linagliptin and Pancreatitis

Topics: Biomarkers; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Hypersensitivity; Drug Interactions; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Immune System; Linagliptin; Pancreatitis; Patient Selection; Purines; Quinazolines; Risk Assessment; Risk Factors; Treatment Outcome

To evaluate the efficacy and safety of linagliptin vs placebo as add-on to empagliflozin and metformin in patients with type 2 diabetes.. Patients with inadequate glycaemic control despite stable-dose metformin received open-label empagliflozin 10 mg (study 1) or 25 mg (study 2) as add-on therapy for 16 weeks. Subsequently, those with HbA1c ≥7.0 and ≤10.5% (>53 and ≤91 mmol/mol) (N = 482) were randomized to 24 weeks' double-blind, double-dummy treatment with linagliptin 5 mg or placebo in study 1, or to linagliptin 5 mg or placebo in study 2; all patients continued treatment with metformin and empagliflozin 10 mg (study 1) or metformin and empagliflozin 25 mg (study 2). The primary endpoint was change from baseline (defined as the last value before first intake of randomized, double-blind treatment) in HbA1c at week 24.. At week 24, HbA1c (mean baseline 7.82-8.04 [62-64 mmol/mol]) was significantly reduced with linagliptin vs placebo; adjusted mean (SE) differences in change from baseline in HbA1c with linagliptin vs placebo were -.32% (.10) (-3.59 [1.08] mmol/mol) ( P = .001) for patients on empagliflozin 10 mg and metformin, and -0.47% (0.10) (-5.15 [1.04] mmol/mol) ( P < 0.001) for patients on empagliflozin 25 mg and metformin. Adverse events were reported in more patients receiving placebo than in those receiving linagliptin: 55.5% vs 48.4% in study 1 and 58.9% vs 52.7% in study 2.. Linagliptin as add-on to empagliflozin and metformin for 24 weeks improved glycaemic control vs placebo, and was well tolerated.

Topics: Aged; Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Pancreatitis; Reproductive Tract Infections; Treatment Outcome; Urinary Tract Infections

The incidence and prevalence of end-stage renal disease (ESRD) is increasing. The most common cause of ESRD is diabetes mellitus (DM). Kidney transplantation offers better quality of life and survival for patients with ESRD. Because of the use of immunosuppressive therapy and steroids post-kidney transplantation, the patients are at an increased risk for the development of posttransplant DM (PTDM). Management of DM after transplantation (whether pre-existing or transplant related) remains a challenge. Multiple treatment options are currently available to manage PTDM. Those medications have good safety and efficacy record in the general population and in patients with mild degrees of kidney disease.. We conducted a retrospective single center analysis of safety and efficacy of linagliptin post-kidney transplantation. The study was approved by the institutional review board. We collected data (demographics, laboratory tests, and any symptoms or hospitalizations) for 42 patients for a period of 12 months.. All 42 patients received linagliptin throughout the study period. Patients' average age was 62 years. Twenty-three were women and all were of Middle Eastern descent and had kidney transplants on average of 25 months when they were included in the study. Nineteen patients had DM before the transplant, and the rest had PTDM. Eighteen patients were on metformin and 15 were on insulin, whereas the rest were not on any other medications at the start of the study. Baseline average creatinine was 1.5 mg/dL (132.9 mmol/L) and glycated hemoglobin (HbA1c) was 8.2 g/dL at the start of the study, whereas creatinine was 1.6 mg/dL (138.5 mmol/L) and HbA1c was 7.4 g/dL at the end. HbA1c dropped 0.8 on average within 3 months of starting linagliptin and remained at the same level for the rest of the study. Urine protein did not change significantly throughout the study. Three patients developed acute myocardial infarction during the study, and a fourth one was hospitalized with an opportunistic infection. Two patients had urinary tract infections. Adverse effects were minimal. No allergic reactions, hypoglycemia, or acute pancreatitis episodes were reported. The average weight and body mass index did not change throughout the study. None of the patients stopped the medication.. In this retrospective analysis, linagliptin seems to be safe and efficacious after kidney transplantation. It can be considered as a treatment option to manage DM after transplantation.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Kidney Transplantation; Linagliptin; Male; Middle Aged; Pancreatitis; Quality of Life; Retrospective Studies

