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How beneficial are thiazolidinediones for diabetes mellitus?
The thiazolidinediones pioglitazone (Actos) and rosiglitazone (Avandia) are effective at lowering fasting plasma glucose (FPG) and glycosylated hemoglobin (Hb A1c) in patients with type 2 diabetes when used either as monotherapy or in combination with sulfonylureas, metformin, or insulin. The glucose-lowering effects appear comparable with those of sulfonylureas and metformin alone. Currently, there are no randomized trials directly comparing patient-oriented outcomes of the thiazolidinediones with those of sulfonylureas and metformin. Grade of recommendation: B (on the basis of extrapolations from randomized trials and low quality randomized trials).
Evidence summary
Proper nutrition and exercise remain the cornerstones of diabetes therapy; medication management, however, is often necessary.1 Both pioglitazone and rosiglitazone have similar glucose-lowering effects. See the tables in the online version of this Clinical Inquiry at www.fpin.org for a summary of monotherapy and combination clinical trials.
Pioglitazone has consistently been shown to decrease triglycerides and increase high-density lipoprotein and rosiglitazone increases total cholesterol, HDL, and low-density lipoprotein. The clinical significance of these effects has not been established. Both medications are generally well tolerated but have the potential to cause edema and mildly decrease hemoglobin and hematocrit.2-9
To date, there have been reports of pulmonary edema and hepatotoxicity associated with the use of rosiglitazone. In all cases, rosiglitazone was found to be a possible, not a definite, cause.10-12
Recommendations from others
The American Diabetes Association and the American Association of Clinical Endocrinologists do not recommend one class of antidiabetic medication over another.1,13 Both of the thiazolidinediones are indicated for monotherapy and in combination with a sulfonylurea and metformin. However, only pioglitazone is indicated in combination with insulin. They are highly metabolized by the liver and should not be used in patients with liver enzymes greater than 2.5 times the upper limit of normal. Routine liver monitoring is recommended at baseline, every 2 months for the first year, and then periodically thereafter.1 Patients with New York Heart Association class III or IV heart failure should not use thiazolidinediones. In addition, thiazolidinediones cost considerably more than sulfonylureas and metformin.14 Therefore, thiazolidinediones are not generally considered for first-line therapy.15 These agents may be most beneficial in patients with insulin resistance and patients with renal dysfunction.1
TABLE
Effects of rosiglitazone and pioglitazone, by dosage
| Drug and dosage | Control | Adjunct medication | Change in Hb A1c vs comparison (%) | Change in FPG vs comparison (mg/dL) |
|---|---|---|---|---|
| Rosiglitazone | ||||
| 4 mg bid2 | placebo | none | -1.5* | -73* |
| 2 mg bid3 | glyburide | none | +0.4 | +5 |
| 4 mg bid | +0.2† | -11 | ||
| 8 mg bid4 | placebo | metformin | -1.3* | -54.3* |
| 2 mg bid5 | placebo | sulfonylurea | -1.1* | -43.6* |
| 4 mg bid6 | placebo | insulin | -1.3‡ | -55.8‡ |
| Pioglitazone | ||||
| 45 mg qd7 | placebo | none | -1.6* | -65.3* |
| 30 mg qd8 | placebo | sulfonylurea | -1.3* | -57.9* |
| 30 mg qd9 | placebo | metformin | -0.83* | -37.7* |
| Hb A1cdenotes glycosylated hemoglobin; FPG, fasting plasma glucose; bid, twice a day; qd, every day. | ||||
