Statin Intolerance and Diabetes Risk: What Do We Know?

Thomas G. Allison, PhD; Francisco Lopez-Jimenez, MD; Vinaya Simha, MBBS, MD


November 24, 2014

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Is Statin Intolerance Real?

Thomas Allison, MD: I'm Dr Thomas Allison, director of exercise testing and sports cardiology at Mayo Clinic, and I have also worked for many years in the preventive-cardiology clinic.

I'm joined today by my colleagues Dr Francisco Lopez-Jimenez, who is the director of preventive cardiology at Mayo, and Dr Vinaya Simha, who is an endocrinologist and specialist in lipidology. We are going to talk about statin intolerance. Many patients complain of this. Is this real? And if so, how common is it?

Francisco Lopez-Jimenez, MD: It seems to be real. So many patients complain of it every day. Even though the idea has been controversial in the medical community, it is so frequent that there seems to be something going on there.

It is reported that approximately 5% of patients taking statins develop some symptoms that can be attributed to the statins.[1] The problem is that we don't really know how common this is, because most clinical trials have run-in periods when they give the medication to patients, and only the patients who come back would be enrolled in the trial. So, unfortunately, we don't have very good evidence.

Dr Allison: So they weeded out the patients who didn't tolerate the drug. On the other side of the coin, how many times do you recommend that the patient increase physical activity and start an exercise program at the same time you prescribe a statin?

Dr Lopez-Jimenez: Very frequently. So I suspect that the problem is real. It exists. Unfortunately, however, many patients, especially when they have a preconceived notion that statins might be harmful, are more aware of any little aches and pains. On the other hand, we are probably dealing with something real in some patients, and the problem is how to identify them.

How Do You Diagnose Statin Intolerance?

Dr Allison: Have we yet found a simple test other than talking to the patient? Is there any lab test or anything we can do to distinguish between the patient who is just complaining and somebody who really is reacting to the statin?

Vinaya Simha, MBBS, MD: We have traditionally been using creatine kinase (CK) levels, and we have realized that a person can have statin-induced myalgias and even myositis in the absence of biochemical evidence of muscle damage. So the short answer is no. There will be people in whom you cannot biochemically establish that there is statin-induced muscle damage.

But in research, we set a very high bar in the sense that unless people have higher than a 10-times elevation in CK levels, we don't label them as having statin-induced myositis. In clinical practice, that is probably a very high bar, and I would never be comfortable waiting for that evidence. If my patient has a three-times to five-times elevation in CK level, that would certainly make me nervous.

Dr Lopez-Jimenez: It isa clinical diagnosis. If the symptoms start soon after the patient starts taking the medication, they disappear when the patient stops the medication, and they recur when we try another statin, we can confidently make the diagnosis.

Do Statins Cause Diabetes?

Dr Allison: Another current concern about statins is diabetes. Do statins cause diabetes? Is this real?

Dr Simha: I think it's real. Statins cause new-onset diabetes, but it is a very small effect as shown in the most recent meta-analysis[2] of 17 trials with more than 100,000 patients. It is a class effect, and not all statins cause the same degree of glucose intolerance. With pravastatin, perhaps the least glucotoxic of all the statins, the odds ratio is about 1.07, about a 7% increase in new-onset diabetes, as opposed to rosuvastatin [Crestor, AstraZeneca], which at a dose of 20 mg causes a 25% increase.

Overall, the use of statins, even when compared with placebo, or a high-dose compared with a low-dose, is associated with a small but definite increase in the risk for diabetes.

Dr Allison: My body-mass index (BMI) is 25 to 26 kg/m2. I go to the gym and exercise every day. I try to eat healthy. If Francisco puts me on a statin, am I likely to develop diabetes? Who is likely to develop diabetes with a statin?

Dr Simha: I am not sure that Francisco would put you on a statin, but if he did, you can breathe more easily. Your risk is much less than somebody who is already predisposed to develop diabetes. Of interest, BMI did not play a role in the meta-analysis, but that could just be because it was diluted.

It is a common clinical practice. A fasting plasma glucose predicts diabetes. People who already have impaired fasting glucose and impaired glucose tolerance are at the highest risk. In addition, polymorphisms and certain genes influence beta-cell function, so if you have a deleterious polymorphism, you are more likely to develop statin-induced new-onset diabetes.

Dr Lopez-Jimenez: It seems to be real, but it's important to put it in perspective. If statins increase the fasting glucose level a certain amount, and that moves some patients from being prediabetic to diabetic, the clinical relevance is minimal. It would be the equivalent, in the inverse point of view, of a medicine that reduced the glucose level by 5 units and moved you from being diabetic to prediabetic.