Dipeptidyl peptidase-4 inhibitors are commonly used drugs for the treatment of type 2 diabetes mellitus. While acute pancreatitis cases induced by saxagliptin, sitagliptin, and vildagliptin (all of which are members of the dipeptidyl peptidase-4 group) have been reported, there is no clear evidence suggesting that linagliptin may cause pancreatitis, and information in this regard is limited to a few studies. Moreover, no pancreatitis cases have been reported that were directly associated with linagliptin.. We present a case of linagliptin-related pancreatitis in a 79-year-old male diabetic patient with biliary calculi. The patient, who was diagnosed with acute pancreatitis 4 months after initiating linagliptin 5 mg/d treatment, was admitted to our hospital.. The patient's pancreatic enzymes were high. Ultrasonography showed multiple biliary calculi, and abdominal computed tomography showed edematous pancreatitis.. Linagliptin was discontinued and clinical improvement was achieved with standard acute pancreatitis treatment.. This is the 1st case report suggesting that linagliptin might be associated with the risk of pancreatitis and could be an etiologic cause of pancreatitis, similar to the other members of its group.. While the results of previous studies stated that there was no data to prove a causal relationship between dipeptidyl peptidase-4 inhibitors and pancreatitis, concerns regarding this subject have continued to arise. Therefore, new and comprehensive studies are needed to determine the long-term effects of dipeptidyl peptidase-4 inhibitors on type 2 diabetes mellitus patients and to shed light on the side effects of these medications.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug-Related Side Effects and Adverse Reactions; Humans; Linagliptin; Male; Pancreatitis; Tomography, X-Ray Computed; Ultrasonography

Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin.. Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I-III, placebo-controlled clinical trials of ≤102 weeks' duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs).. Data from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for >5 years; approximately 75% were receiving ≥1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels.. This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin-treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin.

Topics: Aged; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Heart Failure; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Linagliptin; Male; Middle Aged; Neoplasms; Pancreatitis; Randomized Controlled Trials as Topic; Sulfonylurea Compounds

Topics: Adamantane; Diabetes Mellitus; Dipeptides; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Linagliptin; Pancreatitis; Purines; Pyrazines; Quinazolines; Sitagliptin Phosphate; Triazoles; United States

Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance incretin actions and beta-cell function. Concurrently, sodium-glucose co-transporter 2 (SGLT2) inhibitors block renal glucose reabsorption promoting excretion. In this study, we investigated the effects of linagliptin (a DPP-4 inhibitor) and BI-38335 (an SGLT2 inhibitor), individually and in combination, on glucose homeostasis, islet function, and pancreatic islet morphology in db/db mice. Diabetic and non-diabetic mice received linagliptin (3 mg/kg), BI-38335 (1 mg/kg), the two drugs in combination or control once daily for 8 weeks. Blood glucose homeostasis and insulin sensitivity were assessed. Pancreatic islet function and morphology as well as inflammatory factors and toll like receptor 2 (TLR2) pathways involved in islet inflammation were investigated. Active treatments markedly reduced blood glucose and glycated hemoglobin A1c (HbA(1c)) levels, with the combined treatment showing the greater effects. Insulin resistance was improved in the BI-38335 and combination groups with the enhancement of insulin sensitivity and significant increase of serum adiponectin levels. The combined treatment exhibited greater effects on enhanced islet glucose-stimulated insulin secretion and improved glucose tolerance. Moreover, the combination restored the islet beta-/alpha-cell ratio, reduced beta-cell apoptosis, decreased expression of islet immune cell markers, and suppressed factors related to the TLR2 pathway. In addition, all active treatments reduced serum lipid profiles, though the combination produced more robust effects. Collectively, our data show that combined treatment with BI-38335 and linagliptin work, at least in part, synergistically to benefit islet cell function/architecture and insulin resistance, thus improving glycemic control.

Topics: Animals; Apoptosis Regulatory Proteins; Blood Glucose; Cell Proliferation; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Gene Expression; Hypoglycemic Agents; Inflammation Mediators; Insulin; Insulin Secretion; Islets of Langerhans; Linagliptin; Lipids; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Pancreatitis; Purines; Quinazolines; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Tissue Culture Techniques