| *P < .05 versus control. | ||||
| †P= not significant. | ||||
| ‡P= < .006 versus placebo plus insulin. | ||||
| Find further details online at www.fpin.org. | ||||
Read a clinical commentary by Steven Zweig, MD, at www.fpin.org
1. The American Association of Clinical Endocrinologists. Endocrin Pract 2000;
2. Lebovitz HE, Dole JF, Patwardhan R, et al. J Clin Endocrinol Metab 2001;86:280-8.
3. Charbonnel B, Lonnqvist F, Jones N, et al. Diabetes 1999;48 (suppl 1):A114.-
4. Fonseca V, Rosenstock J, Patwardhan R, et al. JAMA 2000;283:1695-702.
5. Wolffenbuttel BH, Gomist R, Squatrito S, et al. Diabet Med 2000;17:40-7.
6. Raskin P, Rendell M, Riddle MC, et al. Diabetes Care 2001;24:1226-32.
7. Aronoff S, Rosenblatt S, Braithwaite S, et al. Diabetes Care 2000;23:1605-11.
8. Kipnes MS, Krosnick A, Rendell MS, et al. Am J Med 2001;111:10-7.
9. Einhorn D, Rendell M, Rosenzweig J, et al. Clin Ther 2000;22:1395-409.
10. Thomas ML, Lloyd SJ. Ann Pharmacother 2001;35:123-4.
11. Al-Salman J, Arjomand H, Kemp DG, et al. Ann Intern Med 2000;132:121-4.
12. Forman LM, Simmons DA, Diamond RH. Ann Intern Med 2000;132:118-20.
13. The American Diabetes Association. Diabetes 2001;(suppl 1):S1-S133.
14. Holmboe ES. Clinical applications. JAMA 2002;287:373-6.
15. Inzucchi SE. Scientific review. JAMA 2002;287:360-72.
The thiazolidinediones pioglitazone (Actos) and rosiglitazone (Avandia) are effective at lowering fasting plasma glucose (FPG) and glycosylated hemoglobin (Hb A1c) in patients with type 2 diabetes when used either as monotherapy or in combination with sulfonylureas, metformin, or insulin. The glucose-lowering effects appear comparable with those of sulfonylureas and metformin alone. Currently, there are no randomized trials directly comparing patient-oriented outcomes of the thiazolidinediones with those of sulfonylureas and metformin. Grade of recommendation: B (on the basis of extrapolations from randomized trials and low quality randomized trials).
Evidence summary
Proper nutrition and exercise remain the cornerstones of diabetes therapy; medication management, however, is often necessary.1 Both pioglitazone and rosiglitazone have similar glucose-lowering effects. See the tables in the online version of this Clinical Inquiry at www.fpin.org for a summary of monotherapy and combination clinical trials.
Pioglitazone has consistently been shown to decrease triglycerides and increase high-density lipoprotein and rosiglitazone increases total cholesterol, HDL, and low-density lipoprotein. The clinical significance of these effects has not been established. Both medications are generally well tolerated but have the potential to cause edema and mildly decrease hemoglobin and hematocrit.2-9
To date, there have been reports of pulmonary edema and hepatotoxicity associated with the use of rosiglitazone. In all cases, rosiglitazone was found to be a possible, not a definite, cause.10-12
Recommendations from others
The American Diabetes Association and the American Association of Clinical Endocrinologists do not recommend one class of antidiabetic medication over another.1,13 Both of the thiazolidinediones are indicated for monotherapy and in combination with a sulfonylurea and metformin. However, only pioglitazone is indicated in combination with insulin. They are highly metabolized by the liver and should not be used in patients with liver enzymes greater than 2.5 times the upper limit of normal. Routine liver monitoring is recommended at baseline, every 2 months for the first year, and then periodically thereafter.1 Patients with New York Heart Association class III or IV heart failure should not use thiazolidinediones. In addition, thiazolidinediones cost considerably more than sulfonylureas and metformin.14 Therefore, thiazolidinediones are not generally considered for first-line therapy.15 These agents may be most beneficial in patients with insulin resistance and patients with renal dysfunction.1
TABLE
Effects of rosiglitazone and pioglitazone, by dosage
