Two rare complications of lipid-lowering therapies explained
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Although lipid-lowering medications are generally well tolerated, rare complications can include statin-associated autoimmune myopathy and drug-induced acute pancreatitis, a speaker reported.
At the National Lipid Association Scientific Sessions, Mary P. McGowan, MD, FNLA, co-director of the lipid clinic at Dartmouth Hitchcock Heart and Vascular Center and chief medical officer at The Family Heart Foundation in Pasadena, California, described the prevalence and potential mechanisms behind these rare complications tied to statin and fibrate use.
“In fact, we are pretty lucky. They're not an awful lot of complications of lipid-lowering medicines,” McGowan said during a presentation. “In general, lipid-altering medications are well tolerated and they really have an acceptable side effect profile. I would contrast that to other agents. If you're an oncologist, you're putting people on medications that may cause a second malignancy that may cause your white [blood cell] count to plummet and get infections. So, we have it pretty easy in cardiology or lipid metabolism, until we don't.”
The two complications of lipid lower medication discussed during the presentation included statin-associated autoimmune myopathy — otherwise known as HMG-CoA reductase necrotizing myopathy — and drug-induced acute pancreatitis.
Statin-associated autoimmune myopathy
Statin-associated autoimmune myopathy has an incidence of approximately one to two per 100,000 patients. According to the presentation, it can occur soon after statin therapy initiation, after years of treatment or without any statin exposure at all.
“People who get [statin-associated autoimmune myopathy] with statin exposure tend to be over 50,” McGowan said. “People who get it without statin exposure tend to be much younger and they have a much more protracted and difficult course.”
Symptoms of statin-associated autoimmune myopathy include muscle pain and difficulty rising from a chair or ascending stairs. Patients are often treated with a protracted course of immunosuppressives, she said.
McGown explained that expression of HMG CoA reductase is low in most tissues, but increases when muscle and other cells are exposed to statins.
High levels of HMG CoA reductase are required for normal muscle cell differentiation, and statin-induced overexpression in patients who are genetically susceptible may cause autoimmunity against HMG CoA reductase.
In HMG-CoA reductase necrotizing myopathy, patients would typically present with creatine kinase of more than 2000 U/L and muscle edema found on MRI. They would test positive for HMG CoA reductase autoantibodies, and macrophages would be the predominant cell type seen following muscle biopsy, she said.
“Taken together, these observations suggest that statin-induced overexpression of HMG CoA reductase in genetically susceptible individuals may cause this autoimmunity against HMG CoA reductase,” McGowan said. “These genetically susceptible individuals, those people with class 2 HLA-DRB1, represent 7% of Caucasians in the United States.”
Drug-induced acute pancreatitis
Drug-induced acute pancreatitis accounts for between 0.1% and 2% of all acute pancreatitis hospitalizations per year. According to the presentation, a majority of drug-induced acute pancreatitis cases are mild, but some may be severe or even fatal.
McGowan explained that, although more than 500 drugs have been linked to pancreatitis, the mechanisms by which certain drugs cause pancreatitis differ from one to the next and are not well understood.
“Once activated, pancreatic enzymes begin to digest cell membranes of the pancreas leading to an inflammatory response,” McGowan said. “It leads to vascular permeability of the pancreas. You can have hemorrhage, edema, ischemia and necrosis. If somebody develops severe pancreatitis, this can progress to systemic inflammatory response syndrome, sepsis and multi-organ failure.”
Lipid-lowering medications such as fibrates and statins are among those implicated in drug-induced acute pancreatitis.
Fibrates reduce the creation of bile acids/salts with the downregulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase expression. This in turn increases cholesterol concentration in the bile and risk for cholesterol gallstones, according to the presentation.
Statins, McGowan explained, may be directly toxic to the pancreas.
Statins metabolized by CYP3A4, including atorvastatin, lovastatin and simvastatin, appear more likely to cause acute pancreatitis statins compared with statins not metabolized by CYP3A4, which includes rosuvastatin and pravastatin, according to the presentation.
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McGowan MP. Session III: Drug Misadventures. Presented at: National Lipid Association Scientific Sessions; June 2-5, 2022; Scottsdale, Arizona (hybrid meeting).
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