Linagliptin In Type Research Articles

75歳以上の高齢2型糖尿病患者におけるリナグリプチンの効果と肝腎機能，脂質代謝への影響―75歳未満患者との比較及び腎機能低下例での検討―

75歳以上の高齢2型糖尿病患者におけるリナグリプチンの効果と肝腎機能，脂質代謝への影響―75歳未満患者との比較及び腎機能低下例での検討―

Identical hypoglycaemic effect of teneligliptin with linagliptin in type 2 diabetes with chronic kidney disease

Identical hypoglycaemic effect of teneligliptin with linagliptin in type 2 diabetes with chronic kidney disease

Efficacy and safety of linagliptin in type 2 diabetes patients with self-reported hepatic disorders: A retrospective pooled analysis of 17 randomized, double-blind, placebo-controlled clinical trials

AimsLiver disease is highly prevalent among people with type 2 diabetes mellitus (T2DM). We evaluated the dipeptidyl peptidase-4 inhibitor linagliptin in subjects with T2DM and hepatic disorders. MethodsData were pooled from 17 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2DM subjects that included individuals with self-reported history of hepatic disorders at baseline. The primary endpoint was change in HbA1c from baseline to week 24. ResultsOf the 7009 participants (56% white, 39% Asian), 574 had hepatic disorders, most commonly hepatic steatosis (60%). At week 24, adjusted mean±standard error (SE) change in HbA1c from baseline in those with hepatic disorders was −0.75%±0.05 with linagliptin and −0.20%±0.08 with placebo [treatment difference: −0.54% (95% confidence interval−0.72 to −0.36); P<.0001]. There was no significant difference in HbA1c reduction between subjects with or without baseline hepatic disorders (P=.4042). Among subjects with hepatic disorders, 13.5% and 14.8% of the linagliptin and placebo groups, respectively, reported drug-related adverse events while 10.4% and 15.9%, respectively, reported hypoglycemia. Overall, adverse event rates were similar in individuals with or without hepatic disorders. ConclusionsThis large pooled analysis suggests that linagliptin is effective and well tolerated in people with T2DM and liver disease.

Alternate-day dosing of linagliptin in type 2 diabetes patients controlled on once daily dose: A case series.

Linagliptin, a dipeptidyl peptidase 4 (DPP 4) inhibitor with a long terminal half life, significantly inhibits the DPP 4 enzyme at a steady state up to 48 h after the last dose. The present case series examined the hypothesis that linagliptin retains its efficacy during alternate day dosing in type 2 diabetes patients when switched over from once daily (OD) dosing. Eight type 2 diabetes patients maintaining stable glycosylated hemoglobin (HbA1c) with acceptable fasting plasma glucose and postprandial glucose levels and receiving linagliptin 5 mg OD for at least 6 weeks, with a stable dose of concomitant antidiabetic medications were given linagliptin 5 mg every alternate day. The median HbA1c while on the OD regimen was 6.1% (43 mmol/mol) (range: 5.8–6.9% [40–52 mmol/mol]) and median duration of diabetes was 7 years (range: 0.75–16 years). After a median follow-up period of 21weeks,the glycemic control was maintained in all patients similar to their baseline values (median HbA1c: 6.0% [42 mmol/mol], range: 5.1–7.1% [32–54 mmol/mol]). The body weight, fasting, and random glucose levels at baseline were also well maintained at the end of treatment. Optimal glycemic status maintained in our study population favors our hypothesis that linagliptin used alternate daily after switching from initial OD dose of the drug in patients on a stable background antidiabetic medications retains its efficacy. Paradoxically, alternate day dosing may affect compliance if the patient forgets when they took the last dose. Further studies including larger cohorts are needed to validate this finding and identify patients who can benefit from the alternate day regimen.

Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events

BackgroundThe cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM).MethodsPre-specified patient-level pooled analysis of all available double-blind, randomized, controlled trials, ≥12 weeks’ duration (19 trials, 9459 subjects) of linagliptin versus placebo/active treatment. Primary end point: composite of prospectively adjudicated CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina (4P-MACE). Hospitalization for congestive heart failure (CHF) was also evaluated; adjudication of CHF was introduced during the phase 3 program (8 trials; 3314 subjects). 4P-MACE was assessed in placebo-controlled trials (subgroup of 18 trials; 7746 subjects). Investigator-reported events suggestive of CHF from 24 placebo-controlled trials (including trials <12 weeks’ duration, 8778 subjects) were also analyzed.Results5847 patients received linagliptin (5 mg: 5687, 10 mg: 160) and 3612 comparator (glimepiride: 775, voglibose: 162, placebo: 2675); cumulative exposure, 4421.3 and 3254.7 patient-years, respectively. 4P-MACE incidence rates: 13.4 per 1000 patient-years, linagliptin (60 events), 18.9, total comparators (62 events); overall hazard ratio (HR), 0.78 (95% confidence interval [CI], 0.55–1.12). HR for adjudicated hospitalization for CHF (n = 21): 1.04 (0.43–2.47). For placebo-controlled trials, 4P-MACE incidence rates: 14.9 per 1000 patient-years, linagliptin (43 events), 16.4, total comparators (29 events); overall HR, 1.09 (95% CI, 0.68–1.75). Occurrence of investigator-reported events suggestive of CHF was low for linagliptin- (26 events, 0.5%; serious: 16 events, 0.3%) and placebo-treated (8 events, 0.2%; serious: 6 events, 0.2%) patients.ConclusionsLinagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

Kidney Disease End Points in a Pooled Analysis of Individual Patient–Level Data From a Large Clinical Trials Program of the Dipeptidyl Peptidase 4 Inhibitor Linagliptin in Type 2 Diabetes

Although assessment of cardiovascular safety is mandated by regulatory agencies for the development of new drugs to treat type 2 diabetes, evaluation of their renal safety has been relatively neglected. Individual patient-level data pooled analysis of 13 phase 2 or 3 randomized, double-blind, placebo-controlled, clinical trials of the dipeptidyl peptidase 4 inhibitor linagliptin. Participants who participated in any of 13 randomized clinical trials and fulfilled predefined inclusion/exclusion criteria, such as being drug-naive (hemoglobin A1c, 7.0%-11.0% [53-97 mmol/mol]) or being on background glucose-lowering therapy (hemoglobin A1c, 6.5%-10.5% [48-91 mmol/mol]). Of 5,466 consenting individuals with inadequately controlled type 2 diabetes, 3,505 received linagliptin, 5mg/d, and 1,961 received placebo. The primary kidney disease outcome was defined as first occurrence during the study of 6 predefined safety end points: new onset of moderate elevation of albuminuria (urinary albumin-creatinine ratio [ACR] >30 mg/g with baseline values ≤ 30 mg/g), new onset of severe elevation of albuminuria (ACR > 300 mg/g with baseline values ≤ 300 mg/g), reduction in kidney function (serum creatinine increase to ≥250 μmol/L from a baseline value <250 μmol/L), halving of estimated glomerular filtration rate (loss of baseline eGFR >50%), acute renal failure (ascertained from diagnostic codes), or death from any cause. Albuminuria was assessed using ACR. GFR was estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Cumulative exposure (person-years) was 1,751 for linagliptin and 1,055 for placebo. The primary composite outcome occurred in 448 (12.8%) and 306 (15.6%) participants in the linagliptin and placebo groups, respectively. Linagliptin treatment significantly reduced the hazard of kidney disease events by 16% compared with placebo (HR, 0.84; 95% CI, 0.72-0.97; P=0.02). Retrospective and hypothesis-generating study involving short- to midterm clinical trials. Linagliptin was not associated with increased kidney disease risk in patients with type 2 diabetes. The potential of this drug to improve kidney disease outcomes warrants further investigation.

