Caption: Point of care in our pharmacy for checking the levels of blood pressure, blood glucose, A1C and cholesterol. People have those risk factors, statin therapy may be considered for them as for primary prevention of cardiovascular events.
Years ago I studied the course of how to consult patients about their concern of diabetes linked with statins. I learnt the newly reported risk was low, and nothing had changed in the guideline for statin therapy. Therefore I paid little attention to issue. I have never encountered any question regarding this issue in my patient consultation. Later, when evidences were piled up for the benefit of statin used for diabetic patients, the indication of statins for diabetic patients as primary prevention of cardiovascular disease was added to Guideline. Diabetic patients, even if they have the normal level of LDL Cholesterol, are significantly benefited from statin therapy in term of preventing heart attacks, strokes and other CVDs. This addition to the original guideline made our pharmacy staff insanely busy, because we were instructed to consult everyone whoever was taking diabetes medication, informed them that they need to start a statin. So I believed no one would need to be concerned about the issue of the risk of diabetes associated statins. Until recently this issue was dramatized, and it has potentially become a harmful message.
To address the misrepresentation of the risk, many statements have been made by medical community emphatically indicated that he benefits of statins in prevention of cardiovascular diseases outweigh the risk of its related diabetes and the risk of diabetes associated statin is low.
For those who want to further minimize the risk, may seek answers for the following questions before starting their statin therapy. Results of current research findings are not always consistent for answering those questions, but are most certainly helpful:
A. There are several statin drug in this class, do they all have the same level of the risk? I want the one with lowest risk!
A latest review article has summarized results from various reports. A report of 2015 showed the order of risk: from higher to lower. pravastatin > rosuvastatin > fluvastatin > atorvastatin > lovastatin. Another report of 2010: rosuvastatin > atorvastatin > simvastatin > pravastatin > lovastatin.
Majority of previous reports showed that pravastatin had lower risk than others. Pitavastatin has lowest risk. Some reports stated every statin drug carried the same risk without difference. Results have not been consistent. Therefore, taking a statin of higher efficacy to lower LDL cholesterol seems more important than looking for one with lower risk of diabetes.
B. If I take a statin at lower dosage, will I avoid the risk?
Lower dosage, the risk is lower. The risk of diabetes is statin dose-dependent. However, at higher dosage, you have better protection from getting heart attack. The benefit of statins to prevent heart attack, stroke or other CVD is also dose-dependent. If not messing around with the terms of statistics, the comparison of benefit and risk is as such: Risk – It is about two additional cases of diabetes of every 1000 patient in years of high-dose compared to moderate-dose statin therapy. Benefit – It is 6.5 fewer cases of cardiovascular events (cardiovascular death, hearth attack, stroke etc.) of every 1000 patients in years of high dose statin compared to the moderate-dose. Pravastatin 40mg, simvastatin 20mg, atorvastatin 10mg are considered moderate dose. Simvastatin 80 mg, atorvastatin 80mg are considered high dose. This is a result of about 5 years of following up. The Intensity of a statin is different from dose or potency of a statin. But the concept to understand here is the same.
C. Heart attacks and strokes could kill me in a time lapse of having a drink, but it would have to take quite a while for diabetes to do that. I want to start a statin therapy right now. Could I just stop taking the statin anytime if I find any problems with my blood glucose later?
This question may be phrased differently: “ In case that the fasting blood glucose has increased after taking a statin for about a year, I am thinking about discontinuing my statin, will my blood glucose level return back to normal ?” I have searched, but have not found any straight forward answer. It is about whether the insulin resistance caused by statins is reversible. Insulin resistance causes the elevation of blood glucose and fasting blood glucose > 126 mg/dl is considered diabetic. It could just be postulated that high blood glucose may be reversible, and why not? Provided the mechanism of the insulin resistance suggested by the contemporary research is correct. However, in any case, according to Statements, physicians do not recommend discontinuation of statin therapy even if an elevation of blood glucose occurs, for the sake of preventing heart attacks. Change of life styles, weight loss, good diet,etc. are the preferred approaches to lower blood glucose.
D. I understand that the risk is low in term of occurrence, but how severe in term of blood sugar levels cam be affected by statins?
“You need to treat a lot of people with statins for one person to get diabetes” stated by a diabetic specialist in response to a report of exaggerating the increased risk of diabetes associated with statins. The multitude of upswing change of blood glucose has been also considered small. Combined from various reports, the increase of A1C is about 0.3% on average is associated with statin therapy for the new onset diabetes. “Overall, the data support the conclusion that there is a small aggregate effect of statins in increasing hemoglobin A1c.” stated in the summary of a recent review article ( Byron Hoogwerf, MD, Cleveland Clinic Journal of Medicine, January 2023)
A1C is the most important measure of uncontrolled blood glucose in diabetes. Measure of fasting blood glucose is sensitive, but it fluctuates hour to hours. A1C test is more indicative and reliable. It represents the result of average blood sugar levels over the past 3 months. It’s the commonly used tests to diagnose prediabetes and diabetes.
