Balancing the Risk-Benefit Ratio of Statins
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The science of medicine is not static. Rather, it is an evolving mass of clinical data which helps us reshape and rethink our approach to the prevention, diagnosis and treatment of diseases. When clinical recommendations concerning a medication change, it is rarely because the old data were false. Instead, new information has become available that causes health care providers to rethink our approach.
Studies of the same medication conducted decades apart may yield different results because the baseline health profile of adults has changed over time. For example, obesity, high blood pressure, diabetes, high cholesterol and sedentary lifestyle are all much more common in patients today than they were 30 years ago. Furthermore, patients may take medications that simply were not yet developed 10 or 20 years ago. The ever-changing clinical profile of our population can definitely impact the risk-benefit ratio of any medication or treatment in a clinical trial. This is why clinical recommendations regarding the use of a medication may change, even if it that medication has been around for decades.
Statin medications – a brief overview
Changing clinical indications for the use of statin medications demonstrates shifting patterns of use. The first statin, lovastatin, was approved by the FDA in 1987. Since that time, additional statin drugs have been approved by the FDA including pitavastatin, rosuvastatin, atorvastatin, simvastatin, pravastatin and fluvastatin.
Initially, statin medications were prescribed in conjunction with a healthy diet and exercise to reduce LDL (bad) cholesterol in patients who had already experienced atherosclerotic cardiovascular disease (ASCVD) events such as heart attack, stroke, stents and bypass (so called secondary prevention). Studies of statin drugs in this patient population showed a significant reduction in recurrent ASCVD events or death.
Over time, additional clinical trial evidence gave rise to expert recommendations to use statin drugs for primary prevention of ASCVD. This recommendation was based on clinical trial data that showed a reduction in first heart attack or first stroke in patients who were at high risk for developing these events due to the presence of multiple cardiovascular risk factors such as diabetes, hypertension, smoking, very high LDL cholesterol and significant coronary artery calcification shown by a CT scan.
Given that ASCVD is the most common cause of death among adults, it is no surprise statin medications are one of the most widely prescribed types of drug in the United States.
In general, newer statin drugs have increased potency resulting in greater reduction in LDL cholesterol. In the past, statin doses were chosen to achieve a specific LDL target such as <130 mg/dL or <70 mg/dL. More recent guidelines have placed a greater emphasis on the intensity of statin dosing (moderate-intensity dose versus high-intensity dose) rather than on the post-treatment LDL cholesterol value. The intensity of a statin medication dosage is a double-edged sword─the higher the intensity, the greater the reduction in LDL but it also comes with a greater risk of experiencing negative side effects.
Possible side effects of statins
Most patients, whether they use a statin drug or not, are aware of muscle soreness being a possible side effect of statin use. This became a common topic of health news as higher intensity statin medications became more widely prescribed. Some patients left the doctor’s office with a prescription for a statin medication and a prescription for exercise─only the passage of time could differentiate between their muscle soreness being a side effect of medication or a side effect of a new exercise program.
There is often a trial-and-error approach to determine if lowering the dose or switching the statin brand will alleviate muscle soreness. Some patients could run marathons on high-dose statins while others became so symptomatic with muscle soreness on low-dose statins that it was difficult to get up from a chair. Given the robust LDL reduction with statin medications, investigators were keen on trying to figure out the physiological mechanism of this side effect so they could create a means to prevent it.
Over the last decade, studies conducted to better understand the relationship between muscle soreness side effects and statins use generated a lot of discussion regarding the “nocebo effect” of statin drugs and introduced many health care providers to the concept of “n-of-1” trials.
The nocebo effect is the phenomenon in which the negative expectations a person has regarding a treatment results in the treatment having a greater negative effect than it would if the patient had neutral or positive expectations. This is the opposite of the “placebo effect”—the finding of having more favorable outcomes associated with taking a pill if you believe that pill will make you feel better.
The nocebo effect has been documented in numerous studies regarding statin use. In one study of more than 10,000 patients taking placebo or statin medication, during the blinded phase (where patients were unaware if they were given the statin or placebo), the rate of muscle-related symptoms were similar across the two groups. However, once the patients became aware they were taking a statin, muscle-related symptoms were much more likely to be reported by that group.
While health care providers may recommend a change in dosage or brand of statin to alleviate muscle symptoms, this does not completely eliminate the impact of the nocebo effect. The only way to completely eliminate the nocebo effect is to prevent the patient from knowing what they are taking altogether, which is the underlying notion of “n-of-1” trials, otherwise known as “single subject” clinical trials.
