Emerging Targets for Cardiovascular Disease Prevention in Diabetes

Abstract

Type 1 and type 2 diabetes mellitus (T1DM and T2DM) increase the risk of atherosclerotic cardiovascular disease (CVD), resulting in acute cardiovascular events, such as heart attack and stroke. Recent clinical trials point toward new treatment and prevention strategies for cardiovascular complications of T2DM. New antidiabetic agents show unexpected cardioprotective benefits. Moreover, genetic and reverse translational strategies have revealed potential novel targets for CVD prevention in diabetes, including inhibition of apolipoprotein C3 (APOC3). Modeling and pharmacology-based approaches to improve insulin action provide additional potential strategies to combat CVD. The development of new strategies for improved diabetes and lipid control fuels hope for future prevention of CVD associated with diabetes.

Keywords: angiopoietin-like; apolipoprotein C3; atherosclerosis; diabetes; genetics; insulin.

Figure 1.. A human genetic framework to estimate the beneficial and adverse effects of therapeutic agents.

(A) DNA sequence variants resulting in reduced gene expression of therapeutic targets are frequently used as genetic proxies for inhibitory drugs. For example, DNA variation leading to a slight reduction in HMG Co-A reductase is associated with lower plasma LDL-cholesterol; (B) Biomarkers affected by the drug target can be used to validate that the DNA variants are appropriate proxies. The dashed line indicates the reference group; (C) The association between the same DNA variants and disease outcomes can be used to estimate the clinical effects of the drug (for example, DNA variation leading to a slight reduction in HMG Co-A reductase is associated with lower risk of heart attack but increased risk of diabetes). The dashed line indicates an odds ratio of 1 (i.e., no effect).

Figure 2.. Lipoprotein metabolism at a glance.

(A) This schematic shows the genes discussed in relation to lipid metabolism (highlighted by red font). Cholesterol and sterols are taken up from the intestinal lumen via the Nieman Pick C1-like 1 (NPC1L1) transporter (blue, lower left corner) and are then re-assembled into chylomicrons containing apolipoprotein (APO) B48. The liver produces cholesterol through HMG-CoA reductase (HMGCR; upper center), which is incorporated with triglycerides into APOB100-containing VLDL. LPL (purple) hydrolyzes triglycerides into free fatty acids (FFA), resulting in the formation of LDL and RLPs from VLDL and chylomicrons, respectively, which can enter tissues. Most APOB-containing lipoproteins are taken up via the hepatic LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) stimulates internalization and degradation of the LDLR, thereby reducing cell surface expression of the LDLR. Angiopoietin-like (ANGPL) 3, ANGPTL4, and APOC3 are endogenous inhibitors of LPL. APOC3 can also suppress hepatic uptake of APOEcontaining lipoprotein particles (found e.g., on VLDL and RLPs). (B) Diabetes enhances hepatic production of APOC3. Elevated levels of APOC3 increase circulating levels of triglyceride-rich lipoproteins (TRLs), resulting in accumulation of RLPs in the artery wall and accelerated atherosclerosis, in part via increased macrophage lipid loading. An antisense oligonucleotide (ASO) to APOC3 completely blocks diabetes-accelerated atherosclerosis in a mouse model. Other emerging strategies to block APOC3 include small interfering RNA (RNAi) and monoclonal antibodies. Figure 2B is reproduced and modified from [80] with permission from the Journal of Clinical Investigation.