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 β-cell function. The safety profile of linagliptin was comparable with that of placebo.
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.
Aim: This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor with a primarily non‐renal route of excretion, ...in subjects with type 2 diabetes mellitus (T2DM).
Methods: Linagliptin pharmacokinetics was studied under single‐dose and steady‐state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end‐stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM).
Results: Renal excretion of unchanged linagliptin was <7% in all groups. Under single‐dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration–time profiles. These showed a similar decline and almost identical plasma concentrations 24 h postdosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20–60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady‐state AUC and Cmax values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half‐life of linagliptin ranged from 14–15 h in subjects with normal renal function to 18 h in severe renal impairment. Only a weak correlation (r2 = 0.18) was seen between creatinine clearance and steady‐state exposure.
Conclusions: Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM.
Aims: To evaluate the efficacy and safety of initial combination therapy with linagliptin plus metformin versus linagliptin or metformin monotherapy in patients with type 2 diabetes.
Methods: In this ...24‐week, double‐blind, placebo‐controlled, Phase III trial, 791 patients were randomized to one of six treatment arms. Two free combination therapy arms received linagliptin 2.5 mg twice daily (bid) + either low (500 mg) or high (1000 mg) dose metformin bid. Four monotherapy arms received linagliptin 5 mg once daily, metformin 500 mg or 1000 mg bid or placebo. Patients with haemoglobin A1c (HbA1c) ≥11.0% were not eligible for randomization and received open‐label linagliptin + high‐dose metformin.
Results: The placebo‐corrected mean (95% confidence interval) change in HbA1c from baseline (8.7%) to week 24 was −1.7% (−2.0, −1.4) for linagliptin + high‐dose metformin, −1.3% (−1.6, −1.1) for linagliptin + low‐dose metformin, −1.2% (−1.5, −0.9) for high‐dose metformin, −0.8% (−1.0, −0.5) for low‐dose metformin and −0.6 (−0.9, −0.3) for linagliptin (all p < 0.0001). In the open‐label arm, the mean change in HbA1c from baseline (11.8%) was −3.7%. Hypoglycaemia occurred at a similar low rate with linagliptin + metformin (1.7%) as with metformin alone (2.4%). Adverse event rates were comparable across treatment arms. No clinically significant changes in body weight were noted.
Conclusions: Initial combination therapy with linagliptin plus metformin was superior to metformin monotherapy in improving glycaemic control, with a similar safety and tolerability profile, no weight gain and a low risk of hypoglycaemia.
Diabet. Med. 27, 1409–1419 (2010)
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 (HbA1c≥ 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 HbA1c 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 HbA1c 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 HbA1c 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.
Aims: To assess the safety and tolerability of the dipeptidyl peptidase‐4 inhibitor linagliptin in patients with type 2 diabetes.
Methods: Data were pooled from eight randomized, double‐blind, ...placebo‐controlled Phase III clinical trials lasting ≤24 weeks. Incidences were calculated with descriptive statistics for the overall population and for subgroups of elderly and renally impaired patients.
Results: A total of 2523 patients received linagliptin 5 mg once daily and 1049 patients received placebo. The overall incidence of adverse events (AEs) or serious AEs with linagliptin was similar to placebo (AEs 55.8% vs. 55.0%; serious AEs 2.8% vs. 2.7%). Overall aggregated infection incidence was 19.5% for linagliptin and 21.4% for placebo. Similar or reduced incidence of AEs versus placebo were seen with linagliptin for upper respiratory tract infection (3.3% vs. 4.9%), headache (2.9% vs. 3.1%), urinary tract infection (2.2% vs. 2.7%), blood and lymphatic disorders (1.0% vs. 1.2%), hypersensitivity (0.1% vs. 0.1%), hepatic enzyme increase (0.1% and 0.1%) and serum creatinine increase (0.0% and 0.1%). There was a slight increased frequency of nasopharyngitis (5.9% vs. 5.1%) and cough (1.7% vs. 1.0%) with linagliptin. Hypoglycaemia incidence was 8.2% for linagliptin and 5.1% for placebo; incidence was higher in patients with a background of sulphonylurea therapy (20.7% and 13.3%, respectively). In patients not receiving concomitant sulphonylurea, the hypoglycaemic incidence with linagliptin was very low in both the total population (<1%), and elderly and renally impaired patients (both <1%).
Conclusions: This pooled analysis shows that linagliptin is well tolerated, with a low risk of hypoglycaemia.
Aims
This study investigated the efficacy and tolerability of empagliflozin as add‐on to pioglitazone ± metformin in patients with type 2 diabetes (T2DM).
Methods
Patients with HbA1c ≥7 and ≤10% were ...randomized and treated with once daily empagliflozin 10 mg (n = 165), empagliflozin 25 mg (n = 168) or placebo (n = 165) as add‐on to pioglitazone ± metformin for 24 weeks. Endpoints included changes from baseline in HbA1c (primary endpoint), fasting plasma glucose (FPG) and body weight at week 24.
