Thiazolidinediones
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In her otherwise excellent review of thiazolidinediones, Dr. Yki-J?rvinen (Sept. 9 issue)1 states that "the effects of rosiglitazone or pioglitazone on the size of LDL [low-density lipoprotein] particles have not been studied in a double-blind, placebo-controlled trial." That is not quite the case. In a double-blind, randomized trial of pioglitazone as compared with placebo in nondiabetic patients with normolipidemia and hypertension, pioglitazone increased LDL particle size.2 Furthermore, in two open-label studies involving patients with type 2 diabetes, the size of LDL particles was increased by rosiglitazone, as compared with placebo,3 and by pioglitazone, as compared with gliclazide.4
Mayer B. Davidson, M.D.
Charles R. Drew University
Los Angeles, CA 90059
Dr. Davidson reports having served on the speakers bureau and advisory committee for GlaxoSmithKline and on the speakers bureau for Takeda.
References
Yki-J?rvinen H. Thiazolidinediones. N Engl J Med 2004;351:1106-1118.
Winkler K, Konrad T, Fullert S, et al. Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. Diabetes Care 2003;26:2588-2594.
Freed MI, Ratner R, Marcovina SM, et al. Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus. Am J Cardiol 2002;90:947-952.
Lawrence JM, Reid J, Taylor GJ, Stirling C, Reckless JP. Favorable effects of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes. Diabetes Care 2004;27:41-46.
To the Editor: The review article by Yki-J?rvinen omits important evidence regarding the unique, positive, and proven benefits of thiazolidinediones. The author is entitled to her opinion, but her own biases are not appropriate for a review article. To conclude that thiazolidinediones are "expensive alternatives to existing hypoglycemic therapies" does the class an injustice. Multiple studies demonstrate the benefit of thiazolidinediones in preserving beta-cell function, an effect with favorable implications for preventing the development and progression of type 2 diabetes.1 Studies such as Troglitazone in the Prevention of Diabetes (TRIPOD)2 confirm the positive effects of thiazolidinediones on beta-cell function and a reduction in the progression to type 2 diabetes.3,4 The overwhelmingly positive effects on cardiovascular-risk reduction were also downplayed. There is no question that the plethora of ongoing trials regarding prevention and cardiovascular-risk reduction will help us better define the clinical role of thiazolidinediones, but meanwhile, one should not ignore or downplay the clearly demonstrated results observed in studies of this class of drugs.
Steven V. Edelman, M.D.
University of California, San Diego
San Diego, CA 92161
sedelman@ucsd.edu
Dr. Edelman reports having served as a consultant for Lilly, Novo, Aventis, Takeda, GlaxoSmithKline, and Novartis.
References
Cavaghan MK, Ehrmann DA, Byrne MM, Polonsky KS. Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance. J Clin Invest 1997;100:530-537.
Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796-2803.
Finegood DT, McArthur MD, Kojwang D, et al. Beta-cell mass dynamics in Zucker diabetic fatty rats: rosiglitazone prevents the rise in net cell death. Diabetes 2001;50:1021-1029.
Xiang AH, Peters RK, Kjos SL, et al. Continued protection from diabetes during treatment of the TRIPOD cohort with pioglitazone. Presented at the American Diabetes Association's 63rd Annual Scientific Sessions, New Orleans, June 13–17, 2003 (oral presentation).
To the Editor: Yki-J?rvinen does not mention the effect of thiazolidinedione drugs on bone. Osteoblasts and adipocytes share a common mesenchymal precursor in the bone marrow,1 and the stimulation of adipocyte formation by thiazolidinediones seems to occur at the expense of the formation of osteoblasts.2,3 Furthermore, the intake of thiazolidinediones by older patients with diabetes has been shown to decrease bone mineral density in the femoral neck and hip.4 Since patients with diabetes may be at increased risk for fractures,5 physicians should carefully check bone mineral density and the risk of fractures in patients taking thiazolidinediones.
Luca Mascitelli, M.D.
Comando Brigata Alpina Julia
33100 Udine, Italy
lumasci@libero.it
Francesca Pezzetta, M.D.
Ospedale S. Michele
33013 Gemona del Friuli, Italy
References
Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41-49.
Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernick B. Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology 2004;145:401-406.
Akune T, Ohba S, Kamekura S, et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 2004;113:846-855.
Schwartz AV, Sellmeyer DE, Feingold KR, et al. Thiazolidinedione (TZD) use and bone mineral density in older adults with diabetes. Diabetes 2002;51:A237-A237. abstract.
