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© 2005 by the American Diabetes Association, Inc.
Letters: Comments and Responses |
A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia
Response to Bell and Brunzell
1 Division of Endocrinology, Metabolism and Diabetes, University of Miami School of Medicine, Miami, Florida
2 International Diabetes Center, Park Nicollet Institute, Minneapolis, Minnesota
3 Division of Endocrinology and Metabolism, Department of Veterans Affairs and the Indiana University School of Medicine, Indianapolis, Indiana
4 Divisions of Endocrinology and of General Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
5 Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana
6 Takeda Pharmaceuticals North America, Lincolnshire, Illinois
7 Takeda Global Research and Development Center, Lincolnshire, Illinois
Address correspondence to Scott J. Jacober, DO, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, DC 5116, Indianapolis, IN 46285. E-mail: sjacober{at}lilly.com
In his commentary, Bell (1) presents specific criticisms of the head-to-head trial comparing the effects of rosiglitazone with pioglitazone on lipids and lipoproteins. Bell raises a concern over study recruitment (in particular the high rate of screen failures), the exclusion of patients on statin therapy, and the limited data supporting the role of hypertriglyceridemia in cardiovascular risk. By excluding patients on other glucose- and lipid-lowering medication, we were able to demonstrate that the two agents have different effects on each of the components of the lipid profile. In doing so, the differences observed could only be attributed to the active thiazolidinedione (TZD) therapy. Targets for LDL cholesterol were lowered during the active phase of this trial. Given that, recruitment of appropriate subjects was challenging. Although this population does not currently represent the standard of practice, the study as performed allowed careful assessment of the isolated drug effect of each TZD on lipids.
Unfortunately, Bell and others have misrepresented the two prior studies of the add-on effect of statin (2) or statin + ezetemibe (3) therapy to TZD. First, this subanalysis of LDL cholesterol (not lipid profiles as stated by Bell) was over a wide range of doses of the nonrandomized TZD treatments and, unlike our study, was substantially underpowered to compare differences in lipid parameters between agents. Furthermore, only change from baseline (without baseline and end point) LDL cholesterol results were presented in the studies. Therefore, contrary to Bell’s assertion, baseline differences (as anticipated from our data and others [4]) would be expected to be preserved at end point since changes from baseline were similar for the two TZDs. To conclude that there are no differences between the TZD effects on lipids in statin-treated patients without any data is therefore questionable. More recently, the results of the COMPLEMENT study were reported (5) confirming that the difference in the effect of the two TZDs persisted in over 305 subjects on statin therapy.
The role of triglycerides in determining cardiovascular disease risk remains controversial, and we did not evaluate postprandial lipemia in our study. No head-to-head comparative study has been performed assessing the differential impact of the two TZDs on postprandial lipids. In response to Bell’s and Brunzell’s (6) request for data on HDL subclasses, we have reported that both HDL size and large HDL cholesterol increased with pioglitazone and decreased with rosiglitazone (7), and a detailed analysis of the results of lipoprotein particle analysis on LDL, VLDL, and HDL is currently underway.
Lastly, we used a standard definition of "completers" in our patient flow diagram: all patients who completed the full 24 weeks of active therapy. The numbers of patients exposed to the full dose of each active therapy were very similar (323 for pioglitazone and 314 for rosiglitazone). The data presented in Fig. 2 of the report along with the last-observation-carried-forward analysis P value (Table 2) clearly refutes Brunzell’s speculations and underscores the absolute robustness of our data and conclusions (8).
In summary, currently available data clearly demonstrate more favorable effects of pioglitazone on plasma lipids and lipoproteins compared with rosiglitazone (lowering triglycerides, raising HDL to a greater extent, and not increasing non-HDL cholesterol and apolipoprotein B levels or LDL particle concentration). These differences may be associated with long-term vasculoprotective advantages.
Footnotes
D.M.K. has received grant support from Amylin Pharmaceuticals and Eli Lilly. M.A.D. has received honoraria from Takeda Pharmaceuticals.
References
- Bell DSH: A comparison of lipid and glycemic effects of pioglitazone in patients with type 2 diabetes and dyslipidemia (Letter).
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- Lewin AJ, Kipnes MS, Meneghini LF, Plotkin DJ, Perevozskaya IT, Shah S, Maccubbin DL, Mitchel YB, Tobert JA, the Simvastatin/Thiazolidinedione Study Group: Effects of simvastatin on the lipid profile and attainment of low-density lipoprotein cholesterol goals when added to a thiazolidinedione therapy in patients with type 2 diabetes mellitus: a multicenter, randomized double blind placebo controlled trial.
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- Gaudiani LM, Lewin A, Meneghini L, Perevozskaya I, Plotkin D, Mitchel Y, Shah S: Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione treated type 2 diabetic patients.
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- Chiquette E, Ramirez G, Defronzo R: A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors.
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- Khan M, Berhanu P, Perez A, Demissie S, Fleck P, Kupfer S: Effects of pioglitazone in combination with stable statin therapy on lipid levels in subjects with type diabetes and dyslipidemia after treatment conversion from rosiglitazone: results from an open-label study (Abstract).
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- Brunzell JD: A comparison of lipid and glycemic effects of pioglitazone in patients with type 2 diabetes and dyslipidemia (Letter).
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- Deeg MA, Goldberg RB, Buse JB, Kendall DM, Zagar AJ, Pinaire JA, Tan MH, Khan MA, Perez AT, Jacober SJ: The comparative effects of pioglitazone and rosiglitazone on liporpotein sub-fractions in patients with type 2 diabetes and dyslipidemia (Abstract).
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- Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, Tan MH, Khan MA, Perez AT, Jacober SJ, the GLAI Study Investigators: A comparison of lipid and glycemic effects of pioglitazone in patients with type 2 diabetes and dyslipidemia.
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[Abstract/Free Full Text]
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