Reconsidering the role of glycaemic control in cardiovascular disease risk in type 2 diabetes: A 21st century assessment

Abstract

It is well known that the multiple factors contributing to the pathogenesis of type 2 diabetes (T2D) confer an increased risk of developing cardiovascular disease (CVD). Although the relationship between hyperglycaemia and increased microvascular risk is well established, the relative contribution of hyperglycaemia to macrovascular events has been strongly debated, particularly owing to the failure of attempts to reduce CVD risk through normalizing glycaemia with traditional therapies in high-risk populations. The debate has been further fuelled by the relatively recent discovery of the cardioprotective properties of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors. Further, as guidelines now recommend individualizing glycaemic targets, highlighting the importance of achieving glycated haemoglobin (HbA1c) goals safely, the previously observed negative influences of intensive therapy on CVD risk might not present if trials were repeated using current-day treatments and individualized HbA1c goals. Emerging longitudinal data illuminate the overall effect of excess glucose, the impacts of magnitude and duration of hyperglycaemia on disease progression and risk of CVD complications, and the importance of glycaemic control at or early after diagnosis of T2D for prevention of complications. Herein, we review the role of glucose as a modifiable cardiovascular (CV) risk factor, the role of microvascular disease in predicting macrovascular risk, and the deleterious impact of therapeutic inertia on CVD risk. We reconcile new and old data to offer a current perspective, highlighting the importance of effective, early treatment in reducing latent CV risk, and the timely use of appropriate therapy individualized to each patient's needs.

Keywords: cardiovascular disease; diabetes complications; glycaemia; hyperglycaemia; macrovascular disease; type 2 diabetes.

FIGURE 1

Benefits of early treatment of diabetes to reduce latent cardiovascular disease (CVD) risk: The legacy effect. A, UK Prospective Diabetes Study (UKPDS): glycated haemoglobin (HbA1c) over time; B, UKPDS: cardiovascular (CV) outcomes; C, Diabetes Control and Complications Trial (DCCT)/ Epidemiology of Diabetes Interventions and Complications (EDIC): HbA1c over time; D, DCCT/EDIC: CV outcomes. MI, myocardial infarction. A, C and D Reprinted from Ramachandran et al. J Diabetes Metab. 2015;6:4 https://doi.org/10.4172/2155‐6156.1000520 under Creative Commons Attribution License. B From N Engl J Med., B Holman RR, et al. 10‐Year Follow‐up of Intensive Glucose Control in Type 2 Diabetes, 359, 1577‐89. Copyright © 2008. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

FIGURE 2

Microvascular disease is predictive of cardiovascular disease (CVD) risk. Analysis of 49 027 people with type 2 diabetes and no established CVD at baseline. Participants were followed for a median of 5.5 years for the primary outcome of time to first cardiovascular (CV) event. LDL, low‐density lipoprotein. Reprinted from The Lancet, Vol. 4, Brownrigg JRW, et al. Microvascular disease and risk of cardiovascular events among individuals with type 2 diabetes: a population‐level cohort study, 588‐597, Copyright 2016, with permission from Elsevier

FIGURE 3

Contributory mechanisms of hyperglycaemia to vascular and kidney disease. ASCVD, atherosclerotic cardiovascular disease; NO, nitric oxide; SMC, smooth muscular cells