Educate, explore options to limit risks for statin-intolerant patients
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Statin therapy is a first-line recommendation for all adults with established atherosclerotic cardiovascular disease or at high atherosclerotic CVD risk, yet reports show many patients cannot — or will not — take statins as prescribed.
Statin therapy is a cornerstone of CVD prevention and one of the most widely studied classes of medications. For those eligible, particularly for high-intensity statins, data demonstrate strong benefits for LDL lowering by as much as 50% or more, thereby reducing risk for a CV event.
People with type 2 diabetes have two to four times the risk for CVD compared with people without diabetes, and about 75% of adults with type 2 diabetes die of CVD. Though not broadly appreciated, CVD risk may be greater still for those with type 1 diabetes, according to Elias S. Siraj, MD, Dr Med, FACP, FACE, the David L. Bernd Distinguished Chair for the Eastern Virginia Medical School-Sentara Cardiovascular Diabetes Program, professor and chief of the division of endocrine and metabolic disorders and director of the Strelitz Diabetes Center at Eastern Virginia Medical School.
The role of statin therapy in reducing CV risks for people with diabetes was established in the Heart Protection Study, published in The Lancet in 2003. In the study, 5,963 adults in the U.K. with type 1 or type 2 diabetes were randomly assigned to statin therapy or placebo for 5 years. The statin group had a 22% lower rate of major coronary events, stroke or revascularization compared with placebo. CV risk was reduced by 33% for adults who had no diagnosed occlusive arterial disease at enrollment and 27% for adults with a baseline LDL cholesterol level of less than 116 mg/dL.
“That was a landmark study which clearly showed that statins significantly reduced CVD and CV events [for people with diabetes],” Siraj told Healio | Endocrine Today.
However, approximately 10% of people in the U.S. and globally are deemed statin intolerant, often due to patient-reported adverse events, such as muscle pain. Some patients express fear of initiating a statin regimen because of concerns about adverse events. That hesitancy contributes to reduced statin adherence and persistence, as well as higher risk for adverse CV outcomes, according to the National Lipid Association (NLA).
In addition, patients prescribed statins may have increases in glucose levels that could potentially lead to diabetes. However, the American Diabetes Association Standards of Care recommends statin therapy for most adults, stating that the CV risk reduction “far outweighed the risk of incident diabetes.”
“There is a bigger perception of side effects [of statin therapy], more than is the reality,” Siraj said. “That leads to a lot of patients stopping and not continuing the statins. CVD is a silent disease until you get myocardial infarction or stroke. There’s an increased need for both providers and patients to recognize how significant statins are in lowering CV risk.”
Statin avoidance or statin intolerance is one of the most difficult problems to address in cardiology and primary care, according to Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic.
“Patients come to see us and have clear indications for treatment with a statin, and they say they cannot tolerate the drugs. We have needed a clear approach that will work,” Nissen told Healio | Endocrine Today.
For most patients with statin intolerance, clinicians can identify an acceptable statin treatment that may require a different dose, a different statin or different dosing schedule, Kevin C. Maki, PhD, CLS, FNLA, president and chief scientist of Midwest Biomedical Research, adjunct professor at Indiana University School of Public Health and immediate past president of the NLA, told Healio | Endocrine Today. For some patients, that requires a nuanced discussion that does not discount reported symptoms.
“There is a lot of psychology involved and a lot of education involved,” Maki said. “Part of that education is to say, ‘We are going to work together as a team, and we are going to get to something that works. We are going to keep the eye on the prize, which is that low level of LDL cholesterol that is commensurate with reducing your risk.’ Most people who have some symptoms associated with their statin therapy can tolerate some statin regimen. Only a few cannot. If they cannot, then there are other options with other medications.”
True incidence of statin intolerance
The prevalence of statin intolerance remains a matter of debate and depends on how statin intolerance is defined and measured.
In a global meta-analysis from the Lipid and Blood Pressure Meta-Analysis Collaboration and the International Lipid Expert Panel (ILEP), the overall prevalence of statin intolerance was 9.1% (95% CI, 8-10). The prevalence according to societal diagnostic criteria was even lower: 7% (95% CI, 6-8) using NLA criteria, 6.7% (95% CI, 5-8) using ILEP criteria and 5.9% (95% CI, 4-7) using European Atherosclerosis Society criteria.