Meyer HE, Tverdal A, Falch JA. Risk factors for hip fracture in middle-aged Norwegian women and men. Am J Epidemiol 1993;137:1203-1211.
Dr. Yki-J?rvinen replies: I share Dr. Edelman's optimism regarding the possible benefits of thiazolidinediones in preserving beta-cell function. However, I am forced to stick to the facts and repeat what I wrote in the review: "No data are available to support long-term maintenance of glycemic control with rosiglitazone or pioglitazone as compared with other existing therapies." The TRIPOD study randomly assigned women without diabetes to receive treatment with troglitazone or placebo, not to an active comparator. The abstract Dr. Edelman cites describes an uncontrolled, open-label extension of the TRIPOD study in which women were given pioglitazone after either troglitazone or placebo.
Regarding downplaying "the overwhelmingly positive effects of thiazolidinediones on cardiovascular-risk reduction," I am not aware of any studies showing a reduction in cardiovascular risk, since all placebo-controlled end-point studies are still ongoing. Most doctors, including me, wish to treat type 2 diabetes with drugs that have favorable or at least neutral effects on its main complication — that is, cardiovascular disease.
Although thiazolidinediones may increase the size of LDL particles, the increase in LDL cholesterol consistently reported with rosiglitazone cannot, in the absence of mechanistic data regarding the effects of thiazolidinediones on lipoprotein metabolism, be immediately classified as a positive effect. Surrogate markers may not always predict what happens in an outcome trial — the story of hormone-replacement therapy might serve as an example.
Dr. Davidson correctly points out that pioglitazone has been shown to increase the size of LDL particles in a placebo-controlled trial, which was reported after the initial submission of my article. The increase in particle size was observed in the absence of changes in the concentration of LDL cholesterol.
Drs. Mascitelli and Pezzetta suggest that the effects of thiazolidinediones on bone should have been included in the article. The review focused on published data in humans and the treatment of hyperglycemia, which is currently the only condition for which thiazolidinediones are approved. Studies in animals and in vitro studies have examined the effects of thiazolidinediones on many common diseases, including rheumatoid arthritis. However, the effects of thiazolidinediones, such as that on fat content in the liver, may differ between mice and humans, and therefore, reviewing such data may be of little relevance to the treatment of human disease. This remains true for osteoporosis as long as there are no published data on harmful effects of thiazolidinediones on bone density in humans. There are more than 4000 full-length articles available on peroxisome-proliferator–activated receptors, and only about 100 could be included in the review.
Hannele Yki-J?rvinen, M.D.
University of Helsinki
00029 HUS Helsinki, Finland
ykijarvi@cc.helsinki.fi
Mayer B. Davidson, M.D.
Charles R. Drew University
Los Angeles, CA 90059
Dr. Davidson reports having served on the speakers bureau and advisory committee for GlaxoSmithKline and on the speakers bureau for Takeda.
References
Yki-J?rvinen H. Thiazolidinediones. N Engl J Med 2004;351:1106-1118.
Winkler K, Konrad T, Fullert S, et al. Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. Diabetes Care 2003;26:2588-2594.
Freed MI, Ratner R, Marcovina SM, et al. Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus. Am J Cardiol 2002;90:947-952.
Lawrence JM, Reid J, Taylor GJ, Stirling C, Reckless JP. Favorable effects of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes. Diabetes Care 2004;27:41-46.
To the Editor: The review article by Yki-J?rvinen omits important evidence regarding the unique, positive, and proven benefits of thiazolidinediones. The author is entitled to her opinion, but her own biases are not appropriate for a review article. To conclude that thiazolidinediones are "expensive alternatives to existing hypoglycemic therapies" does the class an injustice. Multiple studies demonstrate the benefit of thiazolidinediones in preserving beta-cell function, an effect with favorable implications for preventing the development and progression of type 2 diabetes.1 Studies such as Troglitazone in the Prevention of Diabetes (TRIPOD)2 confirm the positive effects of thiazolidinediones on beta-cell function and a reduction in the progression to type 2 diabetes.3,4 The overwhelmingly positive effects on cardiovascular-risk reduction were also downplayed. There is no question that the plethora of ongoing trials regarding prevention and cardiovascular-risk reduction will help us better define the clinical role of thiazolidinediones, but meanwhile, one should not ignore or downplay the clearly demonstrated results observed in studies of this class of drugs.
Steven V. Edelman, M.D.
University of California, San Diego
San Diego, CA 92161
sedelman@ucsd.edu
Dr. Edelman reports having served as a consultant for Lilly, Novo, Aventis, Takeda, GlaxoSmithKline, and Novartis.
