Lipid Management for Patients With Diabetes Requires More Targeted Approach

The evolution of diabetic lipid management is moving beyond the traditional focus on low-density lipoprotein cholesterol (LDL-C) to a more inclusive model that targets all atherogenic lipoproteins. In patients with type 2 diabetes (T2D), the presence of mixed dyslipidemia—characterized by elevated triglycerides, low high-density lipoprotein cholesterol (HDL-C), and small dense LDL particles—often masks the true risk of cardiovascular events if only LDL-C is monitored.¹

“While low-density lipoprotein cholesterol (LDL-C) reduction is the primary target of lipid management, many patients with diabetes exhibit mixed dyslipidemia characterized by elevated triglycerides and increased concentrations of atherogenic remnant lipoproteins, which are more comprehensively captured by non-high-density lipoprotein cholesterol (non-HDLC),” the study author said.

Consequently, nonHDL-C, calculated simply as total cholesterol minus HDL-C, has emerged as a secondary but vital treatment target that captures the cholesterol content in all apolipoprotein B-100-containing lipoproteins, including very-low density lipoprotein (VLDL) and its remnants. This shift is particularly relevant for pharmacists, as routine clinical data indicates that lipid target attainment remains suboptimal, with only a small fraction of high-risk patients reaching their therapy goals despite the availability of effective treatments.

Pharmacists must recognize that the pathogenetic roots of this atherogenic dyslipidemia are found in abdominal obesity and insulin resistance, which trigger a cascade of metabolic failures, including the overproduction of VLDL1 by the liver. Insulin resistance impairs the activity of lipoprotein lipase, leading to a build-up of remnant particles that can penetrate the endothelium more easily than normal LDL, thereby increasing the risk of thrombosis. Furthermore, the decrease in HDL-C in these patients is not just a numerical change but a functional one, as small HDL particles are rapidly metabolized and lose their ability to provide endothelial protection.^1,2

To combat this, global guidelines now advocate for more aggressive and individualized treatment strategies based on overall cardiovascular risk, which should be assessed using tools like the SCORE2-Diabetes model for patients aged 40 to 69 years.¹

Statins remain the cornerstone of therapy for reducing cardiovascular morbidity and mortality in diabetes, working by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase and upregulating LDL receptors to clear cholesterol from the blood. However, pharmacists often encounter patients who cannot reach their targets with statin monotherapy alone or who experience statin-associated muscle symptoms.^1-3

In such cases, the prompt initiation of combination therapy is essential. Adding ezetimibe can provide an additional 20% to 25% reduction in LDL-C, although newer agents such as bempedoic acid offer a viable alternative for statin-intolerant patients because it is a prodrug that avoids activation in skeletal muscle. For those at extreme risk, PCSK9 inhibitors—available as monoclonal antibodies like alirocumab or as small interfering RNA like inclisiran—can lower LDL-C by up to 60%.^1,3

The pharmacist’s role in managing these complex regimens includes careful monitoring for adverse effects and drug-drug interactions, particularly with statins, which are often metabolized through the cytochrome P450 3A4 pathway. Monitoring baseline lipid profiles, liver function tests, and serum creatinine kinase is standard practice, especially if a patient reports unexplained muscle pain.^2,3

Pharmacists should also be aware of the nocebo effect, where patients report subjective adverse effects that may not be pharmacologically caused by the statin, necessitating shared decision-making and potentially trying different dosing intervals or different statins like rosuvastatin.

Beyond LDL-lowering, high-dose purified eicosapentaenoic acid (icosapent ethyl) has shown a significant 25% reduction in major cardiovascular events for high-risk individuals with residual hypertriglyceridemia.

Although some agents like sodium/glucose cotransporter 2 inhibitors may cause a modest rise in LDL-C, they also reduce triglycerides and promote a beneficial remodeling of lipid metabolism that far outweighs the minimal risk. Glucagon-like peptide-1 receptor agonists have also shown promise in modestly reducing LDL-C and significantly decreasing postprandial triglycerides, providing another layer of cardiovascular protection.

“Lipid management remains a cornerstone of CV risk reduction in diabetes. Current guidelines prioritize LDL-C target attainment as the primary therapeutic goal, with non-HDL-C considered as secondary target,” the study authors said. “However, a comprehensive lipid assessment in individuals with T2D should extend beyond LDL-C to include triglycerides, non-HDL-C, Lp(a), apoB, and HDL-C in order to improve CV risk stratification and enable more personalized treatment strategies.”

As the pharmacological landscape expands to include novel RNA interference molecules targeting angiopoietin-related protein 3 and apolipoprotein C3, the pharmacist's expertise will be crucial in ensuring that patients with diabetes receive the multi-modal care required to address their persistent residual cardiovascular risk.

READ MORE: Diabetes Resource Center

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REFERENCES

1. Brandts J, Verket M, Zambon A, Marx N, Müller-Wieland D, Federici M. Lipid management in type 2 diabetes and non-HDL-cholesterol: target all atherogenic lipoproteins. Cardiovasc Diabetol. Published online April 12, 2026. doi:10.1186/s12933-026-03166-4

2. Daniel MJ. Lipid Management in Patients with Type 2 Diabetes. Am Health Drug Benefits. 2011;4(5):312-322. https://pmc.ncbi.nlm.nih.gov/articles/PMC4105726/pdf/ahdb-04-312.pdf

3. Kim S, Subramanian S. Approach to Lipid Management in the Patient With Diabetes. J Clin Endocrinol Metab. 2025;110(6):1740-1755. doi:10.1210/clinem/dgaf018