Written by: Vishnu Priya Pulipati, MD, Warren Clinic Endocrinology, Tulsa, Oklahoma

Diabetes mellitus (DM) is a globally prevalent chronic disease that directly caused 1.5 million deaths worldwide in 2019. Diabetes and associated dyslipidemia are major contributors to cardiovascular disease (CVD), the leading cause of morbidity and mortality in patients with DM. Diabetic dyslipidemia is characterized by elevated fasting and postprandial serum triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), elevated low-density lipoprotein cholesterol (LDL-C), and predominance of atherogenic small, dense LDL particles. Hypertriglyceridemia (HTG) is exceedingly common in DM, and there is growing evidence that it contributes to residual cardiovascular (CV) risk. This risk was observed even with mild to moderate HTG (TG 150 to 499 mg/dL) and statin-controlled LDL-C. HTG management starts with screening and addressing secondary etiologies. Hyperglycemia is a significant contributor to HTG; hence glycemic control is a priority. The next best and effective strategy is to optimize diet and lifestyle. Therapeutic lifestyle interventions include reducing saturated fat, limiting refined carbohydrates, alcohol avoidance, nicotine cessation, weight loss, and exercise. Statins are always first-line therapy to achieve LDL-C <70 mg/dL in high-risk and <100 mg/dL in moderate-risk patients. Although primarily effective for LDL-C lowering, statins can lower TG by 10-33%, contributing to CVD risk reduction.

In patients with mild to moderate HTG despite at-goal LDL-C, additional TG-lowering therapies are considered. The placebo-controlled randomized controlled trials, fenofibrate intervention and event lowering in DM (FIELD) and the action to control CV risk in DM (ACCORD Lipid) showed no overall reduction in CVD with fenofibrate use in patients with DM. Statin and fibrate combination is generally not recommended due to no CVD benefit and risk of muscle side effects. But, the subgroup analysis of ACCORD lipid supports this combination in patients with DM and optimal LDL-C but persistent, significant HTG (>200 mg/dL) and low HDL-C (<35-40 mg/dL). The evidence for CVD benefit with niacin in patients with DM is scant, and it can increase glucose levels. The statin and niacin combination is not recommended given the lack of CVD outcomes. Despite the overall lack of CVD benefit with fibrates or niacin, there was a striking 25% reduction in CV events with icosapent ethyl (IPE) 2g twice-daily in the reduction of CV events with IPE-intervention trial (REDUCE-IT) [n = 8179, 58% with DM] among patients with LDL-C <100 mg/dL on baseline statin. In contrast, the study to assess statin residual risk with epanova in high CV risk patients with HTG (STRENGTH) [n = 13078, 70% had DM] showed no difference in CV events with 4g/d carboxylic acid formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid vs. placebo in similar patients. The divergent results in these trials have been hypothesized to be due to differences in study drugs, placebos, serum EPA levels achieved, and various other factors, but the large discrepancy in CVD results remains largely unexplained. Based on the REDUCE-IT data, IPE is now widely recommended for CVD risk reduction in patients with severe HTG (TG >500 mg/dL), HTG (TG >150 mg/dL) and established CVD or DM with 2 or more additional risk factors for CVD. Among patients with severe HTG, the primary objective is to reduce the TG levels to <500 mg/dL to prevent acute pancreatitis. Fibrates are potent and inexpensive agents that reduce TG by 30-50%, and they are generally considered first-line for this use. Various TG-lowering therapies are in development, and some with ongoing studies. The pemafibrate to reduce cardiovascular outcomes by reducing TG in patients with DM (PROMINENT) is a multicenter phase III trial examining CV outcomes with pemafibrate (selective peroxisome proliferator-activated receptor alpha agonist) vs. placebo in 10,000 patients with diabetic dyslipidemia. Results are expected within the next year or two. Volanesorsen (an anti-sense inhibitor of apolipoprotein C-III) and evinacumab (a fully human monoclonal antibody against angiopoietin-like 3 protein) are other newer therapies on the horizon for TG-lowering, but their respective impact on diabetic dyslipidemia and safety in patients with DM is yet to be established, and cardiovascular trials of these agents are yet to be started.

In conclusion, in patients with HTG and DM, management of secondary factors, glycemic control, therapeutic diet, and lifestyle interventions are the cornerstones for TG-lowering and CVD prevention. Statins are first-line medications for CVD risk reduction in this population. In patients with persistent HTG, IPE is beneficial for CVD risk reduction. Since the CVD efficacy of fenofibrate in patients with DM remains controversial, its use is generally reserved for severe HTG. Niacin is available but rarely used in this population. The ongoing CVD outcomes trial with pemafibrate shows promise for possible CVD reduction, and it may become another proven therapy for diabetic dyslipidemia management in the future. At present, however, there remains an unmet need for additional TG-lowering agents which could help prevent CVD in patients with HTG and DM.