The statin n-of-1 trials are simple crossover studies in which the order of the administration of the statin medication or placebo is randomized among different subjects. In one trial, investigators in primary care clinics enrolled 200 participants who had stopped statin treatment due to muscle symptoms. Participants were randomized to a series of six double-blinded treatment periods of two months each where they would receive a statin drug or placebo. The participants provided symptom scores after each two-month period, during which time they did not know if they were taking statin medication or placebo. Ultimately, no difference in muscle symptoms scores were found between periods of statin or placebo use and the majority of the participants were able to restart long-term statin treatment without muscle side effects.
While muscle symptoms appear to be driven by the nocebo effect in most patients, it does not mean the patient’s muscle pain is in their head. Their pain is real and can impair their quality of life. The nocebo effect underscores the need for patients and health care providers to have honest discussions about fears related to statin use so patients can approach a trial of statin use with a more positive attitude based on health benefits.
Risk of diabetes
Another potential side effect of statin medication is the effect of statin use on the risk of increased blood sugar (glucose) and the risk of developing diabetes. This is a much more objective side effect to detect compared to symptoms of muscle soreness because this side effect is identified by a change in a blood test result (fasting glucose or hemoglobin A1C).
The notion that statin medications could increase blood sugar gained significant clinical attention following the publication of the JUPITER Trial (2008). This large study was made up of almost 18,000 generally healthy men and women with elevated c-reactive protein, (a marker of inflammation) and LDL levels less than 130 mg/dL. The participants were prescribed a high-intensity statin (rosuvastatin) daily for primary prevention of ASCVD events. While statin use was associated with reduced ASCVD risk, it was also associated with an increase in hemoglobin A1C (a blood test used to detect pre-diabetes and diabetes) and in physician-reported diagnoses of diabetes.
A subsequent meta-analysis of 13 statin trials including more than 91,000 patients showed statin therapy was associated with a 9% increased risk of developing diabetes. Furthermore, in an analysis of five clinical trials of more than 32,000 participants with prior ASCVD events, experts showed the risk of developing diabetes was slightly greater in high-intensity statin users in comparison to moderate-intensity statin users. However, the research also proved high statin use to reduce the occurrence of ASCVD events.
In 2012, the FDA added a warning to statin medications that some patients may experience an increased risk of higher blood sugar levels and of being diagnosed with type 2 diabetes.
Modifiers of diabetes risk with statin use
With that being said, not all subsequent clinical trials have demonstrated an increased risk of diabetes. In a large primary prevention trial of more than 12,000 patients with intermediate ASCVD risk who were treated with moderate-intensity statins saw a reduction in cardiovascular events but no increased risk of developing diabetes.
Why were the findings different across various studies? These differences likely arose because the study populations were different. Those individuals who were already at higher risk for developing diabetes were also at higher risk for developing diabetes as a side effect of statin use.
The risk of developing diabetes over time, independent of statin use, is more likely to occur in individuals with high blood sugar to start with (pre-diabetes glucose levels of 100-126 mg/dL), large waist circumference (more belly fat), body mass index higher than 30 (obesity levels) and high blood triglyceride levels (a marker of insulin resistance).
The presence of these factors also increases the risk of developing diabetes with statin use. In an analysis of 15,000 patients with known ASCVD treated with moderate- or high- intensity statin drugs for an average of five years, the patients with high blood sugar at baseline were much more likely to develop diabetes with statin use compared to those with normal blood sugar levels at baseline (14% versus 3% respectively). Importantly, the use of statin medications reduced the risk of having a heart attack or stroke in all patients treated with statin drugs, regardless of whether they developed diabetes during the study.
These findings that statin use is more likely to be associated with diabetes in patients with diabetes risk factors highlights the importance of practicing healthy habits in an effort to maintain healthy blood sugar levels, waist circumference and weight.
There is no doubt side effects and fear of side effects from statins strongly influence patients’ decisions to discontinue statin medications. Overall, half of all statin patients will discontinue statin therapy at some point despite recommendations from their health care providers. Unfortunately, the decision to discontinue statin medications prematurely in some patients can lead to poor clinical outcomes and is associated with increased risk of serious ASCVD events and even death.
This is why it is important to talk to your health care provider about your symptoms and concerns regarding statin use before stopping medication to determine the best course of treatment for you. These types of patient-physician discussions are what we do best at Cooper Clinic. Heart health and fitness are key components to a healthy mind, body and lifestyle.
To learn more about Cooper Clinic preventive exams and how an annual exam can help you manage and improve your health, click here or call 866.906.2667
Article provided by Nina B. Radford, MD, Cooper Clinic Cardiologist.