linagliptin and Hypoglycemia

The fixed-dose combination of empagliflozin and linagliptin, two glucose-lowering drugs prescribed for type 2 diabetes mellitus, has demonstrated good tolerability in phase III clinical trials. To further evaluate the safety profile of this combination, the data from these trials were pooled and analyzed.. This was a post-hoc pooled analysis of five randomized, double-blind, clinical trials of the empagliflozin/linagliptin fixed-dose combination. Data for adverse events and laboratory parameters were evaluated.. The analysis included 2895 patients: 1410, 1015, and 470 receiving the empagliflozin/linagliptin combination, empagliflozin monotherapy, and linagliptin monotherapy, respectively. Overall, the incidence of adverse events with the empagliflozin/linagliptin combination was similar to that with empagliflozin or linagliptin alone. Fewer than 2% of patients experienced hypoglycemia, and its incidence was similar across treatment groups. Genital infections occurred in more patients receiving empagliflozin/linagliptin (3.0%) or empagliflozin monotherapy (5.1%) than in those receiving linagliptin monotherapy (1.9%). No cases of Fournier's gangrene, diabetic ketoacidosis, or pemphigoid occurred, and no clinically relevant mean changes in laboratory parameters were noted.. The safety profile of the fixed-dose combination of empagliflozin and linagliptin was similar to the individual monotherapies. No new safety signals were identified.

Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Drug Combinations; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors

To investigate the risk of hypoglycaemia in people aged ≥65 years with type 2 diabetes mellitus (T2DM) treated with linagliptin, in the largest pooled analysis performed to date.. One thousand four hundred and eighty-nine patients aged ≥65 years with T2DM were pooled from 11 randomised, double-blind, parallel group, placebo-controlled trials evaluating linagliptin 5 mg alone, or in addition to various background therapies. The primary safety endpoint was the incidence of investigator-defined hypoglycaemia.. There was no significant difference in the risk of hypoglycaemia between linagliptin and placebo in the all-patient population at 24 weeks (hazard ratio [HR] 1.07; 95% confidence interval [CI]: 0.84, 1.36; P = 0.5943)-despite significant (P < 0.0001) improvements in glycaemic control-and 1 year (HR 1.02; 95% CI: 0.81, 1.27; P = 0.8803). Similar findings were observed for linagliptin vs placebo in subgroup analyses by background medication (eg, sulphonylureas (SUs) and/or insulin vs no such drugs), age, baseline glycated haemoglobin (HbA1c), ethnicity, and baseline estimated glomerular filtration rate. Patients with a baseline HbA1c ≥7.5% had significantly higher odds of achieving HbA1c <7.5% without hypoglycaemia in the linagliptin group compared with placebo at 24 weeks (34.1% vs 13.7%; 95% CI: 2.04, 4.12; P < 0.0001).. This pooled analysis indicates that linagliptin was effective in treating older people with T2DM towards their HbA1c targets with a favourable safety and tolerability profile and low risk of hypoglycaemia. The safety profile was maintained even on background therapies with known risk of hypoglycaemia, such as insulin and SU.

Topics: Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Insulin; Linagliptin; Randomized Controlled Trials as Topic; Risk Factors; Sulfonylurea Compounds

This article reviews evidence supporting sodium glucose cotransporter 2 (SGLT2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor combination therapy for management of type 2 diabetes mellitus (T2DM).. We conducted a nonsystematic review of the literature focusing on single-pill or fixed-dose combinations of SGLT2 inhibitors and DPP-4 inhibitors available in the United States.. SGLT2 inhibitors and DPP-4 inhibitors have complementary mechanisms of action that address several of the underlying pathophysiologic abnormalities present in T2DM without overlapping toxicities. The combination of these 2 agents has several advantages including a low risk of hypoglycemia, the potential for weight loss, the ability to coformulate into a pill with once-daily administration, and the possibility to use with other classes of glucose-lowering agents. Cardiovascular outcomes trials reported to date support the safety of the DPP-4 class and suggest possible cardioprotective effects for SGLT2 inhibitors - at least based on the first reported study that used empagliflozin. Recent clinical evidence shows that SGLT2 inhibitor/DPP-4 inhibitor therapy is an effective combination for T2DM treatment, providing glycated hemoglobin (HbA1c) reductions of 1.1 to 1.5%, and weight reductions of approximately 2 kg when added to metformin, which is its primary place in therapy.. The combination of an SGLT2 inhibitor/DPP-4 inhibitor is a safe and effective treatment choice for patients with T2DM who are unable to obtain adequate glycemic control with metformin therapy, cannot use metformin, or have a higher baseline HbA1c.. BP = blood pressure; CI = confidence interval; CVOT = cardiovascular outcomes; DKA = diabetic ketoacidosis; DPP-4 = dipeptidyl peptidase-4; EXAMINE = EXamination of cArdiovascular outcoMes with alogliptiN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome; FDA = Food and Drug Administration; HbA1c = glycated hemoglobin; HR = hazard ratio; MACE = major adverse cardiovascular events; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Type 2 Diabetes Mellitus; SBP = systolic blood pressure; SGLT2 = sodium glucose cotransporter 2; TECOS = Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin; T2DM = type 2 diabetes mellitus; XR = extended release.

Topics: Adamantane; Benzhydryl Compounds; Blood Glucose; Canagliflozin; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Metformin; Piperidines; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Uracil

To assess the efficacy, hypoglycaemia risk and other safety markers of linagliptin as an additional therapy in older patients (aged ≥70 years) inadequately controlled with basal insulin.. A prespecified safety analysis from the linagliptin trials programme was carried out to explore the hypoglycaemia risk when linagliptin was added to background basal insulin therapy in elderly patients (≥70 years). To do this, two eligible, randomized, placebo-controlled, clinical trials (NCT00954447 and NCT01084005) of 24 and ≥52 weeks, respectively, were analysed.. A total of 247 elderly individuals [mean ± standard deviation (s.d.) age 74 ± 4 years, glycated haemoglobin (HbA1c) 8.2 ± 0.8%] on basal insulin (mean ± s.d. baseline dose 36 ± 25 IU/day) were identified. Alongside placebo-adjusted change in HbA1c with linagliptin of -0.77% [95% confidence interval (CI) -0.95 to 0.59; p < 0.0001] after 24 weeks, the hazard ratios (HRs) of both overall and confirmed hypoglycaemia [blood glucose ≤3.9 mmol/l (70 mg/dl)], were significantly lower with linagliptin than with placebo: HR 0.61 (95% CI 0.39-0.97) versus 0.59 (95% CI 0.37-0.94), respectively (both p < 0.05). Moreover, significantly less confirmed hypoglycaemia was present in linagliptin-treated patients with renal impairment [HR 0.45 (95% CI 0.27-0.76)], moderate hyperglycaemia [HbA1c 7.5 to <9.0%; HR 0.51 (95% CI 0.27-0.99)], lower fasting plasma glucose levels [<152 mg/dl; HR 0.49 (95% CI 0.28-0.86)] and those treated with higher insulin doses [insulin ≥35.6 IU/day; HR 0.46 (95% CI 0.23-0.91); p < 0.05 for all]. Severe hypoglycaemia was rare and the incidence was lower with linagliptin (0.8%) versus placebo (2.5%): HR 0.21 (95% CI 0.02-2.30).. Despite improvements in hyperglycaemia and no relevant on-trial insulin dose reductions, adding linagliptin to basal insulin appears to decrease hypoglycaemia risk. The biological basis of this phenomenon warrants further research but may involve counter-regulatory effects of incretin hormones.

