Should TZDs Be Used for Lipid Management?

Ronald B Goldberg, MD

Reported by Joelle Escoffery, PhD

Strong Heart Study observed numerous risk factors for cardiovascular disease (CVD), including: sex, elevated LDL-C, presence of albuminuria, hypertension, low HDL-C, and elevated triglycerides. The UKPDS showed that, on average, people with diabetes have a low HDL-C, high triglycerides, and LDL-C that is average or slightly elevated. Insulin resistance has been shown to affect lipoprotein particle size; as patients become more insulin resistant, VLDL particle size increases, and LDL and HDL particle size decrease.

Guidelines for lipid management have been put forth by the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP ATPIII) Update. They recommend an LDL-C of <100 mg/dL (70 mg/dL is an appropriate therapeutic target for very high risk patients). Similarly, the American Diabetes Association recommends a 30-40% reduction in LDL-C with an optional goal of LDL-C <70 mg/dL. In spite of the awareness of the importance of LDL-C as the primary target for lipid management, 70% of patients are not meeting targets for LDL. Additionally, a comparable amont of patiens are not meeting targets for HDL-C, and there is a great need for therapies that raise HDL cholesterol.

The effect of thiazolidinediones on lipid parameters has been assessed in several different studies. One study examined the agent trogalitazone, which was taken off the market due to adverse events. Troglitazone monotherapy was shown to significantly increased LDL-C, a finding that was concerning as LDL-C is the primary lipid target. A meta-analysis assessing the effect of both rosiglitazone and pioglitazone on LDL-C (based on 11 studies) showed that rosiglitazone was associated with a 10-15% increase in LDL-C, whereas pioglitazone was associated with no change in LDL-C. A head-to-head study examining rosiglitazone and pioglitazone in patients not on statin therapy also showed that rosiglitazone had a greater than on LDL-C than did pioglitazone. In that same study, ApoB was not increased in patients on pioglitazone therapy but was elevated in rosiglitazone patients, whereas both pioglitazone and rosiglitazone were associated with a significant increase in LDL particle size. It has been suggested that pioglitazone may have slight PPARα properties.

In terms of HDL-C, the previously-mentioned meta-analysis found that both rosiglitazone and pioglitazone raise HDL, but pioglitazone was associated with a greater magnitude of HDL increase. Further, administering pioglitazone to subjects with met syndrome (an unlabeled use) was associated with a 15% increase in HDL.

The PROactive study tested the efficacy of pioglitazone to affect lipid parameters among diabetic patients with CVD. The results of this controversial study showed a moderate effect on CVD event reduction, as well as a significant increase in HDL and a 13% reduction in triglycerides from baseline. There was no significant effect on LDL-C.

In conclusion, the HDL raising effect of TZDs is the most beneficial effect, although it might be offset by the tendency of these drugs to increase LDL. Accordingly, it was recommended that TZDs be used in conjunction with a statin. TZD use is most appropriate for patients with hyperglycemia and reduced HDL.