The lowdown on lipoprotein lipase enhancers

CAMBRIDGE, U.K.—Statins are the current standard of care for individuals with high cholesterol, as they help to lower LDL cholesterol (LDL-C) and raise HDL cholesterol, and have been in use since lovastatin became the first commercially approved statin in 1987. For all their efficacy, however, statins do come with side effects. Muscle-related complaints—aches or pain—are somewhat common, but of more concern is the potential for taking statins to increase your risk for type 2 diabetes.

As noted in an article published in the American Heart Association journal Circulation, statins “have been found to modestly increase the risk of developing diabetes mellitus.” These drugs can “modestly raise blood sugars,” and one study found that between individuals who received a statin (rosuvastatin) and individuals who received placebo, 27 percent more patients in the statin group were diagnosed with diabetes mellitus. (They also, however, “had a significant 54% lower risk of heart attack, 48% lower risk of stroke, and 20% lower risk of death from any cause,” as noted in the article.)

A new type of drug could help to address this issue—though not by replacing statins, but rather by being administered alongside them. A genetic study conducted by the Medical Research Council Epidemiology Unit at the University of Cambridge found that lipoprotein lipase (LPL)-enhancing drugs, which lower triglycerides, could be effective at lowering heart attack risk without the increased risk of diabetes. The results of their work appeared in JAMA Cardiology in a paper titled “Association of Genetically Enhanced Lipoprotein Lipase–Mediated Lipolysis and Low-Density Lipoprotein Cholesterol–Lowering Alleles With Risk of Coronary Disease and Type 2 Diabetes.”

“Our study suggests that these new triglyceride-lowering agents could give additional benefits to patients with heart disease when added to statins,” Dr. Luca A. Lotta, senior clinical investigator at the MRC Epidemiology Unit, said in a press release. “This combination could prevent more heart attacks as well as reduce the risk of developing type 2 diabetes.”

LPL's usual role in the human body is to help break down triglycerides, which are a type of lipid stored by the body in fat cells to be released later as energy. As noted in the JAMA Cardiology paper, “Gain-of-function genetic variants in LPL^2,3 and loss-of-function variants in its intravascular inhibitors ANGPTL3,^4-6ANGPTL4,^2,7 and APOC3^8,9 are associated with lower triglyceride levels and lower coronary disease risk, while loss-of-function variants in LPL^2,3,10 and its natural activator APOA5¹¹ are associated with higher triglyceride levels and higher coronary risk.” Additionally, “impaired LPL-mediated lipolysis [the breakdown of lipids/fats] has been linked to insulin resistance and a higher risk of type 2 diabetes.”

While LPL-enhancing drugs are being developed, the majority are only in preclinical development, and no large-scale studies have been conducted to look at combining them with statins. In the absence of any formal studies, the MRC team analyzed genetic data to determine the potential safety and efficacy of such a combination.

“Large-scale clinical trials and the investment of massive resources would be required to study the effect of each of these LPL-enhancing agents on cardiovascular outcomes in the context of LDL-C–lowering therapy,” the authors explained in their paper. “In advance of outcome trials, human genetic approaches can provide evidence of whether or not genetically determined differences in LPL-mediated lipolysis and LDL-C metabolism have independent associations with cardiometabolic disease risk, which can help prioritize or deprioritize these resource-intensive efforts.”

Using the data of 392,220 people in the UK Biobank, EPIC-InterAct and EPIC-Norfolk studies, the researchers used Mendelian randomization to detect the likely effects of statins and LPL-enhancing drugs. Mendelian randomization looks at naturally occurring genetic differences to simulate a clinical trial. One of the genetic differences looked for was a DNA variation some people present with that naturally increases LPL's effectiveness, which would provide an ideal stand-in for the drugs within the data. Variants in other genes that are known to lower cholesterol, mimicking the effect of statins, were also used.

What the team found was that individuals who presented with both sets of variants—those that lowered triglycerides and those that lowered cholesterol—had a lower risk of heart disease than those who only had one set of variants.

Specifically, the MRC scientists found that “Triglyceride-lowering alleles in LPL were associated with protection from coronary disease (approximately 40% lower odds per SD [or mean] of genetically lower triglycerides) and type 2 diabetes (approximately 30% lower odds) in people above or below the median of the population distribution of LDL-C–lowering alleles at 58 independent genomic regions, HMGCR, NPC1L1, or PCSK9. Associations with lower risk were consistent in quintiles of the distribution of LDL-C–lowering alleles and 2 × 2 factorial genetic analyses. The 40Lys variant in ANGPTL4 was associated with protection from coronary disease and type 2 diabetes in groups with genetically higher or lower LDL-C.”

Though the results bode well for the organizations developing LPL-enhancing drugs, the research team did note that there were limitations to this study: “While our analyses show a strong association of LPL alleles with coronary disease and diabetes, this does not necessarily mean that pharmacologically enhancing lipolysis over a short time will yield clinically relevant changes in future risk of coronary disease or new-onset diabetes in high-risk adults for whom these agents are being developed.”

Despite that caution, however, the authors still support the potential of these new drugs based on the results of their study, concluding that “Triglyceride-lowering alleles in the LPL pathway are associated with lower risk of coronary disease and type 2 diabetes independently of LDL-C–lowering genetic mechanisms. These findings provide human genetics evidence to support the development of agents that enhance LPL-mediated lipolysis for further clinical benefit in addition to LDL-C–lowering therapy.”