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

Rosenstock J, Marx N, Neubacher D, Seck T, Patel S, Woerle HJ, Johansen OE - Cardiovasc Diabetol (2015)

Bottom Line: The cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM).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.Linagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

View Article: PubMed Central - PubMed

Affiliation: Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA. juliorosenstock@dallasdiabetes.com.

ABSTRACT

Background: The cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM).

Methods: Pre-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.

Results: 5847 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.

Conclusions: Linagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

No MeSH data available.


Related in: MedlinePlus

HR estimates for secondary composite CV end points with linagliptin versus total comparators based on Cox hazard model. CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration; HR, hazard ratio; MACE, major adverse CV events; MI, myocardial infarction.
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Fig4: HR estimates for secondary composite CV end points with linagliptin versus total comparators based on Cox hazard model. CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration; HR, hazard ratio; MACE, major adverse CV events; MI, myocardial infarction.

Mentions: In line with the results for the primary end point, the incidence rates and the HRs for the secondary end points were similar for linagliptin and total comparators (Tables 7 and 8). The overall risk estimates were also similar for tertiary end points for linagliptin and total comparators (Table 7, Figure 4), with a significantly reduced HR for stroke and TIA favoring linagliptin compared with total comparators. For hospitalization for CHF, a small number of patients reported events (n = 21), and the overall risk estimate was similar for linagliptin (12 events; 2039 patients) and the total comparator group (9 events, 1275 patients), with a HR of 1.04 (95% CI, 0.43–2.47). This was also the case in a sensitivity analysis of the smaller treatment cohort, excluding data beyond 12 weeks from 1 trial (1218.64) in which 107 placebo-treated patients were switched to treatment with glimepiride. In this sensitivity analysis, the total number of adjudicated CHF events was 9 in the linagliptin group and 5 in the placebo group, yielding a non-significant HR of 1.29 (95% CI, 0.43–3.87).Figure 4


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

Rosenstock J, Marx N, Neubacher D, Seck T, Patel S, Woerle HJ, Johansen OE - Cardiovasc Diabetol (2015)

HR estimates for secondary composite CV end points with linagliptin versus total comparators based on Cox hazard model. CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration; HR, hazard ratio; MACE, major adverse CV events; MI, myocardial infarction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4465456&req=5

Fig4: HR estimates for secondary composite CV end points with linagliptin versus total comparators based on Cox hazard model. CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration; HR, hazard ratio; MACE, major adverse CV events; MI, myocardial infarction.
Mentions: In line with the results for the primary end point, the incidence rates and the HRs for the secondary end points were similar for linagliptin and total comparators (Tables 7 and 8). The overall risk estimates were also similar for tertiary end points for linagliptin and total comparators (Table 7, Figure 4), with a significantly reduced HR for stroke and TIA favoring linagliptin compared with total comparators. For hospitalization for CHF, a small number of patients reported events (n = 21), and the overall risk estimate was similar for linagliptin (12 events; 2039 patients) and the total comparator group (9 events, 1275 patients), with a HR of 1.04 (95% CI, 0.43–2.47). This was also the case in a sensitivity analysis of the smaller treatment cohort, excluding data beyond 12 weeks from 1 trial (1218.64) in which 107 placebo-treated patients were switched to treatment with glimepiride. In this sensitivity analysis, the total number of adjudicated CHF events was 9 in the linagliptin group and 5 in the placebo group, yielding a non-significant HR of 1.29 (95% CI, 0.43–3.87).Figure 4

Bottom Line: The cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM).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.Linagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

View Article: PubMed Central - PubMed

Affiliation: Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA. juliorosenstock@dallasdiabetes.com.

ABSTRACT

Background: The cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM).

Methods: Pre-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.

Results: 5847 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.

Conclusions: Linagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

No MeSH data available.


Related in: MedlinePlus