The analysis, which included more than 4 million adults, also showed that as many as 50% of adults prescribed statins take reduced or no doses due to perceived statin intolerance.
The researchers reported higher rates of statin intolerance for adults older than 65 years, women and those of Asian and African American races. Positive associations were noted for those with obesity or diabetes, hypothyroidism or chronic liver or renal disease. A higher dose of statin was associated with more statin intolerance.
Other studies suggest adverse symptoms attributed to statins are no different than symptoms attributed to placebo. In the SAMSON trial, published in 2020 in The New England Journal of Medicine, patients who developed symptoms within 2 weeks of statin initiation reported similar adverse events while on placebo, suggesting a large proportion of burden owed to the “nocebo” effect.
When this nocebo effect was revealed to participants who had initially discontinued statin therapy due to adverse effects, half were open to resuming treatment.
“A lot of times, people are willing to attribute daily aches and pains and things that the aging population experience to their statin, when it is this ‘nocebo’ effect,” Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC, associate professor of medicine and director of women’s cardiovascular health research at Johns Hopkins Medicine, told Healio | Endocrine Today. “When you think something is going to harm you, you are more likely to perceive any adverse symptoms. This can be challenging, because I do talk to patients about the nocebo effect, and I even bring up slides from the SAMSON trial. Regardless of whether it is a nocebo effect or not, it is very real for the patient.”
Professional societies have issued updated guidance for how best to treat patients with true or partial statin intolerance. In June 2022, the NLA published a scientific statement that defined statin intolerance as “one or more adverse effects associated with statin therapy which resolve or improve with dose reduction or discontinuation and can be classified as a complete inability to tolerate any dose of a statin, or partial intolerance with inability to tolerate the dose necessary to achieve the patient-specific therapeutic objective.”
The updated definition was created to reflect a continuum ranging from complete to partial intolerance, which prevents the patient and clinicians from reaching the therapeutic objective and requires a clinician-patient discussion, Maki said.
The updated definition also does not state that any adverse events are necessarily due to pharmacodynamic effects of statins.
“One thing that is very clear is that many more people think they have muscle symptoms related to taking a statin than actually have muscle symptoms related to taking a statin,” said Maki, a co-chair of the NLA scientific statement. “Muscle aches and pains are very common. Most likely, the true incidence of statin intolerance for patients above what you see with placebo is probably in the range of 2% to 4%. But when you look at how many people report what they think is statin intolerance, it is somewhere between 10% and 30%.”
In addition to muscle pain, statin therapy may increase glucose levels. Siraj said multiple studies have found HbA1c increases by about 0.5 percentage points for people who use statins.
“That’s a very slight increase,” Siraj said. “Because of that, occasional patients may convert from prediabetes to diabetes, or on occasion may have a little bit worsening of blood sugar levels. But in the bigger scheme of things, this is not a big deal. If your diabetes worsens a little bit, it can be managed by tweaking other medicines.”
The question of whether statin intolerance is real or a phenomenon attributed to a combination of misleading media reports and symptoms caused by other health issues is ultimately one that does not matter, according to Nissen.
“Some people prescribed statins have these vague neurological complaints; they may call it brain fog,” Nissen said. “I am not sure these symptoms are real, and a certain amount of muscle and tolerance studies have shown these symptoms probably are not real. But it doesn’t really matter. If a patient comes in my office, looks me in the eye, and says, ‘I have tried statins on multiple occasions, I cannot tolerate them and I will not take them,’ then, we have no alternative. They are not going to take a statin, and they are therefore statin intolerant.”
Women consistently underprescribed statins
Compared with men, women with atherosclerotic CVD (ASCVD) are less likely to be prescribed any statin, less likely to be prescribed a high-intensity statin and more likely to be deemed statin-intolerant, data show.
In an analysis of electronic health records prescription data, researchers used a deep learning natural language processing (NLP) approach to identify and interpret discussions of statin prescriptions documented in clinical notes. Statin disparities were more pronounced among women who were younger, had private insurance or did not speak English as a primary language.
