Should all diabetic patients take statin therapy regardless of serum cholesterol level?

1. Introduction

Not all diabetic patients should be routinely started on statin therapy regardless of serum cholesterol level. Current American College of Cardiology (ACC), American Heart Association (AHA) and American Diabetic Association (ADA) guidelines recommend that diabetic patients between the age of 40 to 75 years with low-density lipoprotein – cholesterol (LDL-C) >70 mg/dl should be started on a statin. Patients with diabetes and LDL-C < 70 mg/dl may still benefit from primary prevention with a statin if the 10-year risk of Atherosclerotic Cardiovascular Disease (ASCVD) score is 7.5% or more.

In 2015, thirty million Americans ad diabetes, and one and half million Americans are diagnosed with diabetes every year [1]. The race/ethnic background affects diabetes incidence with the highest among American Indians/Alaskan Natives (15.1%) followed by African Americans (12.7%). After matching for population age and sex differences, average medical costs among people with diagnosed diabetes were 2.3 times higher than what cost would be in the absence of diabetes.

2. Diabetes and dyslipidemia

Dyslipidemia is caused by an increase in total serum cholesterol or serum lipoproteins level (LDL-C, very low-density lipoprotein [VLDL] (chief carrier of triglycerides), and high-density lipoprotein – cholesterol [HDL-C]). High levels of LDL-C (majorly) or VLDL are associated with higher ASCVD (atherogenic) risk. Low HDL-C does not carry atherogenic risk. Non–HDL-C is the combination of LDL-C and VLDL-C and carry more atherogenic than either lipoprotein alone. Apolipoprotein B (apoB) is a structural protein in LDL and VLDL and has indicates atherogenicity better than LDL-C alone [2].

Patients with diabetes mellitus have a significant increase in the risk of developing dyslipidemia [3]. People with diabetes have increased free fatty acid (FFA) release from insulin-resistant fat cells. FFA stimulates triglyceride production and causes the secretion of apoB and VLDL-C; both elevate the risk of ASCVD [2–4]. Also, insulin-resistance reduces HDL-C levels [6, increases lipoproteins (particularly LDL and VLDL) glycosylation and oxidation, and decreases vascular compliance [5]. All of the previously mentioned causes a significant increase in the risk of ASCVD in Diabetics.

3. Diabetes and ASCVD risk

The ASCVD risk calculator is a useful tool that estimates the 10-year ASCVD risk for patients between 40 and 75 years (Table 1). The ASCVD risk calculator is based on age, race, systolic and diastolic blood pressure, total cholesterol, gender, diabetes, treatment for blood pressure and smoking status [6]. The risk calculator estimates the risk of cardiovascular death and helps guide initiation of aspirin and statin therapy for primary prevention. [8]. However, ASCVD risk calculator lacks accounting for the duration of diabetes or the presence of other complications such as albuminuria; which increases ASCVD risk among diabetics. ASCVD risk factors include LDL cholesterol >100 mg/dL (2.6 mmol/L), high blood pressure, smoking, chronic kidney disease, albuminuria, and family history of premature ASCVD. Despite the limitations with risk calculators but they are still widely used in assessing cardiovascular risk in patients with diabetes [7].

Table 1. Statin therapy recommendation based on ASCVD risk score[7].

DM with ASCVD Risk Calculator (%)	Age (Years)	Recommended statin intensity and combination treatment (In addition to lifestyle therapy).
<7.5%	<40	None (only lifestyle therapy).
	40–75	Moderate dose statin^⋆
≥7.5%	40–75	High dose statin.

⋆Moderate-intensity statin may be considered based on LDL-C > 70 mg/dl.

DM – diabetes mellitus; ASCVD – atherosclerosis cardiovascular disease.

4. Management of dyslipidemia in diabetics

Lifestyle modification should be the first intervention to lower risk of ASCVD in diabetic patients. Lifestyle intervention includes weight loss, increased physical activity, and medical nutrition therapy [7].

Multiple large trials have shown that statin therapy decreases cardiovascular outcomes; which includes coronary artery disease (CAD) death and nonfatal myocardial infarction (MI) in diabetic patients. The CARDS study demonstrated that treatment with statin (atorvastatin) results in a 37% reduction in CAD events, a 27% reduction in all-cause mortality and a 48% reduction in stroke [8]. Also, a meta-analysis study supports this result by showing that there is a 9% proportional reduction in all-cause mortality and a 21% reduction in major vascular events for each 1 mmol/L (39 mg/dL) lowering in LDL cholesterol. [9,10]

Similar to 2013 ACC/AHA guidelines for the prevention of cardiovascular disease, the new ADA statement has indicated that statin therapy should be initiated in diabetic patients based on the ASCD risk score and LDL-C serum level [4]. Diabetic patients between the age of 40–75 years and LDL-C > 70 mg/dL should be treated with a moderate-intensity statin. Similarly, individuals aged 40–75 years with diabetes and ≥7.5% ASCVD risk should be treated with a high-intensity statin for secondary prevention based on the Cholesterol Treatment Trialists’ Collaboration [10]. However, individuals aged <40 or >75 years with diabetes should be evaluated for the risk and benefit of statin therapy [10].

