Efficacy and Cardiovascular (CV) Safety of Linagliptin as Add-on to Insulin in Type 2 Diabetes (T2D)—A Pooled Comprehensive Post-Hoc Analysis

Abstract

Combination of a DPP-4 inhibitor with insulin is a novel glucose-lowering strategy in T2D. We assessed the efficacy and CV safety of linagliptin (LINA) as add-on to insulin (basal only or basal/bolus) in 1613 patients enrolled in 4 randomized, controlled trials, lasting 6–18 months. Glycemia, lipid profile, blood pressure (BP) and heart rate (HR) were assessed as change from baseline to last available value. Hypoglycemia was collected as investigator reported adverse events while CV events and overall mortality were prospectively and independently adjudicated. Linagliptin when added to insulin reduced HbA1c significantly as compared to comparator (–0.1±1.0, –0.5±1.0; p<0.001; comparators, LINA respectively) and also provided a relative weight benefit (+0.6±3.5 kg vs. –0.1±4.5 kg; p=0.0024; comparators vs. LINA respectively) and reduced insulin requirement (+2.3±13 vs. 0.7±15.7; p=0.0189; comparators vs. LINA respectively) without affecting lipids, BP or HR (data not shown). Incidence of hypoglycemia, including confirmed with plasma glucose ≤3.9 mmol/L, or severe hypoglycaemia, did not increase. Incidence rates of the composite of CV death, myocardial infarction, stroke and hospitalization for unstable angina (4P-MACE) was ∼ 3%/year, without between-group differences. Linagliptin, when added to ongoing insulin-treatment, provided a beneficial impact on efficacy parameters and had a neutral impact on 4P-MACE and total mortality. The ongoing CAROLINA and CARMELINA trials will provide further insights into this combination. TableBaseline demographics, clinical characteristics, and impact on efficacy/safety parameters from baseline to last treatment. Data given as mean ± SD Comparator (n=802) Linagliptin (n=811) Characteristics Age (years), mean ± SD 62±10 62±10 Male/ Female, % 54.5/45.5 55.2/44.8 BMI, kg/m2 31.4±5.2 31.1±5.6 Race (White/Black/Asian), % 79/6/15 80/7/13 Diabetes duration > 5 years , % 89.3 86.6 CV risk factors and CV medications Current smoker, % 13.3 14.9 Urinary albumine-creatinine ratio (mg/g), %Microalbuminuria (30–300)Macroalbuminuria (≥ 300) 25.417.0 30.313.6 Coronary artery disease/cerebrovascular disease,% 24.1/8.6 23.7/9.0 Hypertension,% 82.9 82.9 Statins/ASA,% 58.5/55.1 55.1/57.5 Exposure to therapy Median days (min, max) 371 (1–707) 372 (1–712) Patient years (cumulative) 863 899 Impact on HbA1c, insulin requirement, weight and hypoglycemia Statistical evaluation HbA1c, % Baseline 8.3±0.9 8.3±0.9 Change from baseline to end of treatment –0.1±1.0 –0.5±1.0 p<0.001 Insulin, U Basal insulin, % 85.8% 86.2% Baseline dose 46±39 48±38 Change from baseline to end of treatment 2.3±13.0 0.7±15.7 p=0.0189 Weight, kg Baseline 86.2±18.9 85.9±19.3 Change from baseline to end of treatment 0.6±3.5 –0.1±4.5 p=0.0024 Hypoglycemia, n (%) patients exhibiting at least 1 event Any asymptomatic or symptomatic hypoglycemia 316 (39.4) 314 (38.7) OR 0.99*(0.81, 1.23) Any severe# or symptomatic hypoglycemia with PG ≤70 mg/dL 237 (29.6) 221 (27.3) Any severe# or symptomatic hypoglycemia with PG <54 mg/dL 135 (16.8) 128 (15.8) OR 0.95*(0.73, 1.24) Any severe# hypoglycemia 17 (2.1) 23 (2.8) Adjudicated CV events/mortality 4P-MACE** Incidence rate per 1000 pat years/n 27.5/24 29.8/27 HR 1.07***(0.62, 1.85) Overall mortality Incidence rate per 1000 pat years/n 9.1/8 8.8/8 HR 0.96***(0.36, 2.57) #: Severe hypoglycemia defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. *: Odds ratio by logistic regression model, **: a composite endpoint of CV death, myocardial infarction, stroke and hospitalization for unstable angina pectoris; ***: Hazard ratio by Cox proportional model. Open table in a new tab #: Severe hypoglycemia defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. *: Odds ratio by logistic regression model, **: a composite endpoint of CV death, myocardial infarction, stroke and hospitalization for unstable angina pectoris; ***: Hazard ratio by Cox proportional model.