Regardless of the degree of glycaemic control, linagliptin has lower hypoglycaemia risk than all doses of glimepiride, at all time points, over the course of a 2-year trial.

AIM: To evaluate the risk of documented hypoglycaemia with glimepiride versus linagliptin. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study.

AIMS: To evaluate the efficacy and safety of linagliptin 5 and 10 mg vs. placebo and voglibose in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: This study enrolled patients with inadequately controlled T2DM who were previously treated with one or two oral antidiabetics or were drug naÏve. After a 2 to 4-week washout and placebo run-in, 561 patients were randomized (2 : 2 : 2 : 1) to double-blind treatment with linagliptin 5 or 10 mg qd, voglibose 0.2 mg tid or placebo. The primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) with linagliptin vs. placebo after 12 weeks and vs. voglibose after 26 weeks. RESULTS: Baseline characteristics were well balanced across treatment groups (overall mean HbA1c was 8.01%). The adjusted mean (95% confidence interval) treatment differences at week 12 were -0.87% (-1.04, -0.70; p < 0.0001) and -0.88% (-1.05, -0.71; p < 0.0001) for linagliptin 5 and 10 mg vs. placebo and at week 26 were -0.32% (-0.49, -0.15; p = 0.0003) and -0.39% (-0.56, -0.21; p < 0.0001) for linagliptin 5 and 10 mg vs. voglibose. At week 12, mean HbA1c was 7.58, 7.48 and 8.34% in patients receiving linagliptin 5 mg, linagliptin 10 mg and placebo, respectively. At week 26, mean HbA1c was 7.63% with linagliptin 5 mg, 7.50% with linagliptin 10 mg and 7.91% with voglibose. Drug-related adverse event rates were comparable across treatment groups over 12 weeks (9.4% linagliptin 5 mg, 8.8% linagliptin 10 mg and 10.0% placebo) and 26 weeks (11.3% linagliptin 5 mg, 10.6% linagliptin 10 mg and 18.5% voglibose). There were no documented cases of hypoglycaemia. CONCLUSIONS: Linagliptin showed superior glucose-lowering efficacy and comparable safety and tolerability to both placebo and voglibose in Japanese patients with T2DM.

[The Gutenberg Health Study]. / Die Gutenberg Gesundheitsstudie.

The Gutenberg Health Study is a population-based, prospective, single-center cohort study that started in 2007 at the University Medical Center Mainz. The project focuses on cardiovascular diseases, cancer, eye diseases, metabolic diseases, diseases of the immune system and mental diseases. The study aims at improving the individual risk prediction for diseases. Therefore, lifestyle, psychosocial factors, environment, laboratory parameters as well as the extent of the subclinical disease are investigated. A comprehensive biobank enables biomolecular examinations including a systems biological approach. During the baseline visit 15,000 individuals aged 35-74 years were invited to a 5 h examination program in the study center. This will be followed by a computer-assisted telephone interview with a standardized interview and assessment of endpoints after 2.5 years. After 5 years a detailed follow-up examination comparable to the visit at study inclusion will be performed in the study center. Further follow-up visits of the cohort are envisaged.

Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study.

AIMS: To examine the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in persons with Type 2 diabetes mellitus inadequately controlled [HbA(1c) 53-86 mmol/mol (7.0-10.0%)] by metformin and sulphonylurea combination treatment. METHODS: A multi-centre, 24-week, randomized, double-blind, parallel-group study in 1058 patients comparing linagliptin (5 mg once daily) and placebo when added to metformin plus sulphonylurea. The primary endpoint was the change in HbA(1c) after 24 weeks. RESULTS: At week 24, the linagliptin placebo-corrected HbA(1c) adjusted mean change from baseline was -7 mmol/mol (-0.62%) [95% CI -8 to -6 mmol/mol (-0.73 to -0.50%); P < 0.0001]. More participants with baseline HbA(1c) ≥ 53 mmol/mol (≥ 7.0%) achieved an HbA(1c) < 53 mmol/mol (<7.0%) with linagliptin compared with placebo (29.2% vs. 8.1%, P< 0.0001). Fasting plasma glucose was reduced with linagliptin relative to placebo (-0.7 mmol/l, 95% CI -1.0 to -0.4; P<0.0001). Improvements in homeostasis model assessment of ß-cell function were seen with linagliptin (P<0.001). The proportion of patients who reported a severe adverse event was low in both groups (linagliptin 2.4%; placebo 1.5%). Symptomatic hypoglycaemia occurred in 16.7 and 10.3% of the linagliptin and placebo groups, respectively. Hypoglycaemia was generally mild or moderate; severe hypoglycaemia was reported in 2.7 and 4.8% of the participants experiencing hypoglycaemic episodes in the linagliptin and placebo groups, respectively. No significant weight changes were noted. CONCLUSIONS: In patients with Type 2 diabetes, adding linagliptin to metformin given in combination with a sulphonylurea significantly improved glycaemic control and this was well tolerated. Linagliptin could provide a valuable treatment option for individuals with inadequate glycaemic control despite ongoing combination therapy with metformin and a sulphonylurea.

