Statin Therapy in Patients with Diabetes

The CDC estimates that from 2003 to 2012, the percentage of adults 40 and older who took a cholesterol-lowering medication increased to 28%, from 20%. From 2011 to 2012, 93% of adults using cholesterol-lowering medication took a statin, also known as an HMG-CoA reductase inhibitor.¹ Because statin medications are commonly prescribed, different guidelines acknowledge the importance of statin therapy and describe how it should be used. Let’s take a look at the role of statin therapy in patients with diabetes, referencing the most widely used guidelines.

Pathophysiology

It is believed that increased production of advanced glycation end product (AGE) in patients with diabetes interferes with extracellular signal-regulated kinase 5 (ERK-5), krup-pel-like factor 2 (KLF-2), and peroxisome proliferator-activated receptor-g (PPARg).² ERK-5 functions by signaling endothelial nitric oxide synthase to produce more nitric oxide for vasodilation. KLF-2 and PPARg are known to block the activity of pro-inflammatory immune cell activity in blood vessels. As a result, patients with diabetes are less likely to benefit from ERK-5, KLF-2, and PPARg mediated cardio-protection compared with patients without diabetes.

Guidelines

ADA: The 2017 American Diabetes Association Standards of Medical Care in Diabetes recommends statin therapy (Table 1) based on *atherosclerotic cardiovascular disease (ASCVD) *cardiovascular disease (CVD) risk factors, rather than low-density lipoproteins (LDL) levels by itself for patients with diabetes.^3,4 Which individuals are candidates for high-intensity statin? Any diabetic patient with a history of ASCVD and individuals from 40 to 75 with ASCVD risk factors (LDL cholesterol ≥100mg/dl, high blood pressure, smoking, chronic kidney disease, albuminuria, and family history of premature ASCVD⁴) may be considered for high-intensity statin therapy. Who would be considered a good candidate for either high-intensity or moderate-intensity statin? Patients under 40 or over 75 carrying ASCVD risk factor. Ezetimibe may be combined with moderate-intensity statin for patients 40 and older with a history of acute coronary syndrome (ACS) who cannot tolerate high-intensity statin or with LDL-C ≥50 mg/dl. Patients younger than 40 without CVD risk factors are not a candidate for statin therapy.

Supporting evidence for the addition of ezetimibe to moderate-intensity statin originates from the results of ezetimibe added to statin therapy after the ACS (IMPROVE-IT) trial.⁵ The combination of simvastatin and ezetimibe resulted in a significantly lower risk of cardiovascular events than that of simvastatin mono-therapy for post-ACS patients who are 50 or older. The simvastatin and ezetimibe combination group resulted in a 2-percentage-point lower rate of primary composite end point cardiovascular death (hazard ratio 0.936). Primary composite end points were cardiovascular death, major coronary events, or nonfatal stroke.

Table 1. Statin Therapy Recommendations for Patients with Diabetes, per the ADA

Statin Intensity

Age and Risk Factors

High

· <40 years with ASCVD

· 40 to 75 years with ASCVD or ASCVD risk factors

· >75 years with ASCVD

High or Moderate

· <40 years with ASCVD risk factors

· >75 years with ASCVD risk factors

Moderate + Ezetimibe

≥40 years with ACS and LDL cholesterol ≥50mg/dl or in patients with a history of ASCVD who cannot tolerate high-intensity statin

Moderate

≥40 years without ASCVD risk factor

ACC/AHA: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults focus on the treatment to reduce ASCVD risk, rather than targeting a certain LDL level.⁶ The ACC/AHA guidelines recognize lifestyle modification as a crucial component to reduce the ASCVD risk factor, and they publish a separate guideline for it: the 2013 ACC/AHA Guideline on Lifestyle Management to Reduce Cardiovascular Risk. Statin therapy initiation follows a four-step process in the ACC/AHA guideline (Table 2). Before considering diabetes as a determining factor for the intensity of statin therapy, we must review other factors such as *clinical ASCVD (ACS, myocardial infarction [MI], angina, coronary revascularization, PAD due to atherosclerosis, stroke or transient ischemic attacks⁶) and LDL-C level ≥190mg/dl. If a patient does not meet either of the 2 criteria, diabetes would be considered. Patients with diabetes (age 40 to 75, LDL-C 70-180mg/dl) are automatically considered for moderate-intensity statin, but when he or she has an estimated 10-year ASCVD risk factor of ≥7.5%, is a candidate for high-intensity statin.