Results
Adjusted mean ± standard error changes in HbA1c were −0.6 ± 0.07% and −0.7 ± 0.07% with empagliflozin 10 mg and 25 mg, respectively, vs. −0.1 ± 0.07% with placebo (both p < 0.001). More patients with HbA1c ≥7% at baseline achieved HbA1c <7% with empagliflozin 10 mg (23.8%) and 25 mg (30.0%) vs. placebo (7.7%) (both p < 0.001). FPG decreased with empagliflozin (−0.94 mmol/l for 10 mg and −1.22 mmol/l for 25 mg) and increased with placebo (+0.36 mmol/l; both p < 0.001). Adjusted mean ± standard error changes in weight were −1.62 ± 0.21 kg and −1.47 ± 0.21 kg with empagliflozin 10 mg and 25 mg, respectively, vs. +0.34 ± 0.21 kg with placebo (both p < 0.001). Similar proportions of patients reported adverse events with empagliflozin (67.3–71.4%) and placebo (72.7%). Confirmed hypoglycaemia was reported by 1.2–2.4% of patients on empagliflozin and 1.8% on placebo.
Conclusion
Empagliflozin 10 mg and 25 mg once daily for 24 weeks as add‐on to pioglitazone ± metformin reduced HbA1c, FPG and weight and were well tolerated in patients with T2DM.
Aims
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.
Methods
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.
Results
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.
Conclusions
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).
What's new?
Combination therapy of two or more oral anti‐hyperglycaemic drugs is often necessary to reach glycaemic targets in patients with Type 2 diabetes mellitus.
The combination of metformin and pioglitazone is often prescribed, but, when HbA1c goals are not achieved, treatment guidelines recommend adding a third oral anti‐hyperglycaemic drug.
Few studies have evaluated the effects of triple oral therapy with a dipeptidyl peptidase‐4 inhibitor, metformin and pioglitazone.
The results of this study show that linagliptin may be an effective and safe treatment option for patients with Type 2 diabetes who have failed to reach glycaemic targets with metformin and pioglitazone.
Aims
To investigate the efficacy and tolerability of empagliflozin added to basal insulin‐treated type 2 diabetes.
Methods
Patients inadequately controlled glycated haemoglobin (HbA1c) >7 to ≤10% ...(>53 to ≤86 mmol/mol) on basal insulin (glargine, detemir, NPH) were randomized to empagliflozin 10 mg (n = 169), empagliflozin 25 mg (n = 155) or placebo (n = 170) for 78 weeks. The baseline characteristics were balanced among the groups mean HbA1c 8.2% (67 mmol/mol), BMI 32.2 kg/m2. The basal insulin dose was to remain constant for 18 weeks, then could be adjusted at investigator's discretion. The primary endpoint was change from baseline in HbA1c at week 18. Key secondary endpoints were changes from baseline in HbA1c and insulin dose at week 78.
Results
At week 18, the adjusted mean ± standard error changes from baseline in HbA1c were 0.0 ± 0.1% (−0.1 ± 0.8 mmol/mol) for placebo, compared with −0.6 ± 0.1% (−6.2 ± 0.8 mmol/mol) and −0.7 ± 0.1% (−7.8 ± 0.8 mmol/mol) for empagliflozin 10 and 25 mg, respectively (both p < 0.001). At week 78, empagliflozin 10 and 25 mg significantly reduced HbA1c, insulin dose and weight vs placebo (all p < 0.01), and empagliflozin 10 mg significantly reduced systolic blood pressure vs placebo (p = 0.004). Similar percentages of patients had confirmed hypoglycaemia in all groups (35–36%). Events consistent with urinary tract infection were reported in 9, 15 and 12% of patients on placebo, empagliflozin 10 and 25 mg, and events consistent with genital infection were reported in 2, 8 and 5%, respectively.
Conclusions
Empagliflozin for 78 weeks added to basal insulin improved glycaemic control and reduced weight with a similar risk of hypoglycaemia to placebo.
ABSTRACT
Aim
To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of empagliflozin in patients with type 2 diabetes following oral administration of 10, 25 or 100 mg doses ...once daily over 28 days.
Methods
A total of 78 patients were assigned to empagliflozin 10 mg (n = 16), 25 mg (n = 16) or 100 mg (n = 30) or placebo (n = 16) for 28 days. Assessments included adverse events (AEs) and pharmacokinetic and pharmacodynamic endpoints.
Results
Empagliflozin exposure increased dose‐proportionally over the dose range 10–100 mg and showed linear pharmacokinetics with respect to time. Urinary glucose excretion (UGE) increased from baseline to day 1 by 74, 90 and 81 g with empagliflozin 10, 25 and 100 mg, respectively. The increases in UGE were maintained over 28 days with multiple dosing. Virtually no change in UGE was observed in the placebo group. Significant reductions from baseline in mean daily plasma glucose and fasting plasma glucose were observed with empagliflozin compared with placebo. The incidence of AEs was similar in the empagliflozin and placebo groups (50.0, 56.3 and 66.7% with empagliflozin rising doses and 62.5% with placebo). The most frequently reported AEs were pollakiuria (10.3%), nasopharyngitis (9.0%), constipation (9.0%) and headache (7.7%).
Conclusions
Oral administration of empagliflozin at doses of 10, 25 or 100 mg once daily over 28 days resulted in significant increases in UGE and reductions in blood glucose compared with placebo, and were well tolerated in patients with type 2 diabetes.
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