The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type 2 diabetes mellitus.

AIM: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of linagliptin in patients with type 2 diabetes mellitus (T2DM). METHODS: After screening and a 14-day washout, subjects received linagliptin 2.5, 5 or 10 mg or placebo once-daily for 28 days in this randomized, double-blind, parallel, placebo-controlled within-dose groups study. RESULTS: Seventy-seven patients entered the study (linagliptin: 61; placebo: 16). Four patients withdrew prematurely. There was little evidence of linagliptin accumulation. Exposure, maximum and trough plasma concentrations of linagliptin increased less than dose-proportionally. Rapid and sustained inhibition of dipeptidyl peptidase-4 reached 91-93% across linagliptin doses at steady state. At the end of the 24-h dosing interval, inhibition was still high (82-90%). There were marked increases in plasma glucagon-like peptide-1 after 28 days of dosing. Compared to placebo, all linagliptin doses resulted in statistically significant decreases of the area under the glucose curve following a meal tolerance test on day 29, that is, 24 h after the last study drug intake. After 28 days of treatment with linagliptin the placebo-corrected mean change in haemoglobin A1c (HbA1c) (median baseline 7.0%) was -0.31% (2.5-mg dose), -0.37% (5-mg dose) and -0.28% (10-mg dose). The frequency of adverse events was similar for linagliptin (31%) and placebo (34%). There were no notable safety concerns. CONCLUSIONS: Linagliptin administration led to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, statistically significant reductions in HbA1c after only 4 weeks of treatment. Linagliptin had a safety and tolerability profile similar to placebo in T2DM patients.

Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study.

AIMS: To compare the efficacy, safety and tolerability of linagliptin or placebo administered for 24 weeks in combination with pioglitazone in patients with type 2 diabetes mellitus (T2DM) exhibiting insufficient glycaemic control (HbA1c 7.5-11.0%). METHODS: Patients were randomized to receive the initial combination of 30 mg pioglitazone plus 5 mg linagliptin (n = 259) or pioglitazone plus placebo (n = 130), all once daily. The primary endpoint was change from baseline in HbA1c after 24 weeks of treatment, adjusted for baseline HbA1c and prior antidiabetes medication. RESULTS: After 24 weeks of treatment, the adjusted mean change (±s.e.) in HbA1c with the initial combination of linagliptin plus pioglitazone was -1.06% (±0.06), compared with -0.56% (±0.09) for placebo plus pioglitazone. The difference in adjusted mean HbA1c in the linagliptin group compared with placebo was -0.51% (95% confidence interval [CI] -0.71, -0.30; p < 0.0001). Reductions in fasting plasma glucose (FPG) were significantly greater for linagliptin plus pioglitazone than with placebo plus pioglitazone; -1.8 and -1.0 mmol/l, respectively, equating to a treatment difference of -0.8 mmol/l (95% CI -1.2, -0.4; p < 0.0001). Patients taking linagliptin plus pioglitazone, compared with those receiving placebo plus pioglitazone, were more likely to achieve HbA1c of <7.0% (42.9 vs. 30.5%, respectively; p = 0.0051) and reduction in HbA1c of ≥0.5% (75.0 vs. 50.8%, respectively; p < 0.0001). ß-cell function, exemplified by the ratio of relative change in adjusted mean HOMA-IR and disposition index, improved. The proportion of patients that experienced at least one adverse event was similar for both groups. Hypoglycaemic episodes (all mild) occurred in 1.2% of the linagliptin plus pioglitazone patients and none in the placebo plus pioglitazone group. CONCLUSION: Initial combination therapy with linagliptin plus pioglitazone was well tolerated and produced significant and clinically meaningful improvements in glycaemic control. This combination may offer a valuable additive initial treatment option for T2DM, particularly where metformin either is not well tolerated or is contraindicated, such as in patients with renal impairment.