Topics: Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Incidence; Insulin, Long-Acting; Linagliptin; Male; Randomized Controlled Trials as Topic; Treatment Outcome

Empagliflozin/linagliptin (Glyxambi(®)) is a once-daily sodium glucose co-transporter type 2 (SGLT2) inhibitor and dipeptidyl peptidase (DPP)-4 inhibitor fixed-dose combination product that is approved in the USA as an adjunct to diet and exercise in adults with type 2 diabetes (T2D) when treatment with both empagliflozin and linagliptin is appropriate. This article reviews the clinical efficacy and tolerability of oral empagliflozin/linagliptin in patients with T2D and summarizes the pharmacological properties of the agents. Results of two randomized controlled trials of 52 weeks' duration in adults with T2D demonstrated that empagliflozin/linagliptin improved glycaemic control significantly more than linagliptin when administered as initial therapy (whereas results vs. empagliflozin were mixed in this setting) and significantly more than linagliptin or empagliflozin when administered as an add-on therapy to metformin. In addition to glycaemic control, empagliflozin/linagliptin provided significant weight loss compared with linagliptin in both trials. Empagliflozin/linagliptin was generally well tolerated in patients with T2D, with a low risk of hypoglycaemia and no reports of exacerbations of, or hospitalizations for, heart failure during the trials. As the first SGLT2 inhibitor/DPP-4 inhibitor fixed-dose combination available, empagliflozin/linagliptin is a useful new option for patients with T2D.

Topics: Adult; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors

Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5 mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI).. In this pooled analysis of three 24-week, placebo-controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60-<90 ml/min/1.73 m(2) , n = 838) or moderate RI (30-<60 ml/min/1.73 m(2), n = 93) were compared with subjects with normal renal function (≥90 ml/min/1.73 m(2), n = 1212).. Subjects with RI were older, had longer duration of diabetes, and increased prevalence of diabetes-related comorbidities. After 24 weeks, linagliptin achieved consistent placebo-corrected mean glycated haemoglobin (HbA1c) changes across the three renal function categories: normal (-0.63%; p < 0.0001), mild RI (-0.67%; p < 0.0001) and moderate RI (-0.53%; p < 0.01), with no inter-group difference (p = 0.74). Renal function with linagliptin remained stable across all categories. In linagliptin-treated subjects, overall adverse event (AE) rates and serious AE rates were similar to placebo. The incidence of hypoglycaemia with linagliptin and placebo was 11.1 versus 6.9%, 11.9 versus 9.0% and 15.9 versus 12.0% in the normal, mild RI and moderate RI categories, respectively.. This pooled analysis provides evidence that linagliptin is an effective, well-tolerated and convenient treatment in subjects with T2DM and mild or moderate RI.

Topics: Adult; Aged; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Placebos; Purines; Quinazolines; Randomized Controlled Trials as Topic; Severity of Illness Index

As type 2 diabetes mellitus (T2DM) progresses, most patients will require insulin replacement therapy. Whether oral antidiabetic drug (OAD) therapy should be retained when initiating insulin is still debated. While the rationale to keep metformin with insulin is strong (mostly as an insulin-sparing agent to limit weight gain), the evidence is less clear for other OADs. In particular, the question now comes up what the expected benefit could be of combining the newer agents, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors with insulin. Additionally, when metformin is no longer a treatment option, as in the case of patients with severe renal impairment, insulin is often used as monotherapy, with little evidence of benefit in maintaining other OADs. In this specific situation, it is also of interest to evaluate the potential benefit of combined treatment with a DPP-4 inhibitor and insulin. Among the classic limitations of insulin therapy in patients with T2DM, hypoglycemia remains a major barrier to glycemic control, along with weight gain exacerbation. The oral DPP-4 inhibitors improve glycemic control by increasing the sensitivity of the islet cells to glucose, and thus are not associated with an increased risk for hypoglycemia and are weight neutral. In addition to the expected benefits associated with limiting insulin dose and regimen complexity, the specific advantages the DPP-4 inhibitor drug class on hypoglycemia and weight gain could justify combining DPP-4 inhibitors with insulin; additionally, a DPP-4 inhibitor may be of special value to decrease glycemic excursions that are not properly addressed by basal insulin therapy and metformin use, even after optimizing titration of the basal insulin. However, given the common original perception that treatment with DPP-4 inhibitors may be less beneficial with increasing disease progression because of the loss of β-cell function, the potential relevance of these agents in the setting of advanced T2DM treated with insulin was not necessarily anticipated. Promising data from studies on the use of these new agents in insulin-treated patients with T2DM have started to emerge. Our article provides a comprehensive overview of the currently available evidence from controlled randomized clinical trials and we discuss the potential role of DPP-4 inhibitors in the this setting. Further clinical experience will allow to fully assess the positioning of these agents in insulin-treated T2DM populations.

Topics: Adamantane; Body Weight; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Drug Therapy, Combination; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

Linagliptin is a dipeptidyl peptidase-4 inhibitor that was approved in 2011 by the US Food and Drug Administration as a treatment adjunctive to diet and exercise for the improvement of glycemic control in adults with type 2 diabetes mellitus (T2DM).. The purpose of this article is to review the pharmacology, pharmacokinetic properties, efficacy, tolerability including drug-drug interactions, contraindications/precautions, and dosage and administration of linagliptin, and the potential role of linagliptin in the management of glycemia in adults with T2DM.. MEDLINE (1966-January 12, 2012), PubMed (1950-January 12, 2012), Science Direct (1994-January 12, 2012), Web of Science (1980-January 12, 2012), and the American Diabetes Association Scientific Abstracts (2008-2011) were searched using the term linagliptin. Articles and abstracts published in English, both original research and review articles, were identified for review. Reference lists from identified articles were also searched for additional references of interest. Manufacturers' prescribing information was additionally examined.. Data from clinical trials of linagliptin suggest clinical efficacy in terms of reductions in hemoglobin A(1c) (A(1c)), fasting plasma glucose, and postprandial glucose when linagliptin was administered as monotherapy or in combination with other oral antidiabetic agents, with placebo-subtracted A(1c) changes ranging from -0.47% to -0.69% in placebo-controlled trials. Adverse events that occurred in ≥2% of patients treated with linagliptin and at a prevalence of ≥2-fold greater compared with placebo were nasopharyngitis, hyperlipidemia, cough, hypertriglyceridemia, and weight increase (when used in combination with a thiazolidinedione [TZD]). Although linagliptin administered as monotherapy or in combination with metformin or a TZD may convey a low risk for hypoglycemia (0%-1.2%), caution is warranted when linagliptin is administered in combination with insulin secretagogues due to an increased risk for hypoglycemic events. Dosage adjustments based on renal or hepatic function are not required. Additionally, according to the currently approved prescribing information, the efficacy of linagliptin may be limited in patients receiving concurrent inducers of the cytochrome P450 3A4 isozyme or P-glycoprotein (eg, rifampin).. Based on the findings from the present review, patients and clinicians should be aware of the risk for hypoglycemia when linagliptin is prescribed as a treatment adjunctive to a regimen of an insulin secretagogue. An initial dose decrease in the secretagogue should be considered to prevent hypoglycemic events. Dosage adjustment of linagliptin is not required in patients with renal impairment.