Linagliptin: farmacology, efficacy and safety in type 2 diabetes treatment

Type 2 diabetes mellitus (T2DM) has a high prevalence and incidence around the world. The complex pathophysiology mechanism is among the barriers for diabetes treatment. Type 2 diabetes patients have dysfunction in incretin hormones (as glucagon-like peptide-1 or GLP-1, and glucose-dependent insulinotropic polypeptide or GIP). By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, it is possible to slow the inactivation of GLP-1 and GIP, promoting blood glucose level reduction in a glucose-dependent manner. Linagliptin is a highly specific and potent inhibitor of DPP-4 that is currently indicated for the treatment of type 2 diabetes. Clinical studies with linagliptin demonstrated efficacy in reducing glycated hemoglobin (HbA1c) levels in type 2 diabetes patients, while maintaining a placebo-like safety and tolerability profile. Linagliptin has an interesting pharmacokinetic profile in terms of its predominantly non-renal elimination and the main implication of this characteristic is that no dose adjustment is necessary in patients with renal disease. Also, no dose adjustment is required in patients with hepatic insufficiency, as well in elderly or obese patients. This article will review the pharmacokinetic profile, efficacy data and safety aspects of linagliptin in type 2 diabetes patients.

Safety and efficacy of linagliptin in type 2 diabetes patients with common renal and cardiovascular risk factors.

Dipeptidyl-peptidase-IV (DPP-4) inhibitors have become an important orally active drug class for the treatment of type 2 diabetes as second-line therapy after metformin failure or as monotherapy or combination therapy with other drugs when metformin is not tolerated or contraindicated. DPP-4 inhibitors act mainly by increasing endogenous incretin hormone concentrations. They stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner with a significantly lower risk for hypoglycaemia than sulfonylureas. Furthermore, DPP-4 inhibitors are weight neutral. Linagliptin is a DPP-4 inhibitor that is eliminated by a hepatobiliary route, whereas the other DPP-4 inhibitors available today show a renal elimination. Therefore, it can be used in normal kidney function as well as in all stages of chronic kidney disease to stage 5 (glomerular filtration rate <15 ml/min/1.73 m(2)) without dose adjustments. Linagliptin was noninferior to metformin and sulfonylureas in clinical studies. In recent studies, it showed a superior safety profile over sulfonylurea treatment regarding hypoglycaemia and weight gain. More patients reached an HbA1c <7% without hypoglycaemia and weight gain with linagliptin compared with glimepiride. The safety profile with respect to a composite cardiovascular endpoint and stroke was also favourable for linagliptin, most likely due to a higher incidence of hypoglycaemia associated with glimepiride therapy and titration. This review gives an overview on the efficacy and safety of linagliptin in comparison with other antidiabetic drugs in type 2 diabetes patients with renal and cardiovascular risk factors as well as an outlook on the perspective for linagliptin in this patient population in the future.

Aliskiren increased adverse events in patients with diabetes and kidney disease who were receiving ACE inhibitors or ARBs

ACP Journal Club19 March 2013Aliskiren increased adverse events in patients with diabetes and kidney disease who were receiving ACE inhibitors or ARBsPeter W. de Leeuw, MDPeter W. de Leeuw, MDMaastricht University Medical Centre and, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands (P.W.D.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-158-6-201303190-02007 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationParving HH, Brenner BM, McMurray JJ, et al; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204-13. https://pubmed.ncbi.nlm.nih.gov/23121378Clinical Impact RatingsCardiology: Endocrinology: Nephrology: References1 Pogue J, Devereaux PJ, Thabane L, Yusuf S. Designing and analyzing clinical trials with composite outcomes: consideration of possible treatment differences between the individual outcomes. PLoS One. 2012;7:e34785. [PMID: 22529934] Google Scholar2 ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-59. [PMID: 18378520] Google Scholar3 Harel Z, Gilbert C, Wald R, et al. The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis. BMJ. 2012;344:e42. [PMID: 22232539] Google Scholar4 Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-906. [PMID: 14610160] Google Scholar Author, Article, and Disclosure InformationAffiliations: Maastricht University Medical Centre and, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands (P.W.D.)This article was published at Annals.org on 5 March 2013. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByKidney Disease End Points in a Pooled Analysis of Individual Patient–Level Data From a Large Clinical Trials Program of the Dipeptidyl Peptidase 4 Inhibitor Linagliptin in Type 2 DiabetesAliskiren, the first direct renin inhibitor: assessing a role in pediatric hypertension and kidney diseasesRenoprotective effect of renal liver-type fatty acid binding protein and angiotensin II type 1a receptor loss in renal injury caused by RAS activationScreening, Early Diagnosis, Genetic Markers, and Predictors of Diabetic Nephropathy 19 March 2013Volume 158, Issue 6Page: JC7KeywordsACE inhibitorsAdverse eventsCardiovascular therapyChronic kidney diseaseHeartHeart failureHypotensionLongitudinal studiesRenal diseasesType 2 diabetes ePublished: 19 March 2013 Issue Published: 19 March 2013 CopyrightCopyright © 2013 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...

