Managing the double-edged sword of diabetes and dyslipidemia

By Naveed Saleh, MD, MS | Medically reviewed by James Beckerman, MD, FACC
Published March 29, 2023

Key Takeaways

  • Diabetic dyslipidemia is underrecognized, underestimated, and undertreated, despite highly effective lipid-lowering therapies.

  • Diabetic dyslipidemia involves hypertriglyceridemia (HTG), lower levels of high-density lipoprotein (HDL), and higher levels of small dense low-density lipoprotein (LDL) particles.

  • If maximally tolerated statins fail to bring down lipid levels, non-statin therapies (eg, PCSK9 inhibitors, ezetimibe, bempedoic acid) may be effective in patients who have diabetes.

Dyslipidemia in patients with type 2 diabetes (ie, diabetic dyslipidemia) is among the most poorly controlled health conditions globally. Only about 25% of type 2 diabetes patients meet their low-density lipoprotein cholesterol (LDL-C) targets.[] In addition to being undertreated, diabetic dyslipidemia carries a risk for atherosclerotic vascular disease that is often underestimated.

Diabetic dyslipidemia may be neglected because of physician inertia and patient non-adherence, but underutilization or underdosing of lipid-lowering therapy secondary to inappropriate cardiovascular risk stratification may also be a factor. Risk stratification of patients with diabetes, at present, is controversial. Nevertheless, drugs are available now that effectively lower lipid levels without heightening the risk of new-onset diabetes or glucose impairment. In fact, some of these newer agents actually facilitate glucose control.

Understanding the risk

Dyslipidemia affects an estimated 72%-85% of patients with type 2 diabetes.[]

According to a review article published in the World Journal of Diabetes, diabetes is a strong risk factor for atherosclerotic cardiovascular disease (ASCVD)—the most frequent cause of death in the United States, responsible for 2300 deaths per day. Individuals with diabetes are 2-4 times more likely to die of ASCVD vs persons without diabetes. 

Diabetes mediates microvascular complications (eg, nephropathy, neuropathy, retinopathy) and macrovascular complications (eg, coronary artery disease, peripheral artery disease, stroke). 

Diabetic dyslipidemia involves hypertriglyceridemia (HTG) and lower levels of high-density lipoprotein (HDL). 

The authors of the review article note that, while LDL levels are not usually elevated, “there is a preponderance of small dense LDL particles which appear to be more atherogenic.” Furthermore, they say, “there is an increase in particle number as evidenced by increased apolipoprotein B levels and non-HDL-cholesterol levels.” These characteristics relate to the two 2 major sequelae of diabetic dyslipidemia: premature ASCVD, from the elevated apolipoprotein B–carrying particles, and pancreatitis, with severe HTG >1000 mg/dL.

The precise pathophysiology of lipoprotein disturbances in diabetes remains to be elucidated, although insulin resistance—rather than hyperglycemia—is thought to play a role. Lipoprotein changes such as HTG, increases in very-low-density-lipoprotein (VLDL) particles and small dense LDL particles and decreases in HDL level are exhibited in patients with impaired fasting glucose and impaired glucose tolerance, and type 2 diabetes.

Statins and lifestyle changes

Treatment of dyslipidemia in diabetes is recommended, as summarized in an Expert Analysis published by the American College of Cardiology (ACC).[] The authors refer to the 2018 American Heart Association/American College of Cardiology (AHA/ACC) Multi-Society Cholesterol Guidelines, which suggest the following: 

  • All diabetic adults aged 40-75 years with an LDL-C >70 should take a moderate or high-intensity statin.

  • Statin therapy should be initiated in patients aged 20-39 years who exhibit higher-risk features. 

Even though cardiovascular events are trending lower in the general population, the experts say this trend is less pronounced in individuals with diabetes.

Many patients on lipid-lowering medications still have their dyslipidemia inadequately controlled. 

Lifestyle modifications are central to reducing LDL-C levels and CVD risk, but these measures may be less effective in patients with diabetes. Nevertheless, recommendations include following a diet with reduced saturated fats and minimal trans fats, like the Mediterranean or DASH diets, as well as exercising for 150 to 300 minutes per week. Clinicians can expect some improvements in weight loss and glycemic control with these efforts, but sustained lifestyle improvement has not been proven to improve mortality statistics in persons with diabetes. 

Non-statin therapies 

A variety of non-statin therapies can further lower lipid levels. 

For patients who have yet to attain their LDL-C goals on maximally tolerated statins and with lifestyle modification, the 2018 AHA/ACC cholesterol guidelines recommend ezetimibe as a first-line add-on treatment.

Another class of drugs, PCSK9 inhibitors (eg, evolocumab, alirocumab), yield approximately a 60% decrease in LDL-C levels when used with statins. One drawback is their cost and need for preauthorization. They are best used in individuals with the greatest ASCVD risk.

Another non-statin therapy mentioned by the guidelines is bempedoic acid. This drug blocks cholesterol synthesis on the same pathway as statins. As a prodrug, it is metabolized in the liver and not the muscles.

In phase 2 and phase 3 clinical trials with bempedoic acid, as discussed in another ACC Expert Analysis, the drug was shown to be effective and safe as monotherapy or in combination with statins or ezetimibe in various patient populations, including those who are intolerant to statins.[] 

Bempedoic acid is currently approved by the FDA as an adjunct to diet and maximally tolerated statins when treating hyperlipidemia.

Ongoing research is aimed at determining whether this drug can decrease hard cardiovascular events.

Although niacin boosts HDL-C levels, clinical trials have demonstrated no positive correlation with improved cardiovascular outcomes. Similarly, although omega-3 fatty acids ameliorate cardiometabolic profiles, they don’t diminish the frequency of cardiovascular events.

The Expert Analysis summed up the dyslipidemia guidance as follows: “When the additional LDL-C lowering desired is less than 25%, ezetimibe is the best first option. The 2018 cholesterol guidelines recommend obtaining a lipid panel at the start of treatment, 4-12 weeks after the initiation/modification of LDL-lowering therapy, and every 3-12 months afterwards. The 2018 American Diabetes Association guidelines also support considering adding a non-statin therapy if maximally tolerated statins do not lower LDL below 70 mg/dL.”

What this means for you

Because patients with diabetic dyslipidemia are at high risk of ASCVD, it’s imperative that these patients adhere to appropriate evidence-based treatment. In addition to lifestyle changes and maximally tolerated statins, additional options to further lower lipid levels in those who need it include ezetimibe as an initial choice. Certain patient populations may benefit from PCSK9 inhibitors.

Share with emailShare to FacebookShare to LinkedInShare to Twitter