Topics: Adult; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

The CAROLINA trial established non-inferiority of linagliptin versus glimepiride for major adverse cardiovascular events in patients with relatively early type 2 diabetes at increased cardiovascular risk. In pre-specified and post-hoc analyses, we investigated treatment effects on total hypoglycaemic burden in CAROLINA.. Patients were randomized and treated with 5 mg linagliptin (n = 3014) or 1-4 mg glimepiride (n = 3000) once daily added to standard care. Hypoglycaemia captured from investigator-reported adverse events was analysed with Poisson and negative binomial regressions for the first and total (first plus recurrent) events, respectively. The influence of insulin initiation and glycated haemoglobin (HbA1c) change on the treatment effect for hypoglycaemia was also explored.. Over 6.3 years median follow-up, average HbA1c over time did not differ between linagliptin versus glimepiride (weighted mean difference [95% confidence interval]: 0.00%, [-0.05, 0.05]), nor did insulin initiation (18.6% vs. 19.2% of patients, respectively), whereas body weight was lower with linagliptin (-1.54 kg, [-1.80, -1.28]). Hypoglycaemia frequency was lower with linagliptin across all hypoglycaemia categories, including severe episodes. Rate ratios (95% confidence interval) for first and total events for investigator-reported hypoglycaemia were 0.21 (0.19-0.24) and 0.12 (0.10-0.14), respectively, with 8.7 first and 60.8 total estimated events prevented/100 patient-years with linagliptin versus glimepiride. These differences occurred during night-time and daytime, and in subgroup analyses of total events. Treatment differences in hypoglycaemia were neither impacted by HbA1c changes nor insulin initiation.. Across the severity spectrum, linagliptin substantially reduced the hypoglycaemic burden versus glimepiride in patients with relatively early type 2 diabetes at increased cardiovascular risk.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulins; Linagliptin; Treatment Outcome

An estimated 4.3 million people aged ≥ 65 years with diabetes live in Japan. We evaluated the efficacy and safety of linagliptin in older Japanese patients with poorly controlled type 2 diabetes (T2DM).. In this phase 4, randomised, placebo-controlled national study (part of a global study) conducted in Japan over a period of 52 weeks, 102 patients on stable treatment with basal insulin ± metformin/alpha-glucosidase inhibitors were randomised (1:1) to receive linagliptin 5 mg qd or placebo. The primary end point was the change in glycated haemoglobin (HbA1c) after 24 weeks of treatment, with additional analyses at 52 weeks.. Mean age and HbA1c of the study population were 71 years and 8.1%, respectively. Approximately two-thirds of participants were aged ≥ 70 years, two-thirds had macrovascular complications, approximately half had a baseline estimated glomerular filtration rate < 60 ml/min/1.73 m. Linagliptin was effective in improving glucose control in Japanese patients aged ≥ 60 years with T2DM on stable glucose-lowering therapy with basal insulin. Linagliptin was well tolerated and no new safety concerns were raised. The results presented here are highly consistent with the results from the global study, which was conducted over a 24-week period.. ClinicalTrials.gov identifier, NCT02240680.. Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.

Topics: Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Linagliptin; Male; Metformin; Middle Aged

Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease.. To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events.. Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018.. Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines.. Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline.. Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m2; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P < .001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis.. Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years.. ClinicalTrials.gov Identifier: NCT01897532.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Kidney Failure, Chronic; Linagliptin; Male; Middle Aged; Proportional Hazards Models; Risk Factors

The use of incretin-based therapy, rather than or complementary to, insulin therapy is an active area of research in hospitalized patients with type 2 diabetes (T2D). We determined the glycaemic efficacy and safety of linagliptin compared to a basal-bolus insulin regimen in hospitalized surgical patients with T2D.. This prospective open-label multicentre study randomized T2D patients undergoing non-cardiac surgery with admission blood glucose (BG) of 7.8 to 22.2 mmol/L who were under treatment with diet, oral agents or total insulin dose (TDD) ≤ 0.5 units/kg/day to either linagliptin (n = 128) daily or basal-bolus (n = 122) with glargine once daily and rapid-acting insulin before meals. Both groups received supplemental insulin for BG > 7.8 mmol/L. The primary endpoint was difference in mean daily BG between groups.. Mean daily BG was higher in the linagliptin group compared to the basal-bolus group (9.5 ± 2.6 vs 8.8 ± 2.3 mmol/L/dL, P = 0.03) with a mean daily BG difference of 0.6 mmol/L (95% confidence interval 0.04, 1.2). In patients with randomization BG < 11.1 mmol/L (63% of cohort), mean daily BG was similar in the linagliptin and basal-bolus groups (8.9 ± 2.3 vs 8.7 ± 2.3 mmol/L, P = 0.43); however, patients with BG ≥ 11.1 mmol/L who were treated with linagliptin had higher BG compared to the basal-bolus group (10.9 ± 2.6 vs 9.2 ± 2.2 mmol/L, P < 0.001). Linagliptin resulted in fewer hypoglycaemic events (1.6% vs 11%, P = 0.001; 86% relative risk reduction), with similar supplemental insulin and fewer daily insulin injections (2.0 ± 3.3 vs 3.1 ± 3.3, P < 0.001) compared to the basal-bolus group.. For patients with T2D undergoing non-cardiac surgery who presented with mild to moderate hyperglycaemia (BG < 11.1 mmol/L), daily linagliptin is a safe and effective alternative to multi-dose insulin therapy, resulting in similar glucose control with lower hypoglycaemia.

Topics: Aged; Amputation, Surgical; Blood Glucose; Diabetes Mellitus, Type 2; Digestive System Surgical Procedures; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Gynecologic Surgical Procedures; Hospitalization; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Short-Acting; Linagliptin; Male; Middle Aged; Orthopedic Procedures; Perioperative Care; Surgical Procedures, Operative; Treatment Outcome; Urologic Surgical Procedures

To assess the addition of linagliptin as an alternative to insulin uptitration in older people with type 2 diabetes on stable insulin therapy.. This phase 4, randomized, multicentre, double-blinded, placebo-controlled, 24-week study recruited individuals on stable insulin, with baseline HbA1c 7.0%-10.0%, aged ≥60 years and body mass index ≤45 kg/m. Addition of linagliptin improves glucose control without an excess of hypoglycaemia in older patients with type 2 diabetes on stable insulin therapy.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Male; Middle Aged

Safe and easily implemented treatment regimens are needed for the management of patients with type 2 diabetes mellitus (T2DM) in long-term care (LTC) and skilled nursing facilities.. This 6-month open-label randomized controlled trial compared the efficacy and safety of a DPP4 inhibitor (linagliptin) and basal insulin (glargine) in LTC residents with T2DM.. Three LTC institutions affiliated with a community safety-net hospital, US Department of Veterans Affairs and Emory Healthcare System in Atlanta, Georgia.. A total of 140 residents with T2DM treated with oral antidiabetic agents or low-dose insulin (≤0.1 U/kg/d), with fasting or premeal blood glucose (BG) > 180 mg/dL and/or HbA1c >7.5%.. Baseline antidiabetic therapy, except metformin, was discontinued on trial entry. Residents were treated with linagliptin 5 mg/d (n = 67) or glargine at a starting dose of 0.1 U/kg/d (n = 73). Both groups received supplemental rapid-acting insulin before meals for BG > 200 mg/dL.. Primary outcome was mean difference in daily BG between groups. Main secondary endpoints included differences in frequency of hypoglycemia, glycosylated hemoglobin (HbA1c), complications, emergency department visits, and hospital transfers.. Treatment with linagliptin resulted in no significant differences in mean daily BG (146 ± 34 mg/dL vs. 157 ± 36 mg/dL, P = .07) compared to glargine. Linagliptin treatment resulted in fewer mild hypoglycemic events <70 mg/dL (3% vs. 37%, P < .001), but there were no differences in BG < 54 mg/dL (P = .06) or <40 mg/dL (P = .05) compared to glargine. There were no significant between-group differences in HbA1c, length of stay, complications, emergency department visits, or hospitalizations.. Treatment with linagliptin resulted in noninferior glycemic control and in significantly lower risk of hypoglycemia compared to insulin glargine in long-term care and skilled nursing facility residents with type 2 diabetes.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Linagliptin; Male; Residential Facilities; Skilled Nursing Facilities