The DPP-4 Inhibitor Linagliptin Counteracts Stroke in the Normal and Diabetic Mouse Brain

Type 2 diabetes is a strong risk factor for stroke. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical use against type 2 diabetes. The aim of this study was to determine the potential antistroke efficacy of linagliptin in type 2 diabetic mice. To understand whether efficacy was mediated by glycemia regulation, a comparison with the sulfonylurea glimepiride was done. To determine whether linagliptin-mediated efficacy was dependent on a diabetic background, experiments in nondiabetic mice were performed. Type 2 diabetes was induced by feeding the mice a high-fat diet for 32 weeks. Mice were treated with linagliptin/glimepiride for 7 weeks. Stroke was induced at 4 weeks into the treatment by transient middle cerebral artery occlusion. Blood DPP-4 activity, glucagon-like peptide-1 (GLP-1) levels, glucose, body weight, and food intake were assessed throughout the experiments. Ischemic brain damage was measured by determining stroke volume and by stereologic quantifications of surviving neurons in the striatum/cortex. We show pronounced antistroke efficacy of linagliptin in type 2 diabetic and normal mice, whereas glimepiride proved efficacious against stroke in normal mice only. These results indicate a linagliptin-mediated neuroprotection that is glucose-independent and likely involves GLP-1. The findings may provide an impetus for the development of DPP-4 inhibitors for the prevention and treatment of stroke in diabetic patients.

Efficacy and safety of linagliptin in type 2 diabetes subjects at high risk for renal and cardiovascular disease: a pooled analysis of six phase III clinical trials.

BackgroundIn patients with type 2 diabetes mellitus (T2DM), hypertension and microalbuminuria are predictive markers for increased renal and cardiovascular risk. This post hoc analysis of data from a global development program aimed to evaluate the efficacy and safety of linagliptin in a population with joint prevalence of these two vascular risk factors.MethodsData for patients with baseline microalbuminuria (urine albumin-to-creatinine ratio 30–300 mg/g) and hypertension (systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg and/or a history of hypertension; and/or an antihypertensive treatment at baseline) who participated in any of six randomized, placebo-controlled, phase III trials were analyzed. Participants received linagliptin 5 mg daily (alone or in combination with other oral antidiabetic drugs) or placebo for 18 to 24 weeks.ResultsOf 3,119 patients, 512 had both microalbuminuria and hypertension (linagliptin, 366; placebo, 146). Baseline mean (SD) HbA1c was 8.3 (0.9)% and 8.4 (0.9)%; median (range) urine albumin-to-creatinine ratio was 60 (30–292) mg/g and 64 (30–298) mg/g; mean (SD) systolic blood pressure was 138 (15) mm Hg and 135 (16) mm Hg; and mean (SD) diastolic blood pressure was 81 (10) mm Hg and 81 (10) mm Hg, for linagliptin and placebo, respectively. Placebo-corrected mean change in HbA1c from baseline to week 18 and week 24 was -0.57% (95% CI: -0.75, -0.39; P < 0.0001) and -0.59% (95% CI: -0.80, -0.39; P < 0.0001), respectively. Placebo-corrected mean change in FPG from baseline to week 24 was -21.3 mg/dl (95% CI: -31.0, -11.6; P < 0.0001). The incidence of drug-related adverse events was similar for linagliptin and placebo (10.4% and 8.2%, respectively). Changes in systolic and diastolic blood pressure, cholesterol and triglyceride levels were similar between linagliptin and placebo.ConclusionIn T2DM patients with the two common vascular risk factors of hypertension and microalbuminuria, linagliptin achieved significant improvements in glycemic control. In this vulnerable patient population at high risk for micro- and macrovascular complications, linagliptin was well tolerated.