References
Cavaghan MK, Ehrmann DA, Byrne MM, Polonsky KS. Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance. J Clin Invest 1997;100:530-537.
Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796-2803.
Finegood DT, McArthur MD, Kojwang D, et al. Beta-cell mass dynamics in Zucker diabetic fatty rats: rosiglitazone prevents the rise in net cell death. Diabetes 2001;50:1021-1029.
Xiang AH, Peters RK, Kjos SL, et al. Continued protection from diabetes during treatment of the TRIPOD cohort with pioglitazone. Presented at the American Diabetes Association's 63rd Annual Scientific Sessions, New Orleans, June 13–17, 2003 (oral presentation).
To the Editor: Yki-J?rvinen does not mention the effect of thiazolidinedione drugs on bone. Osteoblasts and adipocytes share a common mesenchymal precursor in the bone marrow,1 and the stimulation of adipocyte formation by thiazolidinediones seems to occur at the expense of the formation of osteoblasts.2,3 Furthermore, the intake of thiazolidinediones by older patients with diabetes has been shown to decrease bone mineral density in the femoral neck and hip.4 Since patients with diabetes may be at increased risk for fractures,5 physicians should carefully check bone mineral density and the risk of fractures in patients taking thiazolidinediones.
Luca Mascitelli, M.D.
Comando Brigata Alpina Julia
33100 Udine, Italy
lumasci@libero.it
Francesca Pezzetta, M.D.
Ospedale S. Michele
33013 Gemona del Friuli, Italy
References
Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41-49.
Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernick B. Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology 2004;145:401-406.
Akune T, Ohba S, Kamekura S, et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 2004;113:846-855.
Schwartz AV, Sellmeyer DE, Feingold KR, et al. Thiazolidinedione (TZD) use and bone mineral density in older adults with diabetes. Diabetes 2002;51:A237-A237. abstract.
Meyer HE, Tverdal A, Falch JA. Risk factors for hip fracture in middle-aged Norwegian women and men. Am J Epidemiol 1993;137:1203-1211.
Dr. Yki-J?rvinen replies: I share Dr. Edelman's optimism regarding the possible benefits of thiazolidinediones in preserving beta-cell function. However, I am forced to stick to the facts and repeat what I wrote in the review: "No data are available to support long-term maintenance of glycemic control with rosiglitazone or pioglitazone as compared with other existing therapies." The TRIPOD study randomly assigned women without diabetes to receive treatment with troglitazone or placebo, not to an active comparator. The abstract Dr. Edelman cites describes an uncontrolled, open-label extension of the TRIPOD study in which women were given pioglitazone after either troglitazone or placebo.
Regarding downplaying "the overwhelmingly positive effects of thiazolidinediones on cardiovascular-risk reduction," I am not aware of any studies showing a reduction in cardiovascular risk, since all placebo-controlled end-point studies are still ongoing. Most doctors, including me, wish to treat type 2 diabetes with drugs that have favorable or at least neutral effects on its main complication — that is, cardiovascular disease.
Although thiazolidinediones may increase the size of LDL particles, the increase in LDL cholesterol consistently reported with rosiglitazone cannot, in the absence of mechanistic data regarding the effects of thiazolidinediones on lipoprotein metabolism, be immediately classified as a positive effect. Surrogate markers may not always predict what happens in an outcome trial — the story of hormone-replacement therapy might serve as an example.
Dr. Davidson correctly points out that pioglitazone has been shown to increase the size of LDL particles in a placebo-controlled trial, which was reported after the initial submission of my article. The increase in particle size was observed in the absence of changes in the concentration of LDL cholesterol.
Drs. Mascitelli and Pezzetta suggest that the effects of thiazolidinediones on bone should have been included in the article. The review focused on published data in humans and the treatment of hyperglycemia, which is currently the only condition for which thiazolidinediones are approved. Studies in animals and in vitro studies have examined the effects of thiazolidinediones on many common diseases, including rheumatoid arthritis. However, the effects of thiazolidinediones, such as that on fat content in the liver, may differ between mice and humans, and therefore, reviewing such data may be of little relevance to the treatment of human disease. This remains true for osteoporosis as long as there are no published data on harmful effects of thiazolidinediones on bone density in humans. There are more than 4000 full-length articles available on peroxisome-proliferator–activated receptors, and only about 100 could be included in the review.
Hannele Yki-J?rvinen, M.D.
University of Helsinki
00029 HUS Helsinki, Finland
ykijarvi@cc.helsinki.fi