Two 52-week Phase III studies evaluated the efficacy and safety of once-daily combinations of empagliflozin/linagliptin as monotherapy or add-on to metformin in patients with type 2 diabetes (T2DM). The aim of this analysis was to further assess the safety and tolerability of empagliflozin/linagliptin compared with their individual components in patients with T2DM, using pooled data from these trials.. A total of 1363 patients were treated with empagliflozin 25 mg/linagliptin 5 mg (n = 273), empagliflozin 10 mg/linagliptin 5 mg (n = 272), empagliflozin 25 mg (n = 276), empagliflozin 10 mg (n = 275), or linagliptin 5 mg (n = 267). Adverse events (AEs) were assessed descriptively in patients who took ≥ 1 dose of study drug.. Total exposure was 251, 255, 256, 249, and 243 patient-years in the empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg groups, respectively. The proportion of patients with ≥ 1 AE was similar across groups (70.4-74.9%). The percentage of patients with confirmed hypoglycemic AEs (plasma glucose ≤ 70 mg/dL and/or requiring assistance) was low in all groups (1.1-2.2%); none required assistance. Events consistent with urinary tract infection were reported in similar percentages of patients in all groups (11.4-13.8%), and in a greater proportion of female than male patients. Events consistent with genital infection were reported in higher percentages of patients on empagliflozin/linagliptin or empagliflozin (4.0-6.5%) than linagliptin 5 mg (2.6%), and in a greater proportion of females than males. The risks of hypersensitivity reactions and events consistent with volume depletion were low across treatment groups.. Empagliflozin/linagliptin as monotherapy or add-on to metformin for 52 weeks was well tolerated in patients with T2DM, with safety profiles similar to individual components, including a low risk of hypoglycemia.. The Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance.. ClinicalTrials.gov identifiers, NCT01422876 & NCT01422876.

Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Monitoring; Female; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; 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

Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce the risk of hypoglycaemia, possibly through augmentation of glucose-dependent insulinotropic polypeptide (GIP) action, but not that of glucagon-like peptide-1 (GLP-1) on glucagon secretion. To examine this model in Japanese individuals with type 2 diabetes (T2D), the effects of the DPP-4 inhibitor linagliptin on glucagon and other counter-regulatory hormone responses to hypoglycaemia were evaluated and compared with those of the GLP-1 receptor agonist liraglutide in a multi-centre, randomized, open-label, 2-arm parallel comparative, exploratory trial. Three-step hypoglycaemic clamp glucose tests preceded by meal tolerance tests were performed before and after 2-week treatment with the drugs. Glucagon levels were increased during the hypoglycaemic clamp test at 2.5 mmol/L. This increase was similar in the linagliptin and liraglutide groups, both before and after the 2-week treatment. Changes in other counter-regulatory hormones (ie, growth hormone, cortisol, epinephrine and norepinephrine) were also similar between the groups, but were suppressed substantially after 2-week treatment compared to baseline. In conclusion, we confirmed that the glucagon response to hypoglycaemia was not affected by linagliptin or liraglutide treatment in Japanese individuals with T2D.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Epinephrine; Female; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose Clamp Technique; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Japan; Linagliptin; Liraglutide; Male; Middle Aged; Norepinephrine

To evaluate the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on aortic pulse wave velocity (PWV) as a surrogate marker of arterial stiffness and early atherosclerosis in people with early type 2 diabetes.. A total of 45 people with type 2 diabetes (median [interquartile range] age 63 [54-66] years, 61% men, mean ± standard deviation glycated haemoglobin [HbA1c] 6.3% ± 0.4% [45 ± 4.6 mmol/mol]), without cardiovascular disease and naïve to antidiabetic treatment, were randomized (1:1) to treatment with linagliptin 5 mg once daily or placebo for 26 weeks in a double-blind fashion. PWV was assessed at baseline, 4 and 26 weeks of treatment, and again at 30, 4 weeks after treatment. The primary endpoint was between-group difference in PWV (corrected for systolic blood pressure [SBP]) at week 26. Secondary endpoints included differences in central SBP and augmentation index (AIx).. Compared with placebo, 26 weeks of linagliptin decreased PWV by an average of 0.91 m/s (95% confidence interval -1.76 to -0.06; P = .035). PWV returned to baseline after 4 weeks washout. Differences in central SBP and AIx were not different between linagliptin and placebo. Linagliptin decreased HbA1c (-0.4%; P < .001), fasting plasma glucose (-0.7 mmol/L; P = .002) and triglycerides (-0.49 mmol/L; P = .019) as compared with placebo. The changes in body weight, cholesterol and high-sensitivity C-reactive protein did not differ between groups.. Linagliptin decreased aortic PWV in people with early-stage type 2 diabetes as compared with placebo after 26 weeks of treatment. These results suggest that linagliptin has a favourable effect on arterial stiffness.

Topics: Aorta; Atherosclerosis; Biomarkers; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertension; Hypertriglyceridemia; Hypoglycemia; Linagliptin; Male; Middle Aged; Pulse Wave Analysis; Severity of Illness Index; Vascular Stiffness

With the expanding armamentarium of noninsulin therapies for type 2 diabetes mellitus, the use of insulin with various oral agents is becoming more common. In this study, we assessed the efficacy and cardiovascular (CV) safety of the dipeptidyl peptidase-4 inhibitor linagliptin as add-on to insulin in patients with type 2 diabetes.. In this post hoc analysis, data for patients receiving basal or basal-bolus insulin were pooled from 4 randomized, double-blind, phase 3 clinical trials of linagliptin 5 mg once daily or placebo given as add-on to background glucose-lowering treatment. Changes in glycated hemoglobin (A1C) and CV risk factors were assessed from baseline to end of trial. The primary CV endpoint was a composite of CV death, nonfatal myocardial infarction, nonfatal stroke and hospitalization due to unstable angina.. The number of patients receiving basal or basal-bolus insulin as background therapy was 1613 (linagliptin: n=811; placebo: n=802). The placebo-adjusted mean (SE) change from baseline in A1C was -0.41 (0.05)% (95% CI -0.50, -0.32; p<0.0001). Treatment with linagliptin provided a relative weight benefit and reduced insulin requirements without affecting blood pressure, heart rate or lipids. The incidence of hypoglycemia with linagliptin was similar to that for placebo (38.7% vs. 39.4%, respectively). The hazard ratio (HR) for the primary endpoint showed that treatment with linagliptin was not associated with an increased CV risk (HR 1.07 [95% CI 0.62, 1.85]).. Linagliptin, when added to ongoing insulin treatment in patients with type 2 diabetes, improves glycemic control and has a neutral impact on major adverse CV events.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Kaplan-Meier Estimate; Linagliptin; Male; Middle Aged; Mortality; Risk Factors

Linagliptin plus pioglitazone single-pill combinations were evaluated. Patients (n = 936) with insufficient glycaemic control, despite lifestyle interventions, were randomised for 30 weeks to either monotherapy with linagliptin 5 mg; pioglitazone 15, 30 or 45 mg; or single-pill combination with linagliptin 5 mg plus pioglitazone 15, 30 or 45 mg. An extension (⩽54 weeks) planned to evaluate linagliptin plus pioglitazone 30 or 45 mg single-pill combinations was not completed due to a protocol amendment. Adjusted mean (95% confidence interval) differences in HbA1c change from baseline at week 30 for linagliptin plus pioglitazone 15, 30 and 45 mg were -0.17% (-0.41, 0.07), -0.37% (-0.60, -0.14) and -0.41% (-0.64, -0.18) versus pioglitazone monotherapies, respectively, and -0.44% (-0.67, -0.20), -0.68% (-0.91, -0.44) and -0.89% (-1.12, -0.66) versus linagliptin monotherapy, respectively. Single-pill combinations were generally well tolerated. Hypoglycaemia frequency was ⩽1.5% per group. Linagliptin plus pioglitazone combinations were efficacious, with safety profiles comparable to the individual monotherapies.

