The systemic implication of novel non-statin therapies in cardiovascular diabetology: PCSK9 as a case model

Abstract

PCSK9, like other novel non-statin drugs were primarily developed to help patients achieve low-density lipoprotein cholesterol targets, especially in patients with dyslipidemia not achieving lipid goals with statins due to poor tolerance or inadequate response. PCSK9 inhibitors, in addition to modulating lipid metabolism, improve mortality outcomes in cardiovascular disease. These benefits are markedly pronounced in patients with type 2 diabetes mellitus. However, these benefits do not come without associated risk. Multiple trials, studies, and case reports have attempted to explain observed outcomes with PCSK9 expression and administration of PCSK9 inhibitors from multiple perspectives, such as their effects on insulin sensitivity and glucose tolerance, changes in renal physiology, thyroid physiology, vascular tone, intestinal regulation of lipids, and improved cardiovascular function. These agents represent an opportunity for physicians to exercise prudence by using appropriate clinical judgement when managing comorbidities in the hyperglycemic patient, a concept that extends to other novel non-statin drugs.

Keywords: PCSK9; cardiology; cardiovascular disease; diabetes; diabetology; dyslipidemia; heart failure; metabolism; statin; therapeutics; translational biology.

Fig. 1

Trends of age-adjusted death related to atherosclerotic cardiovascular disease per death certificate information in US counties, 1999–2017. Age-adjusted deaths per 100000 attributable to atherosclerotic cardiovascular disease.

Fig. 2

Trends of hospital discharges related to placement of stents within the United States between 2003 and 2015. Number of discharges related to procedures involving placement of coronary artery stents per 100000 (both drug-eluting and non-drug eluting stents).

Fig. 3

Secondary prevention of statin relative to baseline risk in the 4S trial showing persistent elevated risk, adapted from Pedersen et al. Circulation. 1998; 97:1453–1460.

Fig. 4

Cardiovascular event rate within 5 years using most efficacious revascularization modality (CABG) in the SYNTAX surgical trial. Percent CV events at 5 years-best revascularization results in SYNTAX surgical trial. CABG, coronary artery bypass grafting.

Fig. 5

Implications of atheromas on the patient with dyslipidemia and T2DM. T2DM, type 2 diabetes mellitus.

Fig. 6

Effects of lipid-lowering therapy on lipid buildup in an artery. This image was taken from a non-obstructed portion of an angiogram of a 38-year-old patient at UT Health San Antonio with T2DM on statin with previous MI. The yellow ring represents lipid within the wall of the artery, with preservation of arterial lumen. Newer agents under development could reduce the lipid buildup within the wall. Image modality is near infrared spectroscopy with intravascular ultrasound inspired by Danek et al. [42]. This new technology has been shown to help detect vulnerable plaque. Red color represents cardiovascular events in current state of the art trials. T2DM, type 2 diabetes mellitus.