Chapter 34 - Side effects of anti-lipid medications

Statin Intolerance and Noncompliance: An Empiric Approach

VI. Drug Therapy

There are currently eight different classes of drugs available for lowering cholesterol levels. There are currently seven HMG-CoA reductase inhibitors (statins) approved for lowering cholesterol levels and they are the first line drugs for treating lipid disorders and can lower LDL-C levels by as much as 60%. Statins also are effective in reducing triglyceride levels in patients with hypertriglyceridemia. Statins lower LDL levels by inhibiting HMG-CoA reductase activity leading to decreases in hepatic cholesterol content resulting in an up-regulation of hepatic LDL receptors, which increases the clearance of LDL. The major side effects are muscle complications and an increased risk of diabetes. The different statins have varying drug interactions. Ezetimibe lowers LDL-C levels by approximately 20% by inhibiting cholesterol absorption by the intestines leading to the decreased delivery of cholesterol to the liver, a decrease in hepatic cholesterol content, and an up-regulation of hepatic LDL receptors. Ezetimibe is very useful as add on therapy when statin therapy is not sufficient or in statin intolerant patients. Ezetimibe has few side effects. Bile acid sequestrants lower LDL-C by10-30% by decreasing the absorption of bile acids in the intestine which decreases the bile acid pool consequently stimulating the synthesis of bile acids from cholesterol leading to a decrease in hepatic cholesterol content and an up-regulation of hepatic LDL receptors. Bile acid sequestrants can be difficult to use as they decrease the absorption of multiple drugs, may increase triglyceride levels, and cause constipation and other GI side effects. They do improve glycemic control in patients with diabetes, which is an additional benefit. PCSK9 inhibitors, either monoclonal antibodies or small interfering RNA, lower LDL-C by 50-60% by decreasing PCSK9, which decreases the degradation of LDL receptors. PCSK9 inhibitors also decrease Lp(a) levels. PCSK9 inhibitors are very useful when maximally tolerated statin therapy does not reduce LDL sufficiently and in statin intolerant patients. PCSK9 inhibitors have very few side effects. Bempedoic acid lowers LDL-C by 15-25% by inhibiting hepatic ATP citrate lyase activity resulting in a decrease in cholesterol synthesis in the liver, a decrease in hepatic cholesterol content, and an up-regulation of LDL receptors. Bempedoic acid is employed in patients who do not reach their LDL-C goals on maximally tolerated statin therapy or in patients who do not tolerate statins. Bempedoic acid is associated with elevations in uric acid levels and gouty attacks and with tendon ruptures. Lomitapide, and evinacumab are approved for lowering LDL levels in patients with Homozygous Familiar Hypercholesterolemia. Mipomersen, which is no longer available, is a second-generation apolipoprotein anti-sense oligonucleotide that decreases apolipoprotein B synthesis resulting in a reduction in the formation and synthesis of VLDL. Lomitapide inhibits microsomal triglyceride transfer protein decreasing the formation of chylomicrons in the intestine and VLDL in the liver. Both mipomersen and lomitapide have the potential to cause liver toxicity and therefore they were approved with a risk evaluation and mitigation strategy (REMS) to reduce risk. Evinacumab is a monoclonal antibody that inhibits the activity of angiopoietin-like protein 3 resulting in the increased activity of lipoprotein lipase and endothelial cell lipase resulting in a decrease in LDL-C, HDL-C, and triglyceride levels. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG .

New therapeutic agents marketed in 2020: Part 2

Side effects of anti-lipid medications

BackgroundThe uptake of novel lipid‐lowering therapy (LLT) has been low; however, variations in clinician prescribing patterns have not been well studied. This study sought to describe early prescribing patterns of novel LLT and identify factors associated with high usage.MethodsWe identified prescriptions for any LLT using pharmacy transaction data (covering >80% of the United States) from January 1, 2018 to December 31, 2022, and identified patients newly initiated on PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitor) monoclonal antibodies or bempedoic acid (BA). We assessed the proportion of LLT prescribers overall and by specialty who had prescribed PCSK9i and BA, and the volume of patients prescribed. The association between use of PCSK9i and BA was assessed.ResultsOf 996 421 LLT prescribers, only 9.2% (N=91 166) and 2.4% (N=23 674) had prescribed PCSK9i and BA, respectively, by December 31, 2022. Usage was higher among cardiologists, but still only 62.8% and 18.2% of cardiologists had given a PCSK9i or BA prescription. The top 10% of prescribers were responsible for starting 57.3% and 51.2% of PCSK9i and BA prescriptions, respectively.ConclusionsThe majority of US clinicians prescribing LLT have never prescribed a PCSK9i or BA, and among those who do, most have used these therapies in only a few patients. However, there exist distinct groups of early adopters and high‐volume users with higher approval rates, slightly more years in practice, and more cardiologists. Given that prescription approval rates for both PCSK9i and BA have now increased to >80% in our analysis, increasing uptake of novel LLT will require interventions to increase use among clinicians.