E. My LDL cholesterol is high, but I am healthy otherwise although my fasting blood glucose is sometimes a little high. I need to start taking a statin, do I need to be concerned? Who would be prone to be affected with the risk of diabetes associated with statin?
After starting statin therapy, people of prediabetes have almost 5 – 6 times higher risk of diabetes than those who do not have prediabetes.
People with normal fasting blood glucose are rarely affected by statins.
Prediabetes is diagnosed when fasting blood glucose is 100—125 mg/dl, or A1C is 5.7—6.4 (%). [Link]
High BMI (overweight or obese ), high LDL cholesterol or triglycerides, high blood pressure, older age and other risk factors are associated with development of diabetes in general population. People, who have those risk factors in addition to a new statin therapy, have higher risk of new onset diabetes.
F. You are talking about the risk the new onset of diabetes, but I am already a diabetic patient and my physician told me start statin therapy. Will statins make my diabetes worse?
The evidence of benefit of statins for patients with existing diabetes is every strong. As mentioned earlier in this writing. Based on the strong evidence, Guideline of statin therapy added the indication of statins for diabetic patients years ago. Statins may interfere with levels of fasting blood glucose, affecting the A1C level of diabetic patients, but “in patients with diabetes mellitus, the average increase in HbA1c with initiation of statin therapy is small and thus is usually of limited clinical significance.” (Quote from Statement). Reinforce of healthy life style, diet and exercise, and continuation of statin therapy is recommended to counteract the risk.
The occurrence rate of developing new onset of diabetes is higher in the first 2 years of statin therapy. Beyond the time frame, the risk becomes continuously lower.
G. I have learnt that statins are the drugs for lowering LDL cholesterol, thus to prevent heart attack or stroke. But my LDL cholesterol level is not high. I am diabetic. Will I be benefited from statin therapy?
According the guideline of statin therapy, for patients 40 to 75 years of age with diabetes and an LDL ≥70 mg/dL(1.8 mmol/L) a moderate-intensity statin can immediately be started, no need of further assessment. Some patients should start with a high-intensity statin if other atherosclerotic cardiovascular risk factors also exist, such as hypertension, kidney disease, history of cardiovascular events etc. A moderate-intensity statin therapy includes: 20-40mg atorvastatin, 40mg pravastatin. A high-intensity statin therapy includes: 80mg atorvastatin, 80mg simvastatin.
Diabetes has been reported roughly increasing cardiovascular risk by 2 times. Statins can protect the heart and brain by reducing heart attack and stroke risk, even if cholesterol isn’t high.
The following equation is used to estimate the levels of risk of having atherosclerotic cardiovascular disease. The estimated levels are the basis of determining who should be treated with statins and what type of statin therapy needed: Survey studies point to little benefit of statins for primary prevention in patients younger than 40 years or older than 75 years. Primary prevention of atherosclerotic cardiovascular events refers to the preventive treatment for patients with no history of heart attack or stroke, etc., and familial hypercholesterolemia with low-density lipoprotein cholesterol (LDL) equal to or higher than 190 mg/dL.
The ASCVD Risk Estimator Plus can be used to estimate 10-year ASCVD risk. It is available at https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/. https://tools.acc.org/LDL/ascvd_risk_estimator/index.html#!/calulate/estimator
“Statin therapy substantially reduces cardiovascular events in those with and without diabetes mellitus and in the latter case, several cardiovascular events are prevented for every new diagnosis of diabetes mellitus. Furthermore, when considering the increase in newly diagnosed diabetes mellitus, it is important to note that this represents a far less dramatic and threatening event than the occurrence of myocardial infarction, stroke, or cardiovascular death.” Quoted from Statement of Heart Association)
Another issue is the adverse effect of muscle ache caused by statins. It is the primary cause that 9% of people discontinue statin therapy. There are other therapeutic options of lowering LDL cholesterol without this side effect. It may be helpful for friends who want actions to prevent heart attacks or strokes if I would soon be able to organize the information for the solution of this issue.
Key ref:
Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207).
Culver AL, Ockene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med 2012; 172(2):144–152).
John Keaney; Bemoedoic Acid and the Prevention of Cardiovascular Disease, New England Journal of Medicine March 4, 2023
Statins and Diabetes: How Big Is the Risk? Eric Seaborg, Feb 2020, Endocrine News
Byron J. Hoogwerf MD, Statins may increase diabetes, but benefit still outweighs risk, MD, Cleveland Clinic Journal of Medicine January 2023, 90 (1)
Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association, December 2018
PharmcistsLetters, August 2014
Diabetes Mellitus-Related All-Cause and Cardiovascular Mortality in a National Cohort of Adults; Sridharan Raghavan et al. J Am Heart Assoc. 2019 Feb 19; 8(4): e011295.
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