Genetic Testing for Hypertriglyceridemia in Academic Lipid Clinics: Implications for Precision Medicine-Brief Report.

BACKGROUND: Severe hypertriglyceridemia is often caused by variants in genes of triglyceride metabolism. These variants include rare, heterozygous pathogenic variants (PVs), or multiple common, small-effect single nucleotide polymorphisms that can be quantified using a polygenic risk score (PRS). The role of genetic testing to examine PVs and PRS in predicting risk for pancreatitis and severity of hypertriglyceridemia is unknown. METHODS: We examined the relationship of PVs and PRSs associated with hypertriglyceridemia with the highest recorded plasma triglyceride level and risk for acute pancreatitis in 363 patients from 3 academic lipid clinics who underwent genetic testing (GBinsight's Dyslipidemia Comprehensive Panel). Categories of hypertriglyceridemia included: normal triglyceride (<200 mg/dL), moderate (200-499 mg/dL), severe (500-999 mg/dL), or very severe (≥1000 mg/dL). RESULTS: PVs and high PRSs were identified in 37 (10%) and 59 (16%) individuals, respectively. Patients with both had increased risk for very severe hypertriglyceridemia compared with those with neither genetic risk factor. Risk for acute pancreatitis was also increased in individuals with both genetic risk factors (odds ratio, 5.1 [P=0.02] after controlling for age, race, sex, body mass index, and highest triglyceride level), but not in individuals with PV or high PRS alone. CONCLUSIONS: The presence of both PV and high PRS significantly increased risk for very severe hypertriglyceridemia and acute pancreatitis, whereas PV or PRS alone only modestly increased risk. Genetic testing may help identify patients with hypertriglyceridemia who have the greatest risk for developing pancreatitis and may derive the greatest benefit from novel triglyceride-lowering therapies.

Management of Mild-to-Moderate Hypertriglyceridemia.

OBJECTIVE: Hypertriglyceridemia (HTG) is highly prevalent globally, and its prevalence is rising, with a worldwide increase in the incidence of obesity and diabetes. This review examines its current management and future therapies. METHODS: For this review, HTG is defined as mild-to-moderate elevation in the levels of triglyceride (TG): a fasting or nonfasting TG level of ≥150 mg/dL and <500 mg/dL. We reviewed scientific studies published over the last 30 years and current professional society recommendations regarding the evaluation and treatment of HTG. RESULTS: Genetics, lifestyle, and other environmental factors impact TG levels. In adults with mild-to-moderate HTG, clinicians should routinely assess and treat secondary treatable causes (diet, physical activity, obesity, metabolic syndrome, and reduction or cessation of medications that elevate TG levels). Because atherosclerotic cardiovascular disease risk is the primary clinical concern, statins are usually the first-line treatment. Patients with TG levels between ≥150 mg/dL and <500 mg/dL whose low-density lipoprotein cholesterol is treated adequately with statins (at "maximally tolerated" doses, per some statements) and have either prior cardiovascular disease or diabetes mellitus along with at least 2 additional cardiovascular disease risk factors should be considered for added icosapent ethyl treatment to further reduce their cardiovascular disease risk. Fibrates, niacin, and other approved agents or agents under development are also reviewed in detail. CONCLUSION: The treatment paradigm for mild-to-moderate HTG is changing on the basis of data from recent clinical trials. Recent trials suggest that the addition of icosapent ethyl to background statin therapy may further reduce atherosclerotic cardiovascular disease risk in patients with moderate HTG, although a particular TG goal has not been identified.

Pharmacotherapy of obesity in complex diseases.