Target Populations and Treatment Cost for Bempedoic Acid and PCSK9 Inhibitors: A Simulation Study in a Contemporary CAD Cohort

Despite the availability of effective LDL cholesterol (LDL-C)-lowering drugs, only a minority of patients achieves the guideline-recommended treatment targets. This analysis describes treatment pathways of lipid-lowering therapy (LLT) in Germany. Health claims data were used to identify patients at high or very-high cardiovascular risk who received a LLT prescription 2016-2022. Treatment pathways and the time to switch or discontinue LLT were analysed for statins, ezetimibe, bempedoic acid (BA), and PCSK9 inhibitors (PCSK9i). Out of 3,487,827 insured persons, 247,529 met the inclusion criteria. The most frequent first-line LLT were statins in 96.3%. Ezetimibe, BA, and PCSK9i were first-line LLT in only 0.9%, 0.061%, and 0.046%, respectively. Only few patients experienced a change in their treatment regimen following LLT initiation. Prescriptions of BA and PCSK9i were mainly second-, third-, or fourth-line add-on treatment. Termination of treatment with BA and PCSK9i was less frequent compared to statins and ezetimibe. The median time to treatment discontinuation was 1.45, 1.04, 0.60, and 2.45years for statins, ezetimibe, BA, and PCSK9i, respectively, and the median time to switch therapy was 4.81 and 4.87years for ezetimibe and PCSK9i, respectively (median not reached for statins and BA). Changes in LLT were only observed in a minority of patients. BA and PCSK9i were switched more frequently than statins and ezetimibe. BA was discontinued earlier, and PCSK9i later than the other agents. Continued efforts to maintain long-term adherence and overcome therapeutic inertia are needed to realise the potential of available LLT with proven cardiovascular benefit.

Simulation study on LDL cholesterol target attainment, ASCVD events, and treatment cost of bempedoic acid in a representative German cohort of high- and very-high-CV risk patients

IntroductionConventional lipid-lowering agents, including statins, ezetimibe, fibrates, bile acid sequestrants, nicotinic acid, bempedoic acid and Omega-3, are essential to the management of dyslipidaemia. However, these agents have been shown to...

The primary and secondary prevention strategies of atherosclerotic cardiovascular disease (ASCVD) largely rely on the management of arterial hypertension and hypercholesterolemia, two major risk factors possibly linked in pathophysiological terms by the renin-angiotensin system activation and that often coexist in the same patient synergistically increasing cardiovascular risk. The classic pharmacologic armamentarium to reduce hypercholesterolemia has been based in the last two decades on statins, ezetimibe, and bile acid sequestrants. More recently numerous novel, additive resources targeting different pathways in LDL cholesterol metabolism have emerged. They include drugs targeting the proprotein convertase subtilisin/kexin type 9 (PCSK9) (inhibitory antibodies; small-interfering RNAs), the angiopoietin-like protein 3 (inhibitory antibodies), and the ATP-citrate lyase (the inhibitory oral prodrug, bempedoic acid), with PCSK9 inhibitors and bempedoic acid already approved for clinical use. With the potential of at least halving LDL cholesterol levels faster and more effectively with the addition of ezetimibe than with high-intensity statin alone, and even more with the addition of the novel available drugs, this document endorsed by the Italian Society of Hypertension proposes a novel paradigm for the treatment of the hypertensive patient with hypercholesterolemia at high and very high ASCVD risk. Our proposal is based on the use as a first-line of a preferably fixed combination of lipid-lowering drugs, under the motto “Our goal: achieve control. No setback: combine and check”.