Topics: Administration, Oral; Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Combinations; Europe; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Pioglitazone; Tablets; Thiazolidinediones; Time Factors; Treatment Outcome; United States

To evaluate the risk of documented hypoglycaemia with glimepiride versus linagliptin.. This was an exploratory analysis of data from a 2-year, randomized, double-blind study of the dipeptidyl peptidase-4 inhibitor linagliptin 5 mg once daily (n = 764) versus the sulphonylurea glimepiride 1-4 mg once daily (n = 755) in patients with type 2 diabetes uncontrolled by metformin. Patients randomized to glimepiride started on 1 mg and after 4 weeks were allowed to be individually uptitrated stepwise to glimepiride 4 mg if a fasting plasma glucose concentration ≤6.1 mmol/l was not achieved. Investigator-reported hypoglycaemia was evaluated by dose, over time, and by the degree of glycated haemoglobin (HbA1c) reduction.. The percentages of patients with at least one hypoglycaemic event at the individual maximum glimepiride dose were: 1 mg, 45.0%; 2 mg, 50.8%; 3 mg, 36.1%; and 4 mg, 27.7%. The incidence of hypoglycaemia was higher with glimepiride than with linagliptin (36.1 vs. 7.5%; p < 0.0001); after performing sensitivity analyses by excluding events during dose escalation (weeks 0-16), this difference remained significant (weeks 16-104: 25.8 vs. 5.9%; p < 0.0001). Notably, the incidence of hypoglycaemia was higher with glimepiride than with linagliptin in each quartile of HbA1c change from baseline (all p < 0.0001); the incidence of hypoglycaemic episodes was not increased with greater reductions in HbA1c in either group. In all 4-week intervals across the 2-year study, the incidence of hypoglycaemia was lower with linagliptin than with glimepiride.. Linagliptin was associated with a lower risk of hypoglycaemia than glimepiride at all dose levels and time intervals, and regardless of change in HbA1c level.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Risk; Sulfonylurea Compounds; Time Factors; Young Adult

To evaluate the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin.. Subjects were randomized to a combination of empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 141), empagliflozin 10 mg (n = 140), or linagliptin 5 mg (n = 132) as add-on to metformin for 52 weeks. The primary end point was change from baseline in HbA1c at week 24.. At week 24, reductions in HbA1c (mean baseline 7.90-8.02% [62.8-64.1 mmol/mol]) with empagliflozin/linagliptin were superior to those with empagliflozin or linagliptin alone as add-on to metformin; adjusted mean (SE) changes from baseline were -1.19% (0.06) (-13.1 mmol/mol [0.7]) with empagliflozin 25 mg/linagliptin 5 mg, -1.08% (0.06) (-11.8 mmol/mol [0.7]) with empagliflozin 10 mg/linagliptin 5 mg, -0.62% (0.06) (-6.8 mmol/mol [0.7]) with empagliflozin 25 mg, -0.66% (0.06) (-7.2 mmol/mol [0.7]) with empagliflozin 10 mg, and -0.70% (0.06) (-7.6 mmol/mol [0.7]) with linagliptin 5 mg (P < 0.001 for all comparisons). In these groups, respectively, 61.8, 57.8, 32.6, 28.0, and 36.1% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) had HbA1c <7% (<53 mmol/mol) at week 24. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across treatment arms (68.6-73.0%), with no hypoglycemic AEs requiring assistance.. Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and were well tolerated.

Topics: Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Treatment Outcome; Weight Loss

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Purines; Quinazolines; Sulfonylurea Compounds

To evaluate the efficacy and long-term safety of linagliptin added to basal insulin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin with/without oral agents.. This was a post hoc analysis of Asian patients from a global ≥52 week study in which patients on basal insulin were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo (NCT00954447). Basal insulin dose remained stable for 24 weeks, after which adjustments could be made according to the investigator's discretion to improve glycemic control. The primary endpoint was the mean change in glycated hemoglobin (HbA1c) from baseline to 24 weeks.. Data were available for 154 Asian patients (80 linagliptin, 74 placebo). Baseline HbA1c (standard deviation [SD]) was 8.6 (0.9)% (70 [10] mmol/mol). The placebo-corrected mean change (standard error [SE]) in HbA1c from baseline was -0.9 (0.1)% (-10 [1] mmol/mol) (95% confidence interval [CI]: -1.2, -0.7; p<0.0001) at Week 24 and -0.9 (0.1)% (-10 [1] mmol/mol) (95% CI: -1.1, -0.6; p<0.0001) at Week 52. The frequency of adverse events (linagliptin 81.3%, placebo 91.9%) and hypoglycemia (Week 24: linagliptin 25.0%, placebo 25.7%; treatment end: linagliptin 28.8%, placebo 35.1%) was similar between groups. By Week 52, changes (SE) in mean body weight were similar in both groups (linagliptin -0.67 [0.26] kg, placebo -0.38 [0.25] kg).. This study was limited by the post hoc nature of the analysis and the small number of patients in the subgroup. However, the results suggest that linagliptin significantly improves glycemic control in Asian patients with T2DM inadequately controlled by basal insulin, without increasing the risk for hypoglycemia or weight gain. ClinicalTrials identifier: NCT00954447.

Topics: Adult; Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Treatment Outcome; Weight Gain

Glucose-lowering treatment options for type 2 diabetes mellitus patients with chronic kidney disease are limited. We evaluated the potential for linagliptin in combination with insulin in type 2 diabetes mellitus patients with mild-to-severe renal impairment. Data for participants in two phase 3 trials with linagliptin who were receiving insulin were analysed separately (n = 811). Placebo-adjusted mean HbA1c changes from baseline were -0.59% (mild renal impairment) and -0.69% (moderate renal impairment) after 24 weeks and -0.43% (severe renal impairment) after 12 weeks. Drug-related adverse events with linagliptin were similar to placebo (mild renal impairment: 19.9% vs. 26.5%; moderate renal impairment: 22.0% vs. 25.0%; severe renal impairment: 46.3% vs. 43.6%, respectively). Frequencies of hypoglycaemia in patients with mild, moderate and severe renal impairment were 34.9%, 35.6% and 66.7% with linagliptin and 37.5%, 39.7% and 49.1% with placebo, respectively. Episodes of severe hypoglycaemia were low (⩽5.6%). Adding linagliptin to insulin in type 2 diabetes mellitus patients with chronic kidney disease improved glucose control and was well tolerated.

