Abstract

LEADER TRIAL: IMPROVEMENT IN CARDIOVASCULAR OUTCOMES WITH LIRAGLUTIDE IN TYPE 2 DIABETES MELLITUS; EFFECT OF GLYCEMIC CONTROL, NOT LIRAGLUTIDE

*Udaya M. Kabadi

Abstract

It was interesting reading a recent publication which documented that the glycemic control as expressed by the decline in HbA1c is the major contributor to lowering of cardiovascular mortality and morbidity (MACE) in the recent ‘Leader’ trial using Liraglutide in subjects with type 2 diabetes mellitus.[1] It does not come as a surprise since administration of Liraglutide in another study in obese subjects without diabetes did not improve cardiovascular outcomes.[2] Moreover, the degree of improvement in adverse cardiovascular outcomes was correlated with almost identical proportionate lowering of HbA1c levels documented in UKPDS, the landmark gold standard long term study.[3-5] UKPDS consistently demonstrated the role of Glycemic control in Lowering cardiovascular morbidly and mortality in the original trials.[3-5] One point reduction in HbA1c decreased myocardial infarction rates by 14% and all-cause mortality by 20%. Moreover, these cardiovascular benefits persisted despite lapse of glycemic control at 10-20 years described ‘Legacy effect‘ during the ongoing long term follow up period.[6,7] Finally, these cardiovascular benefits ensued and remained persistent irrespective of the drugs used. Metformin lowered the adverse cardiovascular events by 34% in obese subjects whereas Sulfonylureas Glibencllamide and Chlorpropamide or insulin induced a similar decline in non-obese subjects.[3-5] Several recent studies have documented improvement in onset of adverse cardiovascular outcomes in subjects related with insulin glargine.[8,9] Additionally, we have recently documented improvements in cardiovascular surrogate markers as well as outcomes on administration of the newer SU Glimepiride in subjects with type 2 diabetes as well as those manifesting prediabetes.[10,11] Similar long term benefits (metabolic memory effect) over a duration 20- 30 years are also documented despite lapse of attaining initial desirable glycemic goals in subjects with type 1 diabetes participating in Diabetes control complication Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) in USA.[12-15] Alternatively, several recent studies have documented progressively increased cardiovascular outcomes with rising HbA1c levels in subjects with both with and without diabetes mellitus.[16-18] Therefore, based on these extensive data in the literature, I postulated more than 2 years ago (long before the present publication) that the reduction in adverse cardiovascular events in ‘Leader‘ trial may not be attributed to influence of Liraglutide beyond that induced by improvement in glycemic control.[19] Lowering of adverse cardiovascular outcomes may be attributed to Improvement in cardiovascular risk factors, e.g. Lipids, fibrinogen, homocysteine, etc. following attainment and maintenance of glycemic control irrespective of therapeutic modalities.[3-5, 20-22]

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