Are Statins Worth the Risk?

Dr Allison: According to the new guidelines,[3] if you are a man and you are 62 or 63 years of age, you are going to reach that 7.5% risk level and become a candidate for statin therapy. If your blood pressure is a little high, you are going to reach that level of risk at an even younger age, which means that we are going to put a lot of patients on statin therapy. Is it worth the benefit? Is treating large numbers of patients in their 60s and 70s with statin drugs, even though they don't yet have a diagnosis of coronary disease, worth the risk for diabetes and myalgias?

Dr Simha: If you are asking whether it is worth giving statins for primary prevention, the answer is absolutely. We have had many trials. But then in people over age 60 or 65 years, we don't know. Only a few trials (eg, the PROSPER trial[4]) have looked at older people.

On the basis of the Cholesterol Treatment Trialists meta-analysis,[5] if you treat 250 people with statins for 4 years, there will be one new case of diabetes, and during the same period you will prevent a composite vascular event in nine people. So, on balance, you would probably benefit nine people and cause diabetes in one.

Dr Allison: That sounds like a very favorable equation.

Dr Simha: Yes, but this was not only people who were age 65 and older. And the meta-analysis included both primary and secondary prevention.

Dr Lopez-Jimenez: We know that in patients with diabetes, statins actually give a pretty strong benefit. We shouldn't be too concerned about increasing the sugar when the benefit is that high.

Would You Put This Patient on a Statin?

Dr Allison: This is a complex topic. Let's summarize. A patient comes to you with statin intolerance. What is your approach?

Dr Lopez-Jimenez: First, I will try to verify that the intolerance is real. I ask a few questions, and if I confirm that it is intolerance, I will try a low dose of a statin—5 g of rosuvastatin or 10 mg of atorvastatin every other day—to see whether the patient tolerates that dose. If the patient has been on different statins and refuses to try it, I will then focus on very strict dietary recommendations and lifestyle changes.

Dr Allison: Is there any role for intestinal-acting agents in this population?

Dr Lopez-Jimenez: If the patient has a high low-density lipoprotein cholesterol (LDL-C), I will certainly try other medications to lower cholesterol, but if the LDL-C is not high, I will then focus on noncholesterol drugs.

Dr Simha: Endocrinologists have a lot of interest in this, because the bile-acid–binding resins also lower glucose. So if I have a patient in whom we are worried about increasing the risk for diabetes, using a bile-acid–binding resin in a statin-intolerant patient would probably help lower both glucose and LDL cholesterol. We use that quite often.

Dr Allison: Among the healthiest people in the United States are the Seventh-day Adventists, who follow a plant-based diet. Do either of you recommend a plant-based diet to your patients with hyperlipidemia who don't want to take statins or can't take statins?

Dr Simha: That goes without saying. Whatever we do in terms of statins, any pharmacotherapy is an adjunct to lifestyle changes. A plant-based diet with a lot of phytostanol and stanol esters would be very beneficial, and I strongly emphasize that.

Dr Lopez-Jimenez: The other thing that is important to keep in mind—and this is on the preventive side—is to avoid high-intensity statin treatment in the elderly and to be very careful in patients with chronic kidney disease, a history of muscle problems, or rheumatologic conditions, who might be more sensitive to high-dose statins and develop either symptoms or actual myositis.

Has Statin Intolerance Derailed the Polypill?

Dr Allison: Polypill trials are going on around the world. Polypills are advocated particularly in developing countries that may have limited resources for traditional office-space medicine and for laboratory work in checking risk factors. Do these concerns about myalgias and diabetes derail the polypill approach, or is this a still valid approach?

Dr Simha: I believe that it is still a valid approach. The polypill generally implies a lower dose generic statin, and we have over-simplified things by calling statins diabetogenic. There is an ongoing trial of pitavastatin called J-PREDICT[6] in Japan, which is trying to see whether pitavastatin reduces the incidence of diabetes. So, I don't believe that all statins are bad in this regard, and a small dose in a polypill is probably fine.

Dr Allison: Didn't one of the first statin trials, the West of Scotland Coronary Prevention Study (WOSCOPS)[7] show the opposite effect—that there is a reduced risk for diabetes with 40 mg of pravastatin in this population? It caught us by surprise, didn't it?

Dr Simha: Yes, although the definition of diabetes in WOSCOPS was an increase in glucose by 2 mmols. Nonetheless, it's not that all statins cause hyperglycemia.

Dr Allison: Thank you both for your contributions and insights on this interesting, timely, and controversial topic. Thanks to our readers. We hope you will continue to follow our round-table review series at on Medscape.


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