Linagliptin in Subjects at High Risk for Renal and CVD
Across the six studies, 3,119 patients were treated with either linagliptin 5 mg once daily (2,222) or placebo (897). Among that population, 512 patients were identified as having both microalbuminuria and hypertension at baseline and were therefore eligible for inclusion in the pooled analysis. At baseline, patient demographics and clinical characteristic were similar in the linagliptin and placebo groups (Table 1). In the overall evaluated population patients had a mean age of 59.5 years, with mean BMI of 29.9 kg/m. Baseline mean (SD) HbA1c and FPG were similar in both treatment groups (HbA1c: linagliptin, 8.3 [0.9]% and placebo, 8.4 [0.9]%; FPG: linagliptin, 176 [52] mg/dl and placebo, 178 [39] mg/dl). At baseline, the majority of patients were being treated with two OADs (48.6%) and had known diabetes for > 5 years (57.6%). The median (range) UACR at baseline was 60 (30–292) mg/g for linagliptin and 64 (30–298) mg/g for placebo. The mean (SD) SBP was 138 (15) mm Hg and 135 (16) mm Hg, and mean (SD) DBP was 81 (10) mm Hg and 81 (10) mm Hg for linagliptin and placebo, respectively.
Antihypertensive therapy was taken by 86.3% and 84.9% of patients in the linagliptin and placebo groups, respectively. The most commonly reported antihypertensive drugs were angiotensin-converting enzyme (ACE) inhibitors (linagliptin, 40.4% and placebo, 41.1%).
Among patients with microalbuminuria and hypertension, those treated with linagliptin achieved a significantly greater reduction in HbA1c from baseline compared with placebo (Figure 3). The adjusted mean change from baseline (SE) in HbA1c at week 18 was −0.57 (0.06)% for linagliptin and 0.0 (0.08)% for placebo, resulting in a placebo-corrected mean change from baseline in HbA1c of −0.57% (95% confidence interval [CI]: −0.75, −0.39; P < 0.0001). At week 24, the adjusted mean change from baseline in HbA1c was −0.65 (0.06)% and −0.05 (0.09)% in the linagliptin and placebo groups, respectively. In these patients, the placebo-corrected mean change from baseline in HbA1c was −0.59% (95% CI: −0.80, −0.39; P < 0.0001) at week 24.
(Enlarge Image)
Figure 3.
Change from baseline in HbA1c at week 18 (A)and week 24 (B)(FAS LOCF). *Data based on all six clinical trials. Data based on four clinical trials.
Linagliptin was also better than placebo in lowering FPG levels in this population. Adjusted mean change from baseline (SE) in FPG at week 18 was −12.3 (2.3) mg/dl for linagliptin and −1.6 (3.5) mg/dl for placebo, resulting in a placebo-corrected mean change from baseline of −10.6 mg/dl (95% CI: −18.4, −2.9; P = 0.0074). At week 24, the adjusted mean change from baseline in FPG was −13.4 (2.9) mg/dl and 7.9 (4.4) mg/dl in the linagliptin and placebo groups, respectively. The placebo-corrected mean change from baseline in these patients was −21.3 mg/dl (95% CI: −31.0, −11.6; P < 0.0001).
In the treated set, the overall incidences of any AE and serious AEs were comparable between both treatment groups (linagliptin, 62.6% and placebo, 62.3%; linagliptin, 4.1% and placebo, 6.2%). Investigator-determined drug-related AEs were reported by 10.4% and 8.2% of the linagliptin and placebo groups, respectively.
AEs leading to discontinuation of trial medication were reported by 1.4% and 3.4% of patients in the linagliptin and placebo groups, respectively. Less than 1% of subjects experienced hypoglycemia when linagliptin was administered as monotherapy or in addition to metformin or pioglitazone. However, when linagliptin was administered with a sulfonylurea, the number of patients experiencing hypoglycemia was greater than with placebo (linagliptin, 19.8% and placebo, 5.9%).
The median (range) change in UACR from baseline at week 24 was −13.7 (−240.4 to 695.7) mg/g for linagliptin and −4.9 (−234.3 to 2,263.9) mg/g for placebo. The placebo-corrected median change from baseline in UACR at week 24 was −8.8 mg/g.
Mean (SD) SBP decreased by −2.9 (0.9) mm Hg and −2.4 (1.2) mm Hg in the linagliptin and placebo groups, respectively, at LVOT (Table 2). Mean (SD) DBP decreased by −1.2 (0.6) mm Hg and −1.0 (0.8) mm Hg in the linagliptin and placebo groups, respectively, at LVOT.
Minor changes were observed in lipid parameters in the linagliptin group as compared to the placebo group (Table 2). Total cholesterol, low-density lipoprotein and high-density lipoprotein showed small but non-significant differences between the groups. Triglyceride levels decreased in both treatment groups, with a numerically greater decrease seen with linagliptin (−18.5 mg/dl vs. −13.5 mg/dl).
No deaths occurred in either treatment group of the population of patients with microalbuminuria and hypertension. The incidence of the composite endpoint of adjudicated cardiovascular death, myocardial infarction and stroke was 0.27% (n = 1) and 0.68% (n = 1) in the linagliptin and placebo groups, respectively. A list of AEs by system-organ class is presented in Table 3.