However, the American Association of Clinical Endocrinologist (AACE) guidelines suggest more aggressive approach in initiating statin therapy for patients with DM and high risk factors: progressive ASCVD after achieving an LDL-C < 70 mg/dL, established clinical cardiovascular disease in patients with DM, CKD ¾ or heterozygous familial hypercholesterolemia, History of premature ASCVD (<55 male, <65 female). AACE target for these patients is LDL-C < 55 mg/dl, Non-HDL <80 mg/dl, apoB <70 mg/dl [11].

The patients with diabetes aged 40–75 years an age-group well represented in statin trials showing benefit while the evidence is lower for patients aged more than 75 years; as a fairly small number of older patients with diabetes have been included in primary prevention trials. Despite that older age by itself constitute a higher risk, and this makes the absolute benefits outweighs the side effects. Therefore, patients with diabetes that are 75 years or older are recommended to be on moderate dose statin therapy, but there should be a continuous evaluation for the risk-benefit and lowering of the dose as needed [12]. In the Heart Protection Study, patients with age <40 years or type 1 diabetes showed no statistically significant reduction in risk as patients with type 2 diabetes. Despite that, it is recommended that healthcare provider discuss the benefits and risks associated with statin therapy with all diabetic patients favoring the use of moderate-intensity statin therapy [7]. (Table 2)

Table 2. Statin therapy recommendation in diabetic patient based on ASCVD score and LDL serum level [7].

LDL-C Level (mg/dl)	<70 mg/dl	>70 mg/dl	<70 mg/dl
ASCVD Risk Calculator (%)	<7.5%	<7.5%	≥7.5%
Age (years)	Any Age	40–75	40–75
Statin Therapy	None	Moderate Intensity Statin	High Intensity Statin

ASCVD – atherosclerosis cardiovascular disease; LDL-C – low-density lipoprotein – cholesterol.

Patient on statin therapy needs LDL-C levels to be assessed every 4–12 weeks after initiation of statin therapy and any change in dose to monitor for medication adherence and efficacy [12]. If a patient has a side effect, a dose or alternative statin that is tolerable should be tried. Even low dose statin shows significant evidence of benefit for patients [13].

5. Statin therapy

Moderate-intensity statin therapy reduces LDL-C by 30%–45%. It includes atorvastatin 10–20 mg once daily, rosuvastatin 5–10 mg once daily, simvastatin 20–40 mg once daily, pravastatin 40–80 mg once daily, lovastatin 40 mg once daily, fluvastatin XL 80 mg once daily, or pitavastatin 2–4 mg once daily. High-intensity statin therapy, however, reduces LDL-C by>50%. It includes atorvastatin 40–80 mg or rosuvastatin 20–40 mg once daily. Low-dose statin therapy is generally not preferred for diabetics but is sometimes the only dose of statin that a patient can tolerate [14]. Low-dose statin therapy is generally not prescribed for patients with diabetes unless it is the only dose of statin that a patient could tolerate.

6. Additive therapy

Patients with ASCVD who are on high-intensity statin therapy and have an LDL cholesterol >70 mg/dL, the addition of non-statin LDL-lowering therapy is recommended after considering the risk for further ASCVD risk reduction, adverse effects, and patient choices. The IMPROVE-IT trial studied combination therapy for LDL-C lowering statins and ezetimibe. It dempnstrates a significant risk reduction of major adverse cardiovascular events in patients with DM and high-risk without DM [15]. The FOURIER trial, studied the combination of a statin with the PCSK9 Inhibitors (Evolocumab) as adjunctive therapy for patients on a statin with ASCVD or familial hypercholesterolemia who are treated with maximal statin therapy, leading to decrease LDL-C by 59% from a median of 92 to 30 mg/dL. The combined cardiovascular death, MI, or stroke was reduced by 20%, from 7.4 to 5.9% (P < 0.001) [16]. The ACCORD study, the combination of fenofibrate and simvastatin in patients with type 2 diabetes who were at high risk for ASCVD did not lower the risk of fatal cardiovascular events, nonfatal MI, or nonfatal stroke versus simvastatin solely. The risk of rhabdomyolysis is more with high doses of statins, and renal insufficiency appears to be more when statins are combined with gemfibrozil (compared with fenofibrate) [17]. The AIM-HIGH trial was stopped early because it shows no effect on the primary ASCVD outcome including risk event of death from CAD, nonfatal MI, ischemic stroke, hospitalization for an acute coronary syndrome (ACS), or symptom-driven coronary or cerebral revascularization. Therefore, statin and niacin are not recommended due to the absence of efficacy on major ASCVD outcomes and side effects [18].

7. Summary

Statin therapy is recommended for diabetic patients between the age of 40 and 75 years and LDL-C level serum level >70 mg/dl or those with ASCVD risk score ≥7.5%. Therefore, not all diabetic patients should be routinely treated with statin therapy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this paper has disclosed that they have received research support and acted as a consultant for AstraZeneca, Pfizer, Merck and Kowa. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.