Among patients who were not prescribed statins, women were less likely than men to have statin use reported in their clinical notes despite the absence of a recorded prescription (32.8% vs. 42.6%; P < .001). Women were also more likely to be deemed statin intolerant in structured data or clinical notes compared with men (6% vs. 5.3%; P = .003).
“Some of it is clinician therapeutic inertia,” Fatima Rodriguez, MD, MPH, FACC, FAHA, FASPC, associate professor in cardiovascular medicine and section chief of preventive cardiology at Stanford University, told Healio | Endocrine Today. “When people think of heart attacks, they don’t think of women. People think women are at lower CV risk. We know that is simply not true. Unfortunately, there is much better awareness of the risks related to breast cancer or other problems, when really heart disease is the No. 1 killer of women.”
There are also concerns related to statins and pregnancy, Michos said, noting that the FDA has removed its most stringent warnings related to statins and pregnancy.
“Women are not treated with statins because of this theoretical concern that they may get pregnant, but women could have reproductive potential for 4 decades,” Michos said. “To not treat high-risk women because they might possibly get pregnant is doing these women a disservice, especially in the setting of familial hypercholesterolemia, and can doom these women to early-onset CVD.”
Michos said clinicians should first counsel all reproductive-capable women about conception, pregnancy and breastfeeding, and ideal times to stop and start statin therapy.
“It is much better to have short interruptions of a year or 2 than to go decades untreated,” Michos said. “It is really about cumulative burden — not only how high cholesterol is, but the years of exposure. It is also likely that statins are not teratogenic.”
Finding a plan that works
The ADA Standards of Care outlines recommendations for statin therapy for people with diabetes based on age. For adults aged 20 to 39 years, a moderate-intensity statin may be considered for those with additional ASCVD risk factors. Adults aged 40 to 75 years without ASCVD should be prescribed a moderate-intensity statin in addition to lifestyle therapy. For adults at higher risk with multiple ASCVD risk factors or aged 50 to 70 years, a high-intensity statin should be used.
However, the Standards of Care also acknowledges patients may not tolerate the recommended intensity of statin. It states the maximum-tolerated statin should be used, even if it is a low-intensity statin.
“When you decide [to prescribe a statin], age is important, the other risk factors are important and the cholesterol level is important in most cases,” Siraj said. “The issue of side effects is another one that matters. Some people get side effects, and you can’t decide what to do. It does affect your likelihood of continuing the treatment.”
Experts agree that whether statin-associated adverse events are real or not matters little if a patient cannot or will not take the statin because of the symptoms they describe.
“If a person thinks that the aches and pains are related to the statin, you are going to have a hard time keeping the person on the statin,” Maki said. “Clinicians have to work closely with patients to educate them on the value of lowering LDL. We have very good evidence that lower for longer is better when it comes to LDL and reducing event risk. Then, it is a matter of working as a team to say if you have a side effect, we have options.”
Finding a plan that is acceptable to the patient may require switching agents, changing dosages or using alternative regimens, such as dosing on alternate days.
“There are many statins,” Rodriguez said. “If you are taking, for example, simvastatin, which is an older statin that I do not prescribe routinely because of more potential for drug-drug interactions, I will try rosuvastatin. You can also try intermittent dosing or very low dosing. A little bit of statin is better than no statin. Even if we need to add a second nonstatin medication to reduce the LDL, it is still very helpful.”
Nissen said he has some patients who take rosuvastatin 3 days per week, plus ezetimibe.
“One strategy that has worked very well for me is trying a low dose of a statin, 5 mg of rosuvastatin, and then adding ezetimibe,” Nissen said. “If you add ezetimibe to 5 mg rosuvastatin, you get the equivalent LDL lowering to 40 mg of rosuvastatin.”
Nonstatin options
Nonstatin therapies may be required for patients who cannot reach clinical objectives with lifestyle and maximally tolerated statin therapy. The NLA guidance states that clinicians should favor nonstatin therapies with data from outcomes trials showing a reduction in adverse CV events.
In the CLEAR Outcomes trial, bempedoic acid (Nexletol, Esperion Therapeutics) reduced risk for major adverse CV events (CV death, nonfatal MI, nonfatal stroke and coronary revascularization) by 13% compared with placebo, including a 23% lower risk for MI, among adults with a history of CVD or at high risk deemed statin intolerant. To enroll in CLEAR Outcomes, prospective participants needed to sign a statin intolerance confirmation form, stating they were unable to tolerate statins even though they would reduce the person’s risk for MI, stroke or death, making it the first trial designed to exclusively enroll statin-intolerant patients.