Emerging DPP-4 inhibitors: focus on linagliptin for type 2 diabetes

The first dipeptidyl-peptidase-IV (DPP-4) inhibitor for the treatment of type 2 diabetes became available in 2006. Since then, the number of DPP-4 inhibitors has increased and DPP-4 inhibitors have developed into an important drug class. DPP-4 inhibitors act by increasing endogenous GLP-1 and GIP concentrations. Via this mechanism, insulin secretion is glucose-dependently stimulated and glucagon secretion inhibited. This results in a low risk for hypoglycemia. Furthermore, DPP-4 inhibitors are weight-neutral. Linagliptin is a novel DPP-4 inhibitor that, in contrast to the other members of this drug class, is eliminated by a biliary/hepatic route rather than by renal elimination. This property allows the use of linagliptin in type 2 diabetic patients with normal kidney function as well as in patients with renal insufficiency without dose adjustments. In comparative clinical studies, linagliptin was noninferior to other established antidiabetic agents, especially to metformin and sulfonylurea. It showed a superior safety profile over glimepiride regarding hypoglycemia, weight gain, a composite cardiovascular endpoint, and stroke. This review gives an overview on the efficacy and safety of linagliptin in comparison to the classical oral antidiabetic drugs as well as to the other DPP-4 inhibitors.

OP5: Low Cardiovascular (CV) Risk Hazard Ratio Observed with Linagliptin in Type 2 Diabetes: Further Insights from a Predefined CV Meta-Analysis

Background and aims Incidence of cardiovascular (CV) events is increased in type 2 diabetes (T2D) but the potential for CV risk modulation with glucose lowering is debated. Linagliptin, a DPP-4 inhibitor, provides a meaningful reduction in hyperglycaemia and also may have potential CV benefits. To further explore potential mechanisms behind this, we report additional relevant data from a large CV meta-analysis of linagliptin trial data. Materials and Methods In this pre-specified meta-analysis from 8 Phase III randomised, controlled trials, CV events were prospectively adjudicated by a blinded independent expert committee. A composite primary endpoint of CV death, MI, stroke, and hospitalisation for unstable angina pectoris (UAP) was used. Results are given as hazard ratio (HR) for time to first occurrence of any components of the primary endpoint using a Cox regression model for linagliptin vs total comparators with factors of study (grouped by design), treatment (linagliptin vs combined comparators), gender (female vs male), race (Asian vs White), and time since T2D diagnosis (>5 vs ≤5 yr). Comparative data for conventional CV risk factors across treatment groups are reported descriptively. Results 3319 patients received linagliptin once daily (5 mg: 3159, 10 mg: 160) and 1920 comparator (placebo: 977, glimepiride: 781, voglibose: 162). The overall study cohort (N=5239) seemed representative of a general T2D population among which overall HR was higher in patients with longer duration of T2D (1.51 [95% CI: 0.75–3.04]) and reduced in females (0.36 [95% CI: 0.16–0.84]) and Asians [0.28 [95% CI: 0.10–0.82]). A significantly reduced risk for the primary endpoint after treatment with linagliptin was indicated by the HR (0.36 [95% CI: 0.17–0.74]). Between-group changes in cholesterol and systolic and diastolic blood pressure were similar for linagliptin- and comparator-treated patients. Linagliptin treatment was associated with a greater reduction in HbA1c (−0.6 ± 0.9%), fasting triglycerides (−11 ± 136 mg/dL), and no weight gain (0.01 ± 3.09 kg) in contrast to the total comparators (respectively −0.3 ± 1.0%, −6 ± 156 mg/dL, and 0.6 ± 3.42 kg). Conclusion Additional Cox regression analyses support the CV safety profile of linagliptin in a large phase III CV meta-analysis. The low CV HR observed with linagliptin cannot be fully explained by classical CV risk factors such as blood pressure and lipids. Further clinical outcome and mechanistic studies are underway to provide additional insights.