More than 40% of adults in the United States suffer from obesity. Obesity is inextricably linked to many chronic illnesses like type-2 diabetes mellitus, hypertension, hyperlipidemia, heart disease, sleep apnea, stroke, and cancers. When used in combination with lifestyle modifications, pharmacotherapy has a vital role in treating obesity and improves short-term and long-term outcomes. A growing number of physicians are now interested in obesity medicine, and many of them are seeking guidance on how to treat complex patients with co-morbidities. This review provides a practical guide to the use of anti-obesity medications across various obesity-related comorbidities. It provides a general review of the currently approved anti-obesity medications and effective combinations. It discusses the highlights of the major trials and recent studies assessing the benefits of anti-obesity medications in comorbid conditions such as type-2 diabetes mellitus, psychiatric disorders, cardiovascular diseases, hypertension, renal diseases, and liver diseases. This review briefly examines the aspects of recognizing and addressing iatrogenic weight gain; discusses the precautions and prescribing considerations of anti-obesity medications, including side effects and possible dose adjustments in various comorbid conditions; and provides an expert opinion on an individualized choice of the best anti-obesity medication.

The impact of lipid-lowering medications on coronary artery plaque characteristics.

Atherosclerosis is the predominant cause of coronary artery disease. The last several decades have witnessed significant advances in lipid-lowering therapies, which comprise a central component of atherosclerotic cardiovascular disease prevention. In addition to cardiovascular risk reduction with dyslipidemia management, some lipid-based therapies show promise at the level of the atherosclerotic plaque itself through mechanisms governing lipid accumulation, plaque stability, local inflammation, endothelial dysfunction, and thrombogenicity. The capacity of lipid-lowering therapies to modify atherosclerotic plaque burden, size, composition, and vulnerability should correlate with their ability to reduce disease progression. This review discusses plaque characteristics, diagnostic modalities to evaluate these characteristics, and how they are altered by current and emerging lipid-lowering therapies, all in human coronary artery disease.

Hypertriglyceridemia-associated acute pancreatitis: Response to continuous insulin infusion.

OBJECTIVE: To assess the response of serum triglycerides (TG) to continuous insulin infusion (CII) in adults with hypertriglyceridemia-associated acute pancreatitis (HTGP). METHODS: Retrospective analysis of TG response to standardized CII therapy in 77 adults admitted to intensive care with TG >1000 mg/dL and HTGP. RESULTS: Participants had initial TG 3869.0 [2713.5, 5443.5] mg/dL and were 39.3 ± 9.7 years old, 66.2% males, 58.4% Hispanic, BMI 30.2 [27.0, 34.8] kg/m2, 74.0% with diabetes mellitus (DM) and 50.6% with excess alcohol use. TG-goal, defined as ≤1,000 ± 100 mg/dL, was achieved in 95%. Among the 73 TG-goal achievers (responders), 53.4% reached TG-goal in <36 hours after CII initiation (rapid responders). When compared to slow responders taking≥36 hours, rapid responders had lower initial TG (2862.0 [1965.0, 4519.0] vs 4814.5 [3368.8, 6900.0] mg/dL), BMI (29.4 [25.9, 32.8] vs 31.9 [28.2, 38.3] kg/m2), DM prevalence (56.4 vs 94.1%), and reached TG-50% (half of respective initial TG) faster (12.0 [6.0, 17.0] vs 18.5 [13.0, 32.8] hours). Those with DM (n = 57) vs non-DM (n = 20) were obese (31.4 [28.0, 35.6] vs 27.8 [23.6, 30.3] kg/m2), took longer to reach TG-final (41.0 [25.0, 60.5] vs 14.5 [12.5, 25.5] hours) and used more daily insulin (1.7 [1.3, 2.1] vs 1.1 [0.5, 1.9] U/kg/day). Among those with DM, the rapid responders had higher daily use of insulin vs slow responders 1.9 [1.4, 2.3] vs 1.6 [1.1, 1.8] U/kg/day. All results significant. In multivariable analysis, predictors of faster TG response were absence of DM, lower BMI and initial TG. CONCLUSION: CII was effective in reaching TG-goal in 95% of patients with HTGP. Half achieved TG-goal within 36 hours. Presence of DM, higher BMI and initial TG slowed the time to reach TG-goal. These baseline parameters and rate of decline to TG-50% may be real-time indicators to initiate and adjust the CII for quicker response.

The clinical black, white, and gray lessons.