Plasma levels of high-density lipoprotein-cholesterol (HDL-C) are a powerful independent cardiovascular risk factor, bearing an inverse relationship with atherosclerotic cardiovascular disease (with risk rising sharply when levels are <1.04 mmol/L). Apart from its protective role in atherosclerosis, HDL-C increases fibrinolysis, is an antioxidant to low density lipoprotein-cholesterol (LDL-C), and decreases platelet aggregability. Up to a third of patients with atherosclerotic cardiovascular disease have 'desirable' plasma levels of total cholesterol but low HDL-C levels. Benefits of treating low plasma HDL-C levels were clearly demonstrated in the Veterans Affairs HDL Intervention Trial (VA-HIT) where gemfibrozil reduced nonfatal infarcts and coronary deaths by 22%. This was achieved by a 6% increase in plasma HDL-C levels, and a 24.5% decrease in plasma levels of triglycerides, without any significant decrease in LDL-C levels. Multivariate analyses revealed the rise in plasma HDL-C levels after treatment, but not decreases in plasma levels of triglycerides or LDL-C, predicted coronary artery disease events. The typical patient under consideration in this article is one with plasma levels of HDL-C <1 mmol/L, LDL-C <3.37 mmol/L [either receiving therapeutic lifestyle changes or or LDL-C-lowering therapy comprising a hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor or bile acid sequestrant] and fasting triglycerides <2.26 mmol/L. We propose this dyslipidemia be classified as Type VI phenotype following the Frederickson and Lees classification. High-risk patients (with >/=2 risk factors for atherosclerotic cardiovascular disease, or 10-year cardiovascular risk >20%), patients with established atherosclerotic cardiovascular disease, or type 2 diabetes mellitus, or metabolic syndrome should receive pharmacotherapy. Plasma HDL-C levels >1.16 mmol/L may be considered optimal and between 1 and 1.16 mmol/L as desirable. Fibric acid derivatives, nicotinic acid, HMG-CoA reductase inhibitors, estrogens, and ethanol (not recommended as therapy) increase plasma HDL-C levels. Nicotinic acid is the most potent agent and recent reports indicate that, in contrast to gemfibrozil, it selectively increases antiatherogenic HDL subfraction, lipoprotein (Lp) AI (without apolipoprotein AII), in patients with low plasma HDL-C levels. An extended-release formulation, administered once daily, has improved the tolerability of nicotinic acid. Recent evidence also indicates that nicotinic acid may effectively correct dyslipidemia in patients with diabetes mellitus without significantly compromising glycemic control. Fibric acid derivatives and estrogen raise plasma HDL-C levels by different mechanisms of action, and these agents may be used with nicotinic acid. Combination therapy (especially HMG-CoA reductase inhibitor and nicotinic acid) should be considered in patients with atherosclerotic cardiovascular disease and low plasma HDL-C levels.

The long term use of lipid-lowering drugs in the treatment of patients with hyperlipoproteinaemia is aimed at reducing plasma concentrations of known atherogenic lipoproteins with a favourable effect on lipid deposition in the arterial wall. A less common aim is to prevent the adverse sequelae of hyperchylomicronaemia in patients with severe hypertriglyceridaemia. The decision to begin drug therapy should be made only after the exclusion of secondary factors and after an adequate trial of diet has failed to produce acceptable concentrations of plasma lipids and lipoproteins. The bile acid sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibrate and inhibitors of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase (e.g. lovastatin or simvastatin) are the most effective drugs for use in patients with primary hypercholesterolaemia; these agents reduce plasma concentrations of total and LDL-cholesterol by 15 to 45%. For those patients with concurrent hypertriglyceridaemia, nicotinic acid, lovastatin or simvastatin, or fenofibrate are the preferred drugs for initial use; bile acid sequestrants frequently exacerbate hypertriglyceridaemia in these patients. Fibric acid derivatives (e.g. clofibrate, gemfibrozil, bezafibrate or fenofibrate) are all effective in the therapy of patients with type III hyperlipoproteinaemia, as is nicotinic acid and I have found lovastatin to be effective also. Gemfibrozil or nicotinic acid are the most effective agents to use in the treatment of patients with severe hypertriglyceridaemia who are at increased risk of abdominal pain and pancreatitis. Combined therapy with drugs which have different mechanisms of action can be effectively used in the treatment of patients with severe hypercholesterolaemia or combined hyperlipidaemia; for the former group, combinations which use bile acid sequestrants, HMG CoA reductase inhibitors and nicotinic acid are the most effective.

Target populations and treatment cost for bempedoic acid and PCSK9 inhibitors: a simulation study in a contemporary CAD cohort

Lipid-lowering therapy (LLT) includes a diverse group of pharmaceuticals designed to reduce blood levels of cholesterol and triglyceride (TG), helping to prevent cardiovascular diseases like myocardial infarction and stroke. LLT includes treatment with several lipid-lowering drugs (LLD), including hydroxymethylglutaryl (HMG-CoA) reductase inhibitors (statin), PCSK9 Inhibitors, cholesterol-absorbing inhibitors (Ezetimibe), Bile Acid Sequestrants, Fibrates, Niacin (Vitamin B3), Omega-3 Fatty Acids, Bempedoic Acid, and combination therapy. The efficacy and safety of these molecules vary widely. Statins are the first-line LLD for treating hypercholesterolemia and are widely used for cardiovascular disease prevention. Common side effects include muscle-related issues such as myalgia, muscle atrophy, and, rarely, rhabdomyolysis. However, adverse effects on male reproductive health are infrequent and often underreported. Other medication classes employed in LLT mostly share many of the ADRs seen with statins, although individual classes may have unique ADRs depending on the pharmacokinetics and pharmacodynamics. Here, we are reporting a unique case of a 50-year-old male patient with no prior history of sexual dysfunction or testicular issues and other comorbidities or habits, who developed loss of libido, erectile dysfunction (ED) and testicular pain with most of the LLD, which promptly resolved on discontinuation of the LLT. This case highlights the importance of considering potential reproductive side effects when prescribing LLT and monitoring male patients for symptoms of sexual dysfunction.