Effect of linagliptin monotherapy on glycaemic control and markers of ß-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial.

AIM: To assess the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either treatment-naive or who had received one oral antidiabetes drug (OAD). METHODS: This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2-week placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment. RESULTS: Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c ≥ 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ≥0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postprandial glucose of -3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment-%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. CONCLUSIONS: Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of ß-cell function. The safety profile of linagliptin was comparable with that of placebo.

Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study.

AIM: To evaluate the efficacy and safety of the potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin administered as add-on therapy to metformin in patients with type 2 diabetes with inadequate glycaemic control. METHODS: This 24-week, randomized, placebo-controlled, double-blind, parallel-group study was carried out in 82 centres in 10 countries. Patients with HbA1c levels of 7.0-10.0% on metformin and a maximum of one additional antidiabetes medication, which was discontinued at screening, continued on metformin ≥1500 mg/day for 6 weeks, including a placebo run-in period of 2 weeks, before being randomized to linagliptin 5 mg once daily (n = 524) or placebo (n = 177) add-on. The primary outcome was the change from baseline in HbA1c after 24 weeks of treatment, evaluated with an analysis of covariance (ANCOVA). RESULTS: Mean baseline HbA1c and fasting plasma glucose (FPG) were 8.1% and 9.4 mmol/l, respectively. Linagliptin showed significant reductions vs. placebo in adjusted mean changes from baseline of HbA1c (-0.49 vs. 0.15%), FPG (-0.59 vs. 0.58 mmol/l) and 2hPPG (-2.7 vs. 1.0 mmol/l); all p < 0.0001. Hypoglycaemia was rare, occurring in three patients (0.6%) treated with linagliptin and five patients (2.8%) in the placebo group. Body weight did not change significantly from baseline in both groups (-0.5 kg placebo, -0.4 kg linagliptin). CONCLUSIONS: The addition of linagliptin 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin resulted in a significant and clinically meaningful improvement in glycaemic control without weight gain or increased risk of hypoglycaemia.

Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes.

AIMS: The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, linagliptin, added to ongoing metformin therapy, were assessed in patients with Type 2 diabetes who had inadequate glycaemic control (HbA(1c) ≥ 7.5 to ≤ 10%; ≥ 58.5 to ≤ 85.8 mmol/mol) with metformin alone. METHODS: Patients (n=333) were randomized to receive double-blind linagliptin (1, 5 or 10 mg once daily) or placebo or open-label glimepiride (1-3 mg once daily). The primary outcome measure was the change from baseline in HbA(1c) at week 12 in patients receiving combination therapy compared with metformin alone. RESULTS: Twelve weeks of treatment resulted in a mean (sem) placebo-corrected lowering in HbA(1c) levels of 0.40% (± 0.14); 4.4 mmol/mol (± 1.5) for 1 mg linagliptin, 0.73% (± 0.14); 8.0 mmol/mol (± 1.5) for 5 mg, and 0.67% (± 0.14); 7.3 mmol/mol (± 1.5) for 10 mg. Differences between linagliptin and placebo were statistically significant for all doses (1 mg, P = 0.01; 5 mg and 10 mg, P < 0.0001). The change in mean (sem) placebo-corrected HbA(1c) from baseline was -0.90% (± 0.13); -9.8 mmol/mol (± 1.4) for glimepiride. Adjusted and placebo-corrected mean changes in fasting plasma glucose were -1.1 mmol/l for linagliptin 1 mg (P = 0.002), -1.9 mmol/l for 5 mg and -1.6 mmol/l for 10 mg (both P < 0.0001). One hundred and six (43.1%) patients reported adverse events; the incidence was similar across all five groups. There were no hypoglycaemic events for linagliptin or placebo, whereas three patients (5%) receiving glimepiride experienced hypoglycaemia. CONCLUSIONS: The addition of linagliptin to ongoing metformin treatment in patients with Type 2 diabetes was well tolerated and resulted in significant and clinically relevant improvements in glycaemic control, with 5 mg linagliptin being the most effective dose.

Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase-4 inhibitor linagliptin and pioglitazone in healthy volunteers.

OBJECTIVE: Co-administration of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) with pioglitazone may improve glycemic control in patients with Type 2 diabetes due to their complementary mechanisms of action. This study aimed to investigate any potential pharmacokinetic interaction between linagliptin and pioglitazone, a CYP 2C8 substrate. METHODS: 20 (10 male and 10 female) healthy subjects, between 22 and 65 years of age with a BMI range of > = 18.5 and < =29.9 kg/m2, took part in this single center open-label, randomized,two-way cross-over study. The subjects were administered linagliptin 10 mg/day and/orpioglitazone 45 mg/day until steady state was reached. RESULTS: Co-administration of pioglitazone did not significantly affect linagliptin Cmax,ss (geometric mean ratio(GMR) 107.3; 90% confidence interval (CI);92.3 ­ 124.8) or AUC tau,ss (GMR 113.4; 90%CI 103.0 ­ 124.9). Co-administration of linagliptin did not significantly affect pioglitazoneAU tau,ss (GMR 94.4; 90% CI 87.1 ­102.2), but reduced Cmax,ss by 14% (GMR85.6; 90% CI 78.1 ­ 93.8). As expected, linagliptin and pioglitazone were well tolerated,whether administered alone or concomitantly.There were no reported serious adverse events. The investigator defined 5 adverse events as drug-related with linagliptin,and 4 with pioglitazone. CONCLUSIONS: Linagliptinand pioglitazone have no clinically relevant pharmacokinetic interaction and may be co-administered without dose adjustment.These data further confirm that linagliptin is not an inhibitor of CYP2C8 in vivo.As the pharmacokinetic profiles of linagliptin and pioglitazone are similar in Type 2 diabetes patients and healthy subjects, it is reasonable to assume that they may be administered together to Type 2 diabetes patients without dose adjustment.

Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin.

OBJECTIVE: This study was conducted to investigate any potential effect of the dipeptidyl peptidase-4 inhibitor linagliptin (which is being developed to improve glycemic control in patients with Type 2 diabetes) on the pharmacokinetics of simvastatin (a lipid-lowering, HMG-CoA reductase inhibitor). METHODS: This open-label, multiple-dose study was conducted in 20 healthy male Caucasian subjects. Simvastatin (40 mg/day) was administered alone for 6 days, followed by co-administration with linagliptin (10 mg/ day) for 6 days, followed by simvastatin single administration for a further 8 days. Plasma concentrations of simvastatin and its active metabolite simvastatin beta-hydroxy acid were determined on Day 6 (before co-administration of linagliptin) and Days 12, 16 and 20 (after co-administration of linagliptin). RESULTS: The geometric mean ratio (GMR) (90% confidence interval (CI)) following co-administration of linagliptin with simvastatin (Day 12) compared with administration of simvastatin alone (Day 6) for simvastatin AUC was 134.2% (119.4, 150.7) and for simvastatin acid AUC was 133.3% (118.1, 150.3). The GMR (90% CI) for simvastatin Cmax,ss was 110.0% (89.3, 135.6) and for simvastatin acid Cmax,ss was 120.7% (101.5, 143.6). 20 adverse events were reported by 11 subjects. Both simvastatin and linagliptin were well tolerated. CONCLUSIONS: Linagliptin-mediated effects on simvastatin exposure are not considered to be clinically relevant in terms of patient tolerability or safety. Therefore, a dose adjustment of linagliptin is not necessary when these two agents are administered together and linagliptin co-administration is not expected to exert a clinically relevant effect on the pharmacokinetics of other CYP3A4 substrates.

Changes in adiponectin multimer distribution in response to atorvastatin treatment in patients with type 2 diabetes.