Table 2. Statin Therapy Recommendation Algorithm, per the ACC/AHA

• Age

· <21 years: not a candidate for statin therapy

· ≥21 years: candidate for statin therapy, move to No. 2

2. Clinical ASCVD (if no clinical ASCVD, move to No. 3)

· ≤75 years: high-intensity (moderate-intensity, if

patient does not tolerate high-intensity)

· >75 years: moderate-intensity

3. LDL-C ≥190mg/dL (if LDL-C <190mg/dl, move to No. 4)

· High-intensity

· LDL-C <190mg/dl, move to No. 4

4. Diabetes, LDL-C 70-180mg/dL, age 40 to 75 years

· Estimated 10 years ASCVD risk ≥7.5%: high-intensity

· Moderate-intensity

The 10-year ASCVD risk factor calculator can be accessed via the ACC’s website (tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/). The calculator estimates the risk of non-fatal MI, coronary heart disease death, and nonfatal and fatal stroke in the next 10 years. This tool has limitations because it is only validated for African-American and Caucasian patients who are between 45 and 75.⁶ The calculators could either over or underestimate the risk for others as well as anyone younger than 45 or older than 75.

Table. 3 Statin Options

High-intensity

Moderate-Intensity

Low-intensity

≥50% LDL-C lowering efficacy

30% to <50% LDL-C lowering efficacy

<30% LDL-C lowering efficacy

Atorvastatin 40 to 80 mg

Rosuvastatin 20 to 40 mg

Atorvastatin 10 to 40 mg

Fluvastatin 40 mg twice daily

Lovastatin 40 mg

Pravastatin 40 to 80 mg

Rosuvastatin 5 to 10 mg

Simvastatin 20 to 40 mg

Lovastatin 20 mg

Statins indicated in Table 3 includes statins and doses evaluated in randomized control trials included in the 2013 ACC/AHA guidelines.^6,7 An important point is that the atorvastatin 40-mg regimen is considered high-intensity only when it is down-titrated from 80 mg, because it was how atorvastatin was studied in the Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL) trial.

Controversy

According to a recent study published by the BMJ (formerly the British Medical Journal), "Statin use and risk of developing diabetes: results from the Diabetes Prevention Program indicate that long-term statin use in high-risk type 2 diabetes patients is associated with a statistically increased risk of T2DM of about 30% (P=0.36, hazard ratio 1.36, HR range 1.17-1.58, CL: 95%)." The study looked at more than 3200 subjects over the 10-year follow-up period.⁸ Despite this controversial publication, clinical guidelines remain unaffected.

Conclusion

Statin therapy for diabetes should be individualized according to the prescriber’s discretion. It is crucial that both the prescriber and the dispensing pharmacist are aware of the differences between ADA and ACC/AHA guidelines to ensure that patients benefit from the most appropriate statin therapy.

References

1. CDC. Prescription cholesterol-lowering medication use in adults aged 40 and over: United States, 2003—2012. cdc.gov/nchs/products/databriefs/db177.htm. Updated December 23, 2014. Accessed December 11, 2017.

2. University of Rochester Medical Center. How diabetes drives atherosclerosis. ScienceDaily. sciencedaily.com/releases/2008/03/080313124430.htm. Published March 17, 2008. Accessed December 11, 2017.

3. Standards of medical care in diabetes-2017: summary of revisions. Diabetes Care. 2017;40:S4-5.

4. American Diabetes Association. Standards of medical care in diabetes-2017. Abridged for primary care providers. Clin Diabetes. 2017;35(1):5-26. doi: 10.2337/cd16-0067.

5. Cannon CP, Blazing MA. Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-97. doi: 10.1056/NEJMoa1410489.

6. Stone NJ, Robinson JG, Lichtenstein AH, et al. American College of Cardiology/American Heart Association Task Force guidelines: 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol. 2014;63(25 Pt B):2889-934. doi: 10.1016/j.jacc.2013.11.002.

7. Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk. J Am Coll Cardiol. 2016;68(1):92-125. doi: 10.1016/j.jacc.2016.03.519.

8. Crandall JP, Mather K, Rajpathak SN, et al. Statin use and risk of developing diabetes: results from the Diabetes Prevention Program. BMJ Open Diabetes Res Care. 2017;5(1):e000438. doi: 10.1136/bmjdrc-2017-000438.