Topics: Aged; Blood Glucose; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Male; Metformin; Middle Aged; Pioglitazone; Renal Insufficiency, Chronic; Retrospective Studies; Severity of Illness Index; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Glucose-lowering treatment options are limited for uncontrolled type 2 diabetes mellitus (T2DM) patients with advanced stages of renal impairment (RI). This retrospective analysis evaluated glycaemic efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin added to sulphonylurea. Three randomized phase 3 studies (n = 619) including T2DM subjects with moderate or severe RI [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²] were analysed; only sulphonylurea-treated subjects who received additional linagliptin (n = 58) or placebo (n = 33) were evaluated. Linagliptin provided meaningful placebo-adjusted HbA1c reductions of -0.68% (95% confidence interval: -1.19, -0.17), -1.08% (-2.02, -0.14) and -0.62% (-1.25, 0.01) after 24, 18 and 12 weeks, respectively. There was a similar incidence of overall adverse events (linagliptin: 79.3%, placebo: 75.8%) and hypoglycaemia (linagliptin: 37.9%, placebo: 39.4%). Severe hypoglycaemia was more common with placebo (linagliptin: 1.7%, placebo: 6.1%). These data suggest that linagliptin is a safe and effective glucose-lowering treatment in T2DM patients with moderate-to-severe RI for whom sulphonylurea treatment is no longer sufficient.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Kidney; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Renal Insufficiency, Chronic; Retrospective Studies; Severity of Illness Index; Sulfonylurea Compounds

To investigate the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with Type 2 diabetes mellitus inadequately controlled by a combination of metformin and pioglitazone.. This was a multi-centre, phase 3, randomized, double-blind, placebo-controlled study comparing linagliptin 5 mg once daily (n = 183) and placebo (n = 89) as add-on to metformin and pioglitazone. The primary endpoint was the change from baseline in glycated haemoglobin (HbA1c ) after 24 weeks.. The placebo-corrected adjusted mean (se) change in HbA1c from baseline to 24 weeks was -6 (1) mmol/mol [-0.57 (0.13)%] (P < 0.0001). In patients with baseline HbA1c ≥ 53 mmol/mol (7.0%), 32.4% of patients in the linagliptin group and 13.8% in the placebo group achieved HbA1c < 53 mmol/mol (7.0%) (odds ratio 2.94; P = 0.0033). The placebo-corrected adjusted mean (se) change from baseline in fasting plasma glucose at week 24 was -0.57 (0.26) mmol/l [-10.4 (4.7) mg/dl] (P = 0.0280). The incidence of serious adverse events was 2.2% with linagliptin and 3.4% with placebo. Investigator-defined hypoglycaemia occurred in 5.5% of the linagliptin group and 5.6% of the placebo group. No meaningful changes in mean body weight were noted for either group.. Linagliptin as add-on therapy to metformin and pioglitazone produced significant and clinically meaningful improvements in glycaemic control, without an additional risk of hypoglycaemia or weight gain (Clinical Trials Registry No: NCT 00996658).

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Pioglitazone; Purines; Quinazolines; Thiazolidinediones; Treatment Failure; Treatment Outcome; Weight Gain

To investigate individual patient data from a comprehensive trials programme to evaluate the safety and efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin across a range of glucose-lowering regimens in a large elderly population with type 2 diabetes mellitus (T2DM).. Data were pooled from individuals aged ≥ 65 years, who participated in seven phase III, placebo-controlled clinical trials of linagliptin (24-52 weeks). Safety was assessed by incidence and severity of adverse events (AEs) with a focus on hypoglycaemia. The primary efficacy endpoint was change in glycated haemoglobin (HbA1c).. In total, 841 subjects received linagliptin 5 mg once a day and 490 received placebo. At baseline, the population had a mean ± s.d. age of 71.0 ± 4.6 years and a mean HbA1c concentration of 8.0 ± 0.8%; 63.5% of subjects received ≥ 2 antidiabetes drugs. Overall AEs and drug-related AEs were experienced by similar proportions of patients (linagliptin 71.3, placebo 73.3; linagliptin 18.1, placebo 19.8%, respectively). The incidence of investigator-reported hypoglycaemia was 21.4% with linagliptin and 25.7% with placebo. Severe hypoglycaemic events were rare and there were fewer in the linagliptin group (1.0 vs. 1.8%). At week 24, the placebo-corrected adjusted mean ± s.e. reduction in HbA1c with linagliptin was -0.62 ± 0.06% (95% CI: -0.73, -0.51).. Data from this large cohort show that linagliptin is a well-tolerated and efficacious therapy for elderly patients with T2DM. Treatment with linagliptin may support individualized treatment goals, while effectively managing the risk of hypoglycaemia or drug-related side effects.

Topics: Aged; Aged, 80 and over; Blood Glucose; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Incidence; Linagliptin; Male; Purines; Quinazolines; Treatment Outcome

Linagliptin treatment for 104 weeks was recently reported to achieve non-inferior glucose-lowering effects compared with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. Additional analyses from this randomised, active-controlled, double-blind trial have been performed in individuals completing the study on study drug without requiring rescue therapy. In this population, significantly more patients receiving linagliptin achieved HbA1c < 7% without hypoglycaemia and without body weight gain after 2 years compared with those receiving glimepiride (54% and 23%, respectively; odds ratio of 3.9, 95% confidence interval 2.6-5.7, p < 0.0001).

Topics: Analysis of Variance; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds; Treatment Outcome; Weight Gain

Some patients with type 2 diabetes mellitus (T2DM) receiving monotherapy with a sulfonylurea (SU) are unable to meet recommended glycemic targets over the long term and require additional pharmacologic agents to maintain glycemic control. This study was designed to assess the utility of adjunctive therapy with the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with T2DM inadequately controlled with SU monotherapy.. To assess the efficacy and tolerability of linagliptin as add-on therapy in patients with inadequately controlled T2DM despite background therapy with an SU.. In this Phase III, multicenter, randomized, double-blind, placebo-controlled trial, patients with inadequately controlled T2DM on SU monotherapy were randomly assigned to receive treatment with linagliptin 5 mg once daily (n = 161) or placebo (n = 84) for 18 weeks. The primary end point was the mean change in hemoglobin (Hb) A(1c) from baseline to week 18, evaluated using ANCOVA. Tolerability was assessed using laboratory analysis, spontaneous reporting, and physical examination and interview.. Mean baseline characteristics were similar in the linagliptin and placebo groups. Linagliptin treatment was associated with a placebo-corrected mean (95% CI) change in HbA(1c) from baseline (8.6%) to 18 weeks of -0.47% (-0.70 to -0.24; P < 0.0001). Patients in the linagliptin group were more likely compared with placebo to achieve the HbA(1c) target level of <7.0% after 18 weeks of treatment (15.2% vs 3.7%, respectively; odds ratio [OR] = 6.5; 95% CI, 1.7-24.8; P = 0.007). Similarly, patients in the linagliptin group were more likely to achieve an HbA(1c) reduction of ≥0.5% compared with those in the placebo group (57.6% vs 22.0%; OR = 5.1, 95% CI 2.7-9.6; P < 0.0001). The overall frequency of adverse events was similar between the linagliptin and placebo groups (42.2% vs 42.9%). The incidences of hypoglycemic events were not significantly different between the 2 groups (5.6% vs 4.8%), and none of the hypoglycemic episodes were assessed as severe by the investigator. The difference in the changes in mean body weight was not significant (+0.43 vs -0.01 kg; P = 0.12).. The addition of linagliptin to SU therapy for 18 weeks in these patients with T2DM was associated with statistically significant and clinically meaningful reductions in HbA(1c) compared with placebo. The overall tolerability of linagliptin was similar to that of placebo, with a low risk for hypoglycemia and no significant weight gain. These findings support the use of linagliptin as adjunctive therapy in patients with T2DM inadequately controlled on SU monotherapy. ClinicalTrials.gov identifier: NCT00819091.