PURPOSE OF REVIEW: This review examines recent contradictory large, well-controlled randomized control trials assessing the effects of omega-3 fatty acids and colchicine on cardiovascular (CV) outcomes. RECENT FINDINGS: The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) and Statin Residual Risk Reduction with Epanova in high Cardiovascular Risk patients with Hypertriglyceridemia (STRENGTH) trial assessed the CV outcomes using high-dose omega-3 fatty acids in statin-treated patients with moderate hypertriglyceridemia and high-risk for CV disease with differing results. Similarly, Colchicine Cardiovascular Outcomes trial, (COLCOT) second Low Dose Colchicine (LoDoCo2), and Colchicine in patients with Acute Coronary Syndrome (COPS) assessed the CV outcomes using low-dose colchicine in patients with coronary artery disease with inconsistent results. These contradictory findings among studies assessing similar questions with the same drug or a drug within the same class challenge the scientific validity and clinical applicability of the derived conclusions. SUMMARY: A comprehensive review revealed many differences between the trials, which could have contributed to observed divergent results. Consistent findings across multiple trials help strengthen the evidence for specific endpoints or sub-populations, and these findings must be included in guidelines. Large prospective cohort studies with diligent study protocols are warranted in the future to resolve unanswered dilemmas.

How I treat statin-associated side effects in an outpatient setting.

Dyslipidemia promotes atherosclerosis and causes cardiovascular diseases. Statins are potent lipid-lowering medications with a cardiovascular mortality benefit. They are generally safe and well tolerated but sometimes can be associated with side effects of variable severity. The most common side effect is statin-associated muscle symptoms. Uncommon side effects include new-onset diabetes mellitus and elevation in liver enzymes. These effects can lead to noncompliance and premature discontinuation of the medication. Hence, it is crucial to identify patients with true statin-associated side effects (SASE) to ensure optimal statin use. The appropriate evaluation of the patient before starting statins and proactive utilization of available diagnostic tests to rule out alternate etiologies mimicking adverse effects are essential for accurate diagnosis of SASE. In patients with true SASE, timely intervention with modified statin or non-statins is beneficial. Herein, we discuss key clinical trial data on statins and non-statins, and describe our center's approach toward patients with SASE.

Recent advances and emerging therapies in management of dyslipidemias.

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide that have been shown to have a strong association with dyslipidemia. Despite efficacious LDL-C lowering therapies, there is evidence of residual CVD risk prompting a need for a novel approach to mitigate CVD. This review aims to provide a comprehensive overview of recent and emerging therapies for various dyslipidemias.

Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP1RAs) are relatively newer anti-hyperglycemic agents, which have demonstrated cardiovascular benefits in patients with type 2 diabetes mellitus. DESIGN: We performed a meta-analysis of randomized controlled trials to evaluate the cardiovascular outcomes of GLP1RAs compared to placebo in type 2 diabetes mellitus patients. We performed an additional subgroup analysis to evaluate the role of GLP1RAs in patients with chronic kidney disease. METHODS: MEDLINE, Cochrane and ClinicalTrials.gov databases were searched from inception to 15 July 2019. The authors extracted relevant information from articles and independently assessed the study quality. RESULTS: Compared to placebo, GLP1RAs demonstrated a significant reduction in all-cause mortality (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.82-0.95; P < 0.001), cardiovascular mortality (OR 0.88, 95% CI 0.81-0.96; P = 0.004), primary composite endpoint (OR 0.86, 95% CI 0.80-0.91; P < 0.001) and non-fatal stroke (OR 0.86, 95% 0.77-0.95; P = 0.004). There was no statistical difference in non-fatal myocardial infarction (OR 0.92, 95% CI 0.83-1.01; P = 0.09). In subgroup analyses of patients with estimated glomerular filtration rate less than 60 ml/min/1.73 m2 and less than 30 ml/min/1.73 m2, there was no significant difference in the primary composite endpoint. CONCLUSIONS: GLP1RAs demonstrated a significant reduction in all-cause mortality, cardiovascular mortality, primary composite endpoint and non-fatal stroke in patients with type 2 diabetes mellitus. There was no significant difference in the primary composite endpoint in patients with type 2 diabetes mellitus and chronic kidney disease.