At 6 months, LDL reduction in the bempedoic acid group was a median 29.2 mg/dL lower than in the placebo group; the observed difference was 21.1 percentage points in favor of bempedoic acid.
The incidence of a primary endpoint event was lower with bempedoic acid than with placebo, as was incidence of CV death, nonfatal MI and nonfatal stroke; fatal or nonfatal MI; and coronary revascularization.
“Bempedoic acid produces moderate LDL lowering but is now shown to reduce CV events,” Nissen said. “PCSK9 inhibitors are also very effective and well tolerated and tend not to induce statin-type adverse events. They are expensive, as is bempedoic acid, and some people do not want to self-inject medication every 2 weeks.”
Another alternative could be inclisiran (Leqvio, Novartis), Nissen said. Long-term data from the ORION-3 study demonstrated that, for adults with ASCVD or a risk equivalent, twice-yearly inclisiran injections were associated with a 44% reduction in LDL that was sustained over 4 years, with no new safety signals observed.
“After the first two doses, it is once every 6 months,” Nissen said. “It is a really nice approach, and one that may gain additional traction in coming years.”
Siraj said nonstatin therapy could benefit people with diabetes. The clinical trials involving ezetimibe and PCSK9 inhibitors both included a substantial group of participants with diabetes. The ADA Standards of Care advises considering nonstatin therapy following a discussion with the patient about net benefit, safety and cost.
“There is some data [for nonstatins] and the guidelines recommend using them,” Siraj said. “But the data they have is not as profound as what we have for statins. We still need more studies and more data using these nonstatin agents for lowering CV risk.”
The right regimen: ‘Time matters’
Clinicians agree that the overarching message when it comes to LDL and ASCVD risk is “lower for longer.” However, achieving an LDL goal is more complicated when a provider is struggling to find a regimen that works for a patient who cannot or will not take a recommended statin.
For these patients, Maki said, clinicians must strike a careful balance: Finding a therapy regimen that works, without waiting too long to reduce the LDL in a meaningful way. That approach could mean more intense follow-up for some patients, trying multiple statins or alternative therapies and moving on quickly if something does not work to avoid lost time, he said.
“I am not so concerned about how the LDL level is lowered,” Maki said. “But I do not like to see patients, especially those with ASCVD, left untreated or undertreated for a year while a provider is trying to figure out a regimen. Time matters. Lower [LDL] for longer is better, and getting there as fast as you can is ideal.”
- References:
- Bytyci I, et al. Eur Heart J. 2022;doi:10.1093/eurheartj/ehac015.
- Chelley MK, et al. J Clin Lipidol. 2022;doi:10.1016/j.jacl.2022.05.068.
- Collins R, et al. Lancet. 2003;doi:10.1016/s0140-6736(03)13636-7.
- Nissen SE, et al. JAMA. 2016;doi:10.1001/jama.2016.3608.
- Nissen SE, et al. N Engl J Med. 2023;doi:10.1056/NEJM0a2215024.
- Ray KK, et al. FS.09: The present and future of lipid lowering. Presented at: American Heart Association Scientific Sessions; Nov. 5-7, 2022; Chicago (hybrid meeting).
- Wood FA, et al. N Engl J Med. 2023;doi:10.1056/NEJMc2031173.
- For more information:
- Kevin C. Maki, PhD, CLD, FNLA, can be reached at kmaki@mbclinicalresearch.com.
- Erin D. Michos, MD, MHS, FACC, FAHA, FASPC, can be reached at edonnell@jhmi.edu; X (Twitter): @erinmichos.
- Steven E. Nissen, MD, MACC, can be reached at nissens@ccf.org.
- Fatima Rodriguez, MD, MPH, FACC, FAHA, FASPC, can be reached at frodriguez@stanford.edu; X (Twitter): @farodriguezmd.
- Elias S. Siraj, MD, Dr Med, FACP, FACP, can be reached at sirajes@evms.edu.
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