OBJECTIVE: Multimeric high molecular weight (HMW) forms of adiponectin were previously shown to be inversely associated with the extent of atherosclerosis in males and are down-regulated in patients with the metabolic syndrome and type 2 diabetes. In this study, potential influences of atorvastatin therapy on adiponectin multimer distribution were studied in patients with type 2 diabetes. DESIGN, PATIENTS AND MEASUREMENTS: The effect of 40 mg atorvastatin on HMW, medium molecular weight (MMW), and low molecular weight (LMW) isoforms of adiponectin were investigated in 75 patients (23 females; 52 males) with type 2 diabetes in an 8-week-long, placebo-controlled and randomized study. Adiponectin multimeric isoforms were detected by Western blot analysis. RESULTS: After atorvastatin therapy the median serum concentration of HMW adiponectin increased significantly by 42.3% (1.68 vs. 2.39 microg/ml; P < 0.001), while concentrations of MMW adiponectin and LMW adiponectin significantly decreased by 20.8% and 23.2%, respectively (MMW: 3.31 vs. 2.62 microg/ml, P = 0.047; LMW: 0.56 vs. 0.43 microg/ml, P = 0.033). Median total adiponectin levels were not significantly altered by atorvastatin treatment (6.0 vs. 6.2 microg/ml, P = 0.898). Consequently, the HMW: total-adiponectin ratio significantly increased by 25.0% (0.40 vs. 0.50; P = 0.013). CONCLUSIONS: Atorvastatin therapy is associated with significant changes in adiponectin multimer distribution in patients with type 2 diabetes. Since total adiponectin levels were not affected by intervention, atorvastatin may shift adiponectin size towards the HMW form.

Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients.

AIMS: To investigate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of multiple oral doses of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (BI 1356) in patients with type 2 diabetes mellitus. METHODS: Forty-seven male type 2 diabetic patients received linagliptin 1, 2.5, 5 or 10 mg, or placebo, once daily for 12 days. RESULTS: Linagliptin exposure [area under the plasma concentration-time curve and maximum plasma concentration (Cmax)] increased less than proportionally with dose. Accumulation half-life was short (8.6-23.9 h), resulting in rapid attainment of steady state (2-5 days) and little accumulation (range: 1.18-2.03). The long terminal half-life (113-131 h) led to a sustained inhibition of DPP-4 activity. Renal excretion was below 1% on day 1 in all dose groups. Inhibition of plasma DPP-4 activity correlated well with linagliptin plasma concentrations, resulting in DPP-4 inhibition >90% in the two highest dose groups; even 24 h postdose, DPP-4 inhibition was >80%. Following an oral glucose tolerance test, 24 h after the last dose, statistically significant reductions of glucose excursions were observed with linagliptin (2.5, 5 and 10 mg doses) compared with placebo. Linagliptin was well tolerated. The frequency of adverse events (AEs) was not higher with linagliptin (54%) than with placebo (75%). No serious AEs and no episodes of hypoglycaemia were reported. CONCLUSIONS: In type 2 diabetic patients, multiple rising doses of linagliptin were well tolerated and resulted in significant improvements of glucose parameters. Together with the favourable pharmacokinetics, these results confirm the unique profile of linagliptin in the DPP-4 inhibitor class.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers.

This randomized, double-blind, parallel, placebo-controlled, single rising-dose study investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of BI 1356 (once-daily, given orally) in healthy men. BI 1356 was well tolerated and safe up to and including a dose of 600 mg. The incidence of drug-related adverse events was equal in subjects receiving BI 1356 (30%) or placebo (31%). No clinically relevant deviations in laboratory or ECG parameters were reported. Exposure of BI 1356 increased less than proportionally from 2.5 mg to 5 mg, more than proportionally from 25 mg to 100 mg and approximately proportionally for doses from 100 mg to 600 mg. The geometric mean terminal half-life was up to 184 hours. Renal excretion was low. All doses of BI 1356 inhibited plasma dipeptidyl peptidase 4 activity. Single doses of 2.5 mg and 5 mg inhibited dipeptidyl peptidase 4 activity by 72.7% and 86.1% from baseline, respectively. The time to achieve maximum inhibition shifted with increasing doses from 3 hours (2.5 mg) to <0.7 hours (> or =200 mg). Within the dose range tested, a direct pharmacokinetic/pharmacodynamic relationship was observed. The pharmacokinetic and pharmacodynamic profile results demonstrate the potency and full 24-hour duration of action of BI 1356. Based on an estimated therapeutic dose of 5 mg, the therapeutic window of BI 1356 is expected to be >100-fold.

Low hepatic lipase activity is a novel risk factor for coronary artery disease.