Results
Patient Demographics
Across the six studies, 3,119 patients were treated with either linagliptin 5 mg once daily (2,222) or placebo (897). Among that population, 512 patients were identified as having both microalbuminuria and hypertension at baseline and were therefore eligible for inclusion in the pooled analysis. At baseline, patient demographics and clinical characteristic were similar in the linagliptin and placebo groups (Table 1). In the overall evaluated population patients had a mean age of 59.5 years, with mean BMI of 29.9 kg/m. Baseline mean (SD) HbA1c and FPG were similar in both treatment groups (HbA1c: linagliptin, 8.3 [0.9]% and placebo, 8.4 [0.9]%; FPG: linagliptin, 176 [52] mg/dl and placebo, 178 [39] mg/dl). At baseline, the majority of patients were being treated with two OADs (48.6%) and had known diabetes for > 5 years (57.6%). The median (range) UACR at baseline was 60 (30–292) mg/g for linagliptin and 64 (30–298) mg/g for placebo. The mean (SD) SBP was 138 (15) mm Hg and 135 (16) mm Hg, and mean (SD) DBP was 81 (10) mm Hg and 81 (10) mm Hg for linagliptin and placebo, respectively.
Antihypertensive therapy was taken by 86.3% and 84.9% of patients in the linagliptin and placebo groups, respectively. The most commonly reported antihypertensive drugs were angiotensin-converting enzyme (ACE) inhibitors (linagliptin, 40.4% and placebo, 41.1%).
Efficacy
Among patients with microalbuminuria and hypertension, those treated with linagliptin achieved a significantly greater reduction in HbA1c from baseline compared with placebo (Figure 3). The adjusted mean change from baseline (SE) in HbA1c at week 18 was −0.57 (0.06)% for linagliptin and 0.0 (0.08)% for placebo, resulting in a placebo-corrected mean change from baseline in HbA1c of −0.57% (95% confidence interval [CI]: −0.75, −0.39; P < 0.0001). At week 24, the adjusted mean change from baseline in HbA1c was −0.65 (0.06)% and −0.05 (0.09)% in the linagliptin and placebo groups, respectively. In these patients, the placebo-corrected mean change from baseline in HbA1c was −0.59% (95% CI: −0.80, −0.39; P < 0.0001) at week 24.
(Enlarge Image)
Figure 3.
Change from baseline in HbA1c at week 18 (A)and week 24 (B)(FAS LOCF). *Data based on all six clinical trials. Data based on four clinical trials.
Linagliptin was also better than placebo in lowering FPG levels in this population. Adjusted mean change from baseline (SE) in FPG at week 18 was −12.3 (2.3) mg/dl for linagliptin and −1.6 (3.5) mg/dl for placebo, resulting in a placebo-corrected mean change from baseline of −10.6 mg/dl (95% CI: −18.4, −2.9; P = 0.0074). At week 24, the adjusted mean change from baseline in FPG was −13.4 (2.9) mg/dl and 7.9 (4.4) mg/dl in the linagliptin and placebo groups, respectively. The placebo-corrected mean change from baseline in these patients was −21.3 mg/dl (95% CI: −31.0, −11.6; P < 0.0001).
Safety and Tolerability
In the treated set, the overall incidences of any AE and serious AEs were comparable between both treatment groups (linagliptin, 62.6% and placebo, 62.3%; linagliptin, 4.1% and placebo, 6.2%). Investigator-determined drug-related AEs were reported by 10.4% and 8.2% of the linagliptin and placebo groups, respectively.
AEs leading to discontinuation of trial medication were reported by 1.4% and 3.4% of patients in the linagliptin and placebo groups, respectively. Less than 1% of subjects experienced hypoglycemia when linagliptin was administered as monotherapy or in addition to metformin or pioglitazone. However, when linagliptin was administered with a sulfonylurea, the number of patients experiencing hypoglycemia was greater than with placebo (linagliptin, 19.8% and placebo, 5.9%).
The median (range) change in UACR from baseline at week 24 was −13.7 (−240.4 to 695.7) mg/g for linagliptin and −4.9 (−234.3 to 2,263.9) mg/g for placebo. The placebo-corrected median change from baseline in UACR at week 24 was −8.8 mg/g.
Mean (SD) SBP decreased by −2.9 (0.9) mm Hg and −2.4 (1.2) mm Hg in the linagliptin and placebo groups, respectively, at LVOT (Table 2). Mean (SD) DBP decreased by −1.2 (0.6) mm Hg and −1.0 (0.8) mm Hg in the linagliptin and placebo groups, respectively, at LVOT.
Minor changes were observed in lipid parameters in the linagliptin group as compared to the placebo group (Table 2). Total cholesterol, low-density lipoprotein and high-density lipoprotein showed small but non-significant differences between the groups. Triglyceride levels decreased in both treatment groups, with a numerically greater decrease seen with linagliptin (−18.5 mg/dl vs. −13.5 mg/dl).
No deaths occurred in either treatment group of the population of patients with microalbuminuria and hypertension. The incidence of the composite endpoint of adjudicated cardiovascular death, myocardial infarction and stroke was 0.27% (n = 1) and 0.68% (n = 1) in the linagliptin and placebo groups, respectively. A list of AEs by system-organ class is presented in Table 3.
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