Takeda Pharmaceutical Company Limited (Takeda) has announced that a post hoc analysis of data from the global EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) cardiovascular (CV) safety outcomes trial were published in The Lancet.1, 2 An analysis of data from the study showed that in patients with Type 2 diabetes and recent acute coronary syndrome (ACS), dipeptidyl peptidase 4 (DPP-4) inhibitor alogliptin compared to placebo did not increase the risk of heart failure (HF) outcomes.1 Alogliptin (n=201, 7.4%) compared with placebo (n=201, 7.5%) had no effect on the extended exploratory post hoc composite endpoint of CV death and hospitalised heart failure (HHF) (HR=1.00, 95% CI, 0.82, 1.21). Patients with a history of HF prior to randomisation had a higher risk of HF outcomes in EXAMINE. The sub-analysis showed that the risk of the composite of CV death and HHF was not increased with alogliptin (n=107, 13.9%) compared with placebo (n=120, 15.7%) (HR=0.90, 95% CI, 0.70, 1.17). In patients without a history of HF at baseline, there was also no increased risk of the composite endpoint of CV death and HHF for alogliptin (HR=1.14 [95% CI 0.85-1.54], p=0.337) versus placebo, although there was in this sub group of patients a small absolute increase in HHF for alogliptin versus placebo (0.9%).
Alogliptin is the first DPP-4i to report results on CV safety outcomes in Type 2 diabetes patients that are at high risk due to recent ACS.2 Heart disease, or cardiovascular disease (CVD), is the leading cause of morbidity and mortality in patients with Type 2 diabetes3, and is responsible for between 50 and 80 percent of deaths in people with diabetes.4
"It is vital that diabetes treatments manage glucose levels effectively, without risk of long-term complications such as cardiovascular disease." said Professor Simon Heller, Professor of Clinical Diabetes, University of Sheffield, "The findings from the EXAMINE study demonstrates that alogliptin compared with placebo does not increase the combined rate of cardiovascular mortality and hospitalised heart failure in this high risk population of patients with diabetes."
The EXAMINE trial was designed to evaluate CV safety following treatment with alogliptin in addition to standard of care, versus placebo in addition to standard of care, in patients with Type 2 diabetes and a recent ACS.2 The EXAMINE trial's primary composite endpoint (CV death, nonfatal myocardial infarction and nonfatal stroke) established non-inferiority of alogliptin compared to placebo in addition to standard of care, showing no increase in CV risk in a Type 2 diabetes patient population at high risk for CV events.
For the present study published in The Lancet, HF outcomes by quartile of baseline brain natriuretic peptide (BNP), as well as assessments of changes of N-Terminal proBNP (NT-proBNP) from baseline to six months were investigated.1 Patients in the highest quartile of baseline BNP were at the highest risk of HF outcomes; however, the risk of the composite endpoint of CV death and HHF was not increased with alogliptin (n=120, 17.5%) compared with placebo (n=121, 19.4%) (HR=0.90, 95% CI, 0.70, 1.16). Consistent with these outcomes, the change from baseline to six months for NT-proBNP was not different between alogliptin and placebo in this subgroup or in the overall study population.
About the EXAMINE Trial
EXAMINE randomised 5,380 patients in 49 countries with Type 2 diabetes with an ACS within the previous 15-90 days.2 The EXAMINE primary endpoint of non-inferiority compared to placebo in addition to standard of care was met, showing no increase in CV risk in a Type 2 diabetes patient population at high risk for CV events based on the primary composite endpoint of CV death, nonfatal myocardial infarction and nonfatal stroke. The primary endpoint occurred at similar rates in the alogliptin and placebo groups (in 11.3 percent of patients vs. 11.8 percent of patients during a median follow-up period of 18 months; HR, 0.96; upper boundary of the one-sided repeated CI, 1.16).
In the alogliptin group, 71.4 percent of patients received 25 mg, 25.7 percent received 12.5 mg, and 2.9 percent received 6.25 mg daily.2 Alogliptin doses were adjusted according to renal function: estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease formula ≥ 60 ml/min/1.73 m2, 25 mg daily; < 60 ml/min/1.73 m2 but ≥ 30 ml/min/1.73 m2, 12.5 mg daily; and < 30 ml/min/1.73 m2, 6.25 mg daily. Premature discontinuation of the study drug was similar in the alogliptin and placebo groups (20.9 percent of patients vs. 22.6 percent). The median duration of exposure to study drug was 533 days (interquartile range, 280 to 751 days). By the end of the study, the mean change from baseline in HbA1c was -0.33 percent and 0.03 percent in the alogliptin and placebo groups respectively, and the least square means difference in HbA1c between alogliptin and placebo was -0.36 percent (95 percent CI, -0.43, -0.28, p<0.001). In the analysis of the components of the primary endpoint, the hazard ratios were consistent with the overall result. Hazard ratios for death from any cause and CV death were consistent with the primary composite endpoint.
Takeda conducted the global EXAMINE trial in accordance with the United States (U.S.) Food and Drug Administration's (FDA) 2008 Guidance, titled "Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes," for all new Type 2 diabetes treatments.5
About Vipidia (Alogliptin)
Alogliptin is a prescription oral anti-diabetes agent and is part of the dipeptidyl-peptidase-4 inhibitor (DPP-4i) class of drugs. It is indicated for the treatment of Type 2 diabetes in adults aged 18 years and older to improve glycaemic control in combination with other glucose lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.6
Alogliptin is designed to stimulate the body's normal response to glucose regulation. Alogliptin is a selective DPP-4 inhibitor, designed to slow the inactivation of incretin hormones.6
Alogliptin is also available in a fixed-dose combination (FDC) therapy in the UK. Vipdomet combines alogliptin with metformin (12.5 mg alogliptin/1,000 mg metformin hydrochloride), a widely used Type 2 diabetes medication, in a single twice-daily tablet indicated for use in the treatment of adult patients aged 18 years and older with Type 2 diabetes mellitus:7
- as an adjunct to diet and exercise to improve glycaemic control in adult patients, inadequately controlled on their maximal tolerated dose of metformin alone, or those already being treated with the combination of alogliptin and metformin
- in combination with pioglitazone (i.e. triple combination therapy) as an adjunct to diet and exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and pioglitazone
- in combination with insulin (i.e. triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when insulin at a stable dose and metformin alone do not provide adequate glycaemic control
Further information on alogliptin can be found in the Summary of Product Characteristics (SmPC) and Patient Information Leaflet (PIL) which can be obtained at www.medicines.org.uk.