BACKGROUND: The crucial function of hepatic lipase (HL) in lipid metabolism has been well established, but the relationship between HL activity and coronary artery disease (CAD) is disputed. METHODS AND RESULTS: We measured HL activity in the postheparin plasma of 200 consecutive men undergoing elective coronary angiography and determined the degree of CAD with the extent score, which has been shown to be better correlated with known risk factors than other measures of CAD extent. We found a significant inverse correlation between HL activity and the extent of CAD (r=-0.19, P<0.01). This association was mainly due to patients with HDL levels >0.96 mmol/L (n=94, r=-0.30, P<0.005). HL activity was lower in 173 patients with CAD than in 40 controls with normal angiograms (286+/-106 versus 338+/-108 nmol. mL(-1). min(-1), P<0.01). To correct for potential confounding factors, we performed multivariate analyses that confirmed the independent association of HL activity with CAD extent. In addition, the presence of the T allele at position -514 in the HL promoter, which leads to a reduced HL promoter activity, was associated with lower HL activity (r=0.30, P<0.001) and higher CAD extent (42.2+/-20.8 versus 35.3+/-23.6 [extent score], P<0.05). In patients with heterozygous familial hypercholesterolemia, calcified lesions in ECG-gated spiral computed tomography were higher in patients with low HL activity (6.3+/-6.8 versus 1.5+/-3.1, P=0.01). CONCLUSIONS: Our data show that low HL activity is associated with CAD. Therefore, HL might be useful for CAD risk estimation and might be a target for pharmacological intervention.

Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozygous familial hypercholesterolemia.

The high concentrations of low-density lipoprotein cholesterol in plasma lead to accelerated atherosclerosis in patients homozygous for familial hypercholesterolemia (FH). We addressed the hypothesis that lipid deposition in the arterial vasculature and in nonvascular tissues in these patients correlates with both the duration and severity of their hypercholesterolemia. The severity of calcific atherosclerosis was defined by calcification scores and a calcified volume determined by electron beam tomography. The extent of tendinous xanthomatosis was quantitated by computed tomography. A cholesterol-year score was calculated based on the age and the yearly mean serum cholesterol concentration of each patient. Seventeen patients homozygous for FH were followed up. The average total cholesterol concentration in the study group was 780 +/- 231 mg/dl (20.2 mmol/L), and the cholesterol-year scores ranged from 2,172 mg-year/dl (56 mmol-year/L) to 32,260 mg-year/dl (834 mmol-year/L). Achilles tendon width (r=0.86) and cross-sectional area (r=0.81; both p <0.001) were best correlated with the cholesterol-year score. In addition, the coronary (r=0.61; p<0.05), ostial (r=0.45; p<0.05), and total (r= 0.77; p<0.001) calcification atherosclerosis scores all were best correlated with the cholesterol-year score. Calcific atherosclerosis was not observed in these patients until the cholesterol-year score exceeded 10,000 mg-year/dl (260 mmol-year/L). These findings establish a direct association of cholesterol-year with extravascular lipid deposition in tissues of patients with FH. The cholesterol-year score may be useful in defining the risk of atherosclerosis in patients with more common forms of hypercholesterolemia.

Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects.

OBJECTIVE: Linagliptin (BI 1356) is a novel, orally available inhibitor of dipeptidyl peptidase-4 (DPP-4). Linagliptin improves glycaemic control in type 2 diabetic patients by increasing the half-life of the incretin hormone glucagon-like peptide-1 (GLP-1). Linagliptin is expected to be used as monotherapy or in combination with other antihyperglycaemic agents. This study was conducted to investigate potential pharmacokinetic or pharmacodynamic interactions between linagliptin and metformin. METHODS: This randomised, monocentric, open-label, two-way crossover design study was conducted in 16 healthy male subjects. Linagliptin (10 mg/day) and metformin (850 mg three times daily) were each administered alone and concomitantly. The steady-state pharmacokinetics of linagliptin and metformin and the inhibition of DPP-4 activity were determined at the end of each dosing period. RESULTS: Co-administration of linagliptin had no apparent effect on metformin exposure (metformin AUC(tau,ss); geometric mean ratio [GMR] co-administration:individual administration was 1.01; 90% confidence interval [CI] was 0.89-1.14). Effects on maximum concentration (C(max,ss)) were small (GMR: 0.89; 90% CI: 0.78-1.00). Co-administration of metformin did not significantly affect C(max,ss) of linagliptin (GMR: 1.03; 90% CI: 0.86-1.24), but increased AUC(tau)(,ss) by 20% (GMR: 1.20; 90% CI: 1.07-1.34). Metformin alone had no effect on DPP-4 activity, and the inhibition of DPP-4 caused by linagliptin was not affected by concomitant administration of metformin. Tolerability was good whether linagliptin and metformin were administered alone or concomitantly. No serious adverse events occurred and the frequency of adverse events was low; 7 events in 6 subjects. The most frequent events were related to the gastrointestinal tract, as expected with metformin. Importantly, no subjects experienced signs or symptoms relating to episodes of hypoglycaemia. CONCLUSION: In this small, multiple dose study carried out in healthy subjects, co-administration of linagliptin with metformin did not have a clinically relevant effect on the pharmacokinetics or pharmacodynamics of either agent. This study suggests linagliptin and metformin can safely be administered concomitantly in type 2 diabetes patients without dose adjustment; larger, longer-term clinical trials in diabetic patients are underway.