Topics: Aged; Analysis of Variance; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds; Treatment Outcome

To investigate the efficacy and safety of linagliptin, a dipeptidyl peptidase-4 inhibitor, in type 2 diabetes mellitus (T2DM) patients for whom metformin was inappropriate.. This 1-year double-blind study (ClinicalTrials.gov, NCT00740051) enrolled T2DM patients with inadequate glycaemic control, treatment-naïve [glycated haemoglobin (HbA1c) 7.0-10.0%] or previously treated with one oral antidiabetes drug (HbA1c 6.5-9.0% before washout), ineligible for metformin because of contraindications (e.g. renal impairment) or previous intolerable side effects. Patients were randomized to monotherapy with linagliptin 5 mg once daily (n = 151) or placebo (n = 76) for 18 weeks, after which placebo patients switched to glimepiride 1-4 mg once daily and treatments continued for another 34 weeks. The primary endpoint was change from baseline in HbA1c after 18 weeks (full-analysis set, last observation carried forward).. At week 18, adjusted mean difference in change from baseline HbA1c (8.1%) was -0.60% (95% confidence interval -0.88, -0.32; p < 0.0001) (-0.39% with linagliptin, +0.21% with placebo). At week 52, mean HbA1c was decreased from baseline in both groups [linagliptin: -0.44%; placebo/glimepiride: -0.72% (observed cases)]. Adverse events occurred in 40.4 and 48.7% of linagliptin and placebo patients, respectively, during the initial 18 weeks. During the 34-week extension, patients receiving linagliptin experienced less hypoglycaemia (2.2% vs. 7.8%) and no weight gain (mean change from baseline of -0.2 and +1.3 kg, respectively) compared with glimepiride patients.. In T2DM patients for whom metformin was inappropriate, linagliptin improved glycaemic control and was well tolerated, with less hypoglycaemia and relative weight loss compared with glimepiride.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds; Treatment Outcome

Older patients managed with intensive antidiabetic therapy are more likely to be harmed. Our study's primary endpoint was to analyze the safety and efficacy of linagliptin in combination with basal insulin versus basal-bolus insulin in patients with 75 years of age or older hospitalized in medicine and surgery departments in real-world clinical practice.. We retrospectively enrolled non-critically patients ≥75 years with type 2 diabetes admitted to medicine and non-cardiac surgery departments with admission glycated hemoglobin <8%, admission blood glucose <240 mg/dL, and without at-home injectable therapies managed with our hospital's antihyperglycemic protocol (basal-bolus or linagliptin-basal regimens) between January 2016 and December 2018. To match each patient who started on the basal-bolus regimen with a patient who started on the linagliptin-basal regimen, a propensity matching analysis was used.. Postmatching, 198 patients were included in each group. There were no significant differences in mean daily blood glucose levels after admission (P=0.203); patients with mean blood glucose 100-140mg/dL (P=0.134), 140-180mg/dL (P=0.109), or >200mg/dL (P=0.299); and number and day of treatment failure (P=0.159 and P=0.175, respectively). The total insulin dose and the number of daily injections were significantly lower in the linagliptin-basal group (both, P<0.001). Patients on the basal-bolus insulin regimen had more total hypoglycemic events than patients on the linagliptin-basal insulin regimen (P<0.001).. The linagliptin-basal insulin regimen was an effective alternative with fewer hypoglycemic events and daily insulin injections than intensive basal-bolus insulin in very old patients with type 2 diabetes with mild-to-moderate hyperglycemia treated at home without injectable therapies.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Retrospective Studies; Treatment Outcome

Hyperglycaemia in hospitalized patients with type 2 diabetes is preferably managed with insulin. We aimed to analyse the glycaemic efficacy, treatment simplicity, and safety of our hospital's antihyperglycemic regimens (linagliptin-basal insulin versus basal-bolus insulin) in patients with type 2 diabetes admitted for heart failure decompensation.. In this real-world study, we included patients with mild-to-moderate hyperglycaemia managed with our antihyperglycemic regimens between 2016 and 2018. To match patients who started one of the regimens, a propensity matching analysis was used.. After propensity matching, 146 patients were included in each group. There were no differences in mean blood glucose levels (163.6±21.2 vs 159.6±19.2mg/dl, p=.210). Patients on the linagliptin-basal insulin regimen had a lower total number of hypoglycaemic episodes (36 vs 64, p<.001), lower total insulin dose (24.1±5.3 vs 32.0±5.6 units, p<.001), and lower number of daily injections (2.4±.8 vs 4.0±.0, p<.001) than those on the basal-bolus regimen.. Linagliptin-basal insulin was a safe, simple, and efficacious regimen and could be considered standard of care for these vulnerable, high complex patients to simplify in-hospital management.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Heart Failure; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Treatment Outcome

The potential of anti-aging effect of DPP-4 inhibitors is unknown. This study was performed to determine whether linagliptin, a DPP-4 inhibitor, could protect against premature aging in klotho-/- mice.. Klotho-/- mice exhibit multiple phenotypes resembling human premature aging, including extremely shortened life span, cognitive impairment, hippocampal neurodegeneration, hair loss, muscle atrophy, hypoglycemia, etc. To investigate the effect of linagliptin on these aging-related phenotypes, male klotho-/- mice were divided into two groups: (1) control group fed the standard diet, and (2) linagliptin group fed the standard diet containing linagliptin. Treatment with linagliptin was performed for 4 weeks. The effect of linagliptin on the above mentioned aging-related phenotypes was examined.. Body weight of klotho-/- mice was greater in linagliptin group than in control group (11.1 ± 0.3 vs 9.9 ± 0.3 g; P < 0.01), which was associated with greater gastrocnemius muscle weight (P < 0.01) and greater kidney weight (P < 0.05) in linagliptin group. Thus, linagliptin significantly prevented body weight loss in klotho-/- mice. Survival rate of klotho-/- mice was greater in linagliptin group (93%) compared to control group (67%), although the difference did not reach statistical significance (P = 0.08). None of linagliptin-treated klotho-/- mice had alopecia during the treatment (P < 0.05 vs control klotho-/- mice). Latency of klotho-/- mice in passive avoidance test was larger in linagliptin group than in control group (P < 0.05), indicating the amelioration of cognitive impairment by linagliptin. Cerebral blood flow of klotho-/- mice was larger in linagliptin group than in control group (P < 0.01), being associated with greater cerebral phospho-eNOS levels (P < 0.05) in linagliptin group. Neuronal cell number in hippocampal CA1 region was greater in linagliptin group than in control group (P < 0.05). Linagliptin group had greater cerebral phospho-Akt (P < 0.05) and phospho-CREB (P < 0.05) than control group. Thus, linagliptin ameliorated brain aging in klotho-/- mice. The degree of hypoglycemia in klotho-/- mice was less in linagliptin group than in control group, as estimated by the findings of OGTT.. Out work provided the evidence that DPP-4 inhibition with linagliptin slowed the progression of premature aging in klotho-/- mice, and provided a novel insight into the potential role of DPP-4 in the mechanism of premature aging.

