. Compared with BP insulin therapy alone, the sitagliptin-BP combination led to a lower mean daily BG (158.8 vs 175.0 mg/dL, P = 0.014), a higher percentage of readings within a BG range of 70-180 mg/dL (75.9 % vs 64.7 %, P < 0.001), and a lower number of BG readings >180 mg/dL (P < 0.001). Sitagliptin-BP resulted in fewer basal and supplementary insulin doses (P = 0.024 and P = 0.017, respectively) and lower daily insulin injections (P = 0.023) than those with insulin alone. The proportion of patients with hypoglycemia was similar in the two groups. CONCLUSIONS: For inpatients with T2D and hyperglycemia, the sitagliptin and BP regimen combination is safe and more effective than insulin therapy alone. CLINICALTRIALS: gov identifier: NCT05579119.

Precooked Jack Bean [Canavalia ensiformis (L.) DC] Sprout: Generation of Dipeptidyl Peptidase-IV Inhibitory Peptides during Simulated Digestion.

Bioactive peptides generated from jack bean sprouts are reported to function as dipeptidyl peptidase IV (DPP-IV) inhibitors. However, no studies have investigated the effect of precooking followed by simulated digestion using pepsin-pancreatin to increase DPP-IV inhibitory peptide generation in jack bean sprouts. Therefore, the present study aimed to explore the generation of DPP-IV inhibitory peptides from precooked jack bean [Canavalia ensiformis (L.) DC] sprouts during simulated digestion with pepsin-pancreatin. The results showed that peptide fractions of the sample hydrolysate with molecular weight <1 kDa exhibited the strongest DPP-IV inhibitory activity (84.77%±0.49%) after simulated digestion. This activity was slightly greater than that (74.12%±0.85%) observed prior to simulated digestion. These findings demonstrate that the DPP-IV inhibitory activity of precooked jack bean sprouts can be retained following simulated digestion. Moreover, our investigation revealed the sequences of two novel peptides following simulated digestion with critical amino acids. The presence of alanine and glycine at the penultimate N-terminus of AAGPKP and LGDLLK confirmed the presence of DPP-IV inhibitors. Both peptide sequences are nontoxic and interact with the catalytic sites of enzymes through hydrogen bonds.