The proline 12 alanine substitution in the PPARgamma2 gene is associated with increased extent of coronary artery disease in men.

OBJECTIVE: To determine whether there is an independent association between the Pro12Ala polymorphism in the peroxisome proliferator-activated-receptor gamma2 (PPARgamma2)-gene and the extent of coronary artery disease in men. RESEARCH DESIGN AND METHODS: We determined the Pro12Ala polymorphism in the PPARgamma2 gene in 240 male patients undergoing elective coronary angiograpy, and quantitated the degree of CAD by evaluating the extent-score which better correlates with known risk factors than other measures of CAD. RESULTS: The presence of the 12Ala allele was significantly associated with higher CAD extent (r=0.27, p<0.01). CAD extent was also correlated with the extent of insulin resistance (HOMA, r=0.22, p<0.01), and age (r=0.16, p<0.05). Multivariate analysis revealed an independent association between the 12Ala allele PPARgamma2 with extent-score (beta=0.32, p<0.01). CONCLUSIONS: The 12Ala allele in PPARgamma2 correlates with a significantly increased CAD extent in men, which suggest that lower activity of the transcription factor PPARgamma2 is associated with more severe CAD.

Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease.

AIMS/HYPOTHESIS: Retinol-binding protein 4 (RBP4) has recently been reported to be associated with insulin resistance and the metabolic syndrome. This study tested the hypothesis that RBP4 is a marker of insulin resistance and the metabolic syndrome in patients with type 2 diabetes or coronary artery disease (CAD) or in non-diabetic control subjects without CAD. METHODS: Serum RBP4 was measured in 365 men (126 with type 2 diabetes, 143 with CAD and 96 control subjects) and correlated with the homeostasis model assessment of insulin resistance index (HOMA-IR), components of the metabolic syndrome and lipoprotein metabolism. RBP4 was detected by ELISA and validated by quantitative Western blotting. RESULTS: RBP4 concentrations detected by ELISA were shown to be strongly associated with the results gained in quantitative Western blots. There were no associations of RBP4 with HOMA-IR or HbA(1c) in any of the groups studied. In patients with type 2 diabetes there were significant positive correlations of RBP4 with total cholesterol, LDL-cholesterol, VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity. In patients with CAD, there were significant associations of RBP4 with VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity, while non-diabetic control subjects without CAD showed positive correlations of RBP4 with VLDL-cholesterol and plasma triacylglycerol. CONCLUSIONS/INTERPRETATION: RBP4 does not seem to be a valuable marker for identification of the metabolic syndrome or insulin resistance in male patients with type 2 diabetes or CAD. Independent associations of RBP4 with pro-atherogenic lipoproteins and enzymes of lipoprotein metabolism indicate a possible role of RBP4 in lipid metabolism.

Structure, function and role of lipoprotein lipase in lipoprotein metabolism.

In the past several years the importance of lipoprotein lipase (LPL) as a multifunctional protein, involved in several different aspects of lipid and lipoprotein metabolism, has become evident. Thus, in addition to its traditional role in mediating the initial hydrolysis of circulating plasma triglycerides, recent studies implicate LPL in the binding of lipoproteins to cell surfaces and receptors, as well as indicating a potential role for LPL in the pathogenesis of atherosclerosis. Enhanced understanding of LPL structure, function and mechanism of action has provided insights into new potential pathways by which defects in LPL function may result in the development of different hyperlipidemic disorders and/or atherosclerosis.