Triglycerides

Plasma triglycerides vary over a wide range and ASCVD risk increases continuously as levels rise, so percentile-based cut-offs are considered inappropriate for defining normal and abnormal values. ^[5] Triglyceride-rich lipoproteins and remnants accumulate at fasting triglycerides above 1.2 mmol/L (100 mg/dL), and there is consensus that ASCVD risk becomes clinically relevant above 1.7 mmol/L (150 mg/dL). ^[5] In large Copenhagen cohorts, non-fasting triglycerides of 6.6 versus 0.8 mmol/L were associated with five-, three- and two-fold higher adjusted risks of myocardial infarction, ischaemic stroke and all-cause mortality, respectively. ^[2] Triglyceride-rich lipoproteins and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized LDL-lowering therapy. ^{[5] [11]} Triglyceride concentrations of 2 to 10 mmol/L confer increased risk of cardiovascular disease, whereas concentrations above 10 mmol/L confer increased risk of acute pancreatitis and possibly cardiovascular disease. ^[12] Hypertriglyceridemia is the third most common cause of acute pancreatitis, and hypertriglyceridemia-induced pancreatitis is more likely to run a severe course with persistent organ failure. ^[13] Most people with triglycerides above 10 mmol/L never develop pancreatitis: cohort studies suggest acute pancreatitis in about 3% of those with levels of 10 to 20 mmol/L and 15% of those above 20 mmol/L. ^[2]

With severe triglyceride elevation (500 mg/dL or higher), the primary objective is to prevent pancreatitis, and ASCVD risk reduction becomes secondary. ^[14] Correcting secondary causes and optimizing lifestyle, including restriction of alcohol, added sugars and refined starches, daily physical activity and reduction of adiposity in people with overweight or obesity, comes before drug treatment. ^{[3] [14]} Approximate triglyceride lowering is about 8 mg/dL per kg of weight lost, 10% to 20% with aerobic exercise and up to 80% with alcohol abstinence in people with high triglycerides and excess intake. ^[2] Statins are the mainstay of cardiovascular prevention in hypertriglyceridemia, with eicosapentaenoic acid ethyl esters added in very-high-risk individuals, whereas the role of fibrates in cardiovascular prevention remains unclear. ^[8] In REDUCE-IT, icosapent ethyl 4 g daily reduced ASCVD events (HR 0.75) over 4.9 years in 8179 high-risk statin-treated patients with elevated triglycerides, although whether the benefit reflects the formulation, the dose, the population or the mineral oil placebo remains unclear. ^[2] The American Association of Clinical Endocrinology suggests eicosapentaenoic acid, but not eicosapentaenoic plus docosahexaenoic acid, for adults with hypertriglyceridemia and ASCVD or increased ASCVD risk, strongly recommends against niacin, and found insufficient evidence for drug recommendations in severe hypertriglyceridemia (500 mg/dL or higher). ^[15] An earlier Endocrine Society clinical practice guideline recommends a fibrate as first-line therapy in severe or very severe hypertriglyceridemia, and a later review advises that, after hypertriglyceridemia-induced pancreatitis, long-term treatment should target triglycerides below 500 mg/dL, with emerging agents acting on apolipoprotein CIII and angiopoietin-like protein 3. ^{[10] [16]}