Practical Pearls: The Potential for Hypoglycemic Agents to Affect Lipid Parameters

Clinical Question: What are the common hypoglycemic agents that can affect lipid parameters and which parameters are effected?

Many patients with diabetes mellitus have indications for statin based lipid-lowering therapy because of their high risk of cardiovascular disease as recommended by the American College of Cardiology/ American Heart Association, American Association of Clinical Endocrinologists, American Diabetes Association and the National Lipid Association.^1-4 More than two-thirds of patients with diabetes mellitus die from CVD or its sequelae.⁵ In addition; most patients with diabetes mellitus require pharmacotherapy to help manage their glycemic control. It is important to factor in the potential of hypoglycemic therapy to affect a patient’s lipid levels, as many patients require more than one agent to improve their glucose control.

In the last couple of years, there have been a number of new hypoglycemic agents approved by the Federal Drug Administration (FDA) and thus a review of the agents, which can positively and negatively affect lipid parameters, is warranted. A complete list of hypoglycemic medication classes and their lipid affects are reported in Table 1.

The biguanide, metformin remains the first line therapy for most patients with type 2 diabetes and does have some effects on lipid parameters.³ Of note, metformin has been shown to consistently reduce total cholesterol (TC), reduce triglycerides (TG) and increase high density lipoprotein cholesterol (HDL-C) to a small extent.⁶ Recent meta-analysis of sulfonylurea impact on lipid parameters based on randomized controlled trials demonstrated an increase in TC and low density lipoprotein (LDL-C) compared to metformin. In addition, a reduction in TC, LDL-C, HDL-C, and increase in TG compared to thiazolidinedione’s (TZD) was noted.⁷ Overall, TZDs have been shown to have beneficial effects on lipid parameters. The most commonly prescribed TZD pioglitazone has been shown to decrease TG, while increasing HDL-C, and increasing LDL particle size.^8-9

Insulin remains a highly used and effective glycemic lowering medication in both a basal and bolus form. The primary lipid change seen with the initiation of insulin therapy is a lowering of TGs, which correlates with a lowering of glucose and hemoglobin A1c.^10,11 No significant changes in LDL-C or HDL-C have been shown with insulin therapy.

Incretin-based therapy with glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have potential lipid affects. Liraglutide, a GLP-1 Agonist has been shown to decrease LDL-C, decrease TGs and increase HDL-C.^12-13 The GLP-1 agonist exenatide has been shown to decrease TG and increase HDL-C as well.^14-15 DPP-4 inhibitors have been shown as a class to have minor impact on lipid parameters. These small improvements in lipid parameters may be contributing to the positive CV event lowering findings that have now been seen with liraglutide and semiglutide in patients with type 2 diabetes mellitus and CVD.

The newest class of hypoglycemic medication is the sodium-glucose cotransporter-2 (SGLT-2) inhibitors. The SGLT-2 inhibitor with the most published data on the potential effect on lipids is dapagliflozin. Dapagliflozin has been shown to increase HDL-C and to decrease small dense LDL-C with no overall change in concentration of LDL-C.¹⁶ A recent retrospective analysis of all SGLT-2 inhibitors and their potential effects on metabolic parameters demonstrated a decrease in LDL-C, a decrease in TG, and an increase in HDL-C across the class of medications.¹⁷ The beneficial lipid changes see with SGLT-2 inhibitors even if small in nature may be contributors to the CV event lowering which has been seen with empagliflozin and canagliflozin.

Overall, with the recent CV event lowering seen in RCTs with the SGLT-2 inhibitors (empagliflozin and canagliflozin) and the GLP-1 agonists (liraglutide and semaglutide) one must consider whether the beneficial impact on lipids is contributing to the CV event lowering demonstrated in patients with type 2 diabetes mellitus and existing CVD and/ or high risk of CVD. Consideration on lipid affects with the choice of hypoglycemic agents should be one of the many factors to assess when choosing optimal therapy.

Disclosure statement: Dr. Marrs has no conflicts of interest to disclose.

References can be found here.