Topics: Age Factors; Aging; Aging, Premature; Alopecia; Animals; Avoidance Learning; Behavior, Animal; Brain; Cerebrovascular Circulation; Cognition; Cyclic AMP Response Element-Binding Protein; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Genotype; Glucuronidase; Hypoglycemia; Klotho Proteins; Linagliptin; Male; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Nitric Oxide Synthase Type III; Phenotype; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Time Factors; Weight Loss

To evaluate the efficacy and safety of linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin.. This was a post hoc subanalysis of participants who received basal insulin and metformin in a global phase III study that randomized participants (1:1) to receive linagliptin 5 mg once daily or placebo for ≥52 weeks as add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone. During the first 24 weeks, the background dose of basal insulin remained stable; thereafter, adjustments based on glucose concentrations were recommended. The primary endpoint of the subanalysis was the change from baseline in HbA1c after 24 weeks. The safety analysis incorporated data up to a maximum of 110 weeks.. A total of 950 participants receiving background insulin and metformin were included in this subanalysis (linagliptin and placebo, both n = 475). At week 24, the placebo-corrected adjusted mean (±se) change from baseline in HbA1c with linagliptin was -7 (±1) mmol/mol [-0.7 (±0.1) %; 95% CI -0.8, -0.6; P < 0.0001]. The overall frequency of drug-related adverse events (linagliptin, 18.9%; placebo, 21.9%) and investigator-reported hypoglycaemia (linagliptin, 30.7%; placebo, 31.6%) were similar in both groups at the end of treatment. The frequency of severe hypoglycaemia was low (linagliptin, 1.7%; placebo, 0.8%). No meaningful changes in mean (±sd) body weight were noted in either group [week 52: linagliptin, -0.5 (±3.2) kg; placebo, 0.0 (±3.1) kg].. Linagliptin added to basal insulin and metformin improved glycaemic control, without increasing the risk of hypoglycaemia or body weight gain.

Topics: Aged; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Male; Metformin; Middle Aged; Treatment Outcome; Weight Gain; Weight Loss

Hypoglycemia poses a significant clinical and economic burden to patients with type 2 diabetes mellitus (T2DM). Minimizing the risk of hypoglycemia is an important component when managing patients with T2DM. Understanding hypoglycemia rates and the associated economic consequences can help to inform health care decision makers.. To assess hypoglycemia incidence rates and associated costs in patients who initiated second-line treatment with the antidiabetic agents linagliptin or a sulfonylurea (SU) after metformin.. A large U.S. administrative claims database was used to identify patients with T2DM (during the identification period July 2011-October 2013) who initiated linagliptin or a SU after metformin use. The date of the first prescription for linagliptin or a SU during the identification period was designated as the index date. Linagliptin users were matched to SU users based on demographic and clinical characteristics identified within a 12-month period before the index date using propensity scores (1:3 ratio, caliper: ±0.001). Rates and costs (2013 U.S. dollars) of hypoglycemia resulting in any health care resource use were quantified during a variable follow-up period (i.e., end of the study, end of the 12-month follow-up, treatment regimen change, or disenrollment, whichever came first). Hypoglycemia rates per 100 person-years were compared using univariate Poisson regression, and hazard of hypoglycemia was obtained from multivariate Cox proportional hazards regression. Mean monthly hypoglycemia-related costs, all-cause costs, and T2DM-related costs were computed for patients with hypoglycemia and compared using t-tests.. Propensity-score matching resulted in a sample of 11,536 patients (linagliptin = 2,884; SU = 8,652) with a mean age of 56 years and 59% male. The rate of hypoglycemia (per 100 person-years) was lower in the linagliptin than the SU user groups (2.51 vs. 3.63; P= 0.049). Linagliptin users had a 33% lower risk of hypoglycemia compared with SU users (HR = 0.67; 95% CI = 0.47-0.97; P= 0.031). Among patients who had hypoglycemia, linagliptin users showed numerically lower mean monthly hypoglycemia-related costs compared with SU users ($300 vs. $890; P= 0.092), which was primarily driven by differences in hypoglycemia-related costs in the hospital setting. A similar theme was observed with monthly all-cause costs (linagliptin users, $1,971 vs. SU users, $3,758; P= 0.092).. Linagliptin use was associated with a lower incidence rate of hypoglycemia compared with SU use in patients initiating second-line therapy after metformin monotherapy. Among patients who experienced hypoglycemia, linagliptin users appeared to have lower monthly hypoglycemia-related and all-cause costs than SU users. Careful consideration of newer treatment alternatives may be prudent for optimal T2DM management, especially with regard to hypoglycemia.. Funding for the research study and resultant publication was provided by Boehringer Ingelheim. Shetty is an employee of Boehringer Ingelheim. Cai was an employee of Boehringer Ingelheim at the time of the study. Raju and D'Souza are employees of Xcenda, which received research funding from Boehringer Ingelheim for the conduct of this study and for the preparation of this manuscript. All authors contributed to concept and study design. Raju took the lead in data analysis, along with D'Souza, and all authors contributed equally to data interpretation. The manuscript was written by Raju, D'Souza, Cai, and Shetty and revised primarily by Raju, along with Shetty and D'Souza.

Topics: Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Health Care Costs; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Linagliptin; Male; Metformin; Middle Aged; Propensity Score; Sulfonylurea Compounds

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

Long duration of type 2 diabetes mellitus (T2DM) is associated with progressive β-cell loss and may pose a challenge to maintenance of good glycemic control. This study aimed to assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in an understudied population of patients with long-standing T2DM.. Data from 202 individuals with T2DM for >10 years were pooled from 2 randomized, placebo-controlled, Phase III trials. Participants received either linagliptin 5 mg once daily (n = 122) or placebo (n = 80) for 24 weeks as an add-on to their current glucose-lowering therapy.. Long-standing T2DM was associated with older age (mean [SD], 69.1 [10.0] years) and a high prevalence of diabetes-related complications (78% with diabetic kidney disease and 83% with macrovascular disease). The mean baseline glycosylated hemoglobin (HbA1c) level was 8.22% (1.08%), and mean baseline fasting plasma glucose level was 161.8 (49.2) mg/dL. Linagliptin significantly improved glycemic control after 24 weeks, with a placebo-adjusted mean change in HbA1c from baseline of -0.66% (95% CI, -0.95 to -0.38; P < 0.0001). This change was accompanied by a significant reduction in fasting plasma glucose, with a placebo-adjusted mean change from baseline of -15.5 mg/dL (95% CI, -29.6 to -1.3; P = 0.0323) at week 24. Overall, linagliptin was well tolerated, with drug-related adverse events in 21.3% and 16.3% of the linagliptin and placebo groups, respectively. Investigator-reported hypoglycemia occurred more often with linagliptin (25.4%) compared with placebo (12.5%). However, no severe hypoglycemic events were reported with linagliptin. Moreover, in patients not receiving concomitant sulfonylureas, the incidence of hypoglycemia with linagliptin (12.5%) was similar to that with placebo (12.2%). Patients' mean weight remained unchanged in both groups.. This pooled analysis found that linagliptin was well tolerated and significantly improved hyperglycemia in a clinically challenging population of patients with long-standing T2DM (>10 years). Although T2DM is commonly associated with diminished β-cell function, the extent of glucose lowering was similar to that in linagliptin trials, which largely included patients in earlier stages of the disease. Thus, this observation supports the hypothesis that regulation of glucagon release from pancreatic α cells may be of particular relevance for improving hyperglycemia in patients with long-term T2DM (NCT01194830 and NCT01084005).

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Randomized Controlled Trials as Topic; Retrospective Studies; Sulfonylurea Compounds; Treatment Outcome