| Drug and dosage | Control | Adjunct medication | Change in Hb A1c vs comparison (%) | Change in FPG vs comparison (mg/dL) |
|---|---|---|---|---|
| Rosiglitazone | ||||
| 4 mg bid2 | placebo | none | -1.5* | -73* |
| 2 mg bid3 | glyburide | none | +0.4 | +5 |
| 4 mg bid | +0.2† | -11 | ||
| 8 mg bid4 | placebo | metformin | -1.3* | -54.3* |
| 2 mg bid5 | placebo | sulfonylurea | -1.1* | -43.6* |
| 4 mg bid6 | placebo | insulin | -1.3‡ | -55.8‡ |
| Pioglitazone | ||||
| 45 mg qd7 | placebo | none | -1.6* | -65.3* |
| 30 mg qd8 | placebo | sulfonylurea | -1.3* | -57.9* |
| 30 mg qd9 | placebo | metformin | -0.83* | -37.7* |
| Hb A1cdenotes glycosylated hemoglobin; FPG, fasting plasma glucose; bid, twice a day; qd, every day. | ||||
| *P < .05 versus control. | ||||
| †P= not significant. | ||||
| ‡P= < .006 versus placebo plus insulin. | ||||
| Find further details online at www.fpin.org. | ||||
Read a clinical commentary by Steven Zweig, MD, at www.fpin.org
The thiazolidinediones pioglitazone (Actos) and rosiglitazone (Avandia) are effective at lowering fasting plasma glucose (FPG) and glycosylated hemoglobin (Hb A1c) in patients with type 2 diabetes when used either as monotherapy or in combination with sulfonylureas, metformin, or insulin. The glucose-lowering effects appear comparable with those of sulfonylureas and metformin alone. Currently, there are no randomized trials directly comparing patient-oriented outcomes of the thiazolidinediones with those of sulfonylureas and metformin. Grade of recommendation: B (on the basis of extrapolations from randomized trials and low quality randomized trials).
Evidence summary
Proper nutrition and exercise remain the cornerstones of diabetes therapy; medication management, however, is often necessary.1 Both pioglitazone and rosiglitazone have similar glucose-lowering effects. See the tables in the online version of this Clinical Inquiry at www.fpin.org for a summary of monotherapy and combination clinical trials.
Pioglitazone has consistently been shown to decrease triglycerides and increase high-density lipoprotein and rosiglitazone increases total cholesterol, HDL, and low-density lipoprotein. The clinical significance of these effects has not been established. Both medications are generally well tolerated but have the potential to cause edema and mildly decrease hemoglobin and hematocrit.2-9
To date, there have been reports of pulmonary edema and hepatotoxicity associated with the use of rosiglitazone. In all cases, rosiglitazone was found to be a possible, not a definite, cause.10-12
Recommendations from others
The American Diabetes Association and the American Association of Clinical Endocrinologists do not recommend one class of antidiabetic medication over another.1,13 Both of the thiazolidinediones are indicated for monotherapy and in combination with a sulfonylurea and metformin. However, only pioglitazone is indicated in combination with insulin. They are highly metabolized by the liver and should not be used in patients with liver enzymes greater than 2.5 times the upper limit of normal. Routine liver monitoring is recommended at baseline, every 2 months for the first year, and then periodically thereafter.1 Patients with New York Heart Association class III or IV heart failure should not use thiazolidinediones. In addition, thiazolidinediones cost considerably more than sulfonylureas and metformin.14 Therefore, thiazolidinediones are not generally considered for first-line therapy.15 These agents may be most beneficial in patients with insulin resistance and patients with renal dysfunction.1
TABLE
Effects of rosiglitazone and pioglitazone, by dosage
| Drug and dosage | Control | Adjunct medication | Change in Hb A1c vs comparison (%) | Change in FPG vs comparison (mg/dL) |
|---|---|---|---|---|
| Rosiglitazone | ||||
| 4 mg bid2 | placebo | none | -1.5* | -73* |
| 2 mg bid3 | glyburide | none | +0.4 | +5 |
| 4 mg bid | +0.2† | -11 | ||
| 8 mg bid4 | placebo | metformin | -1.3* | -54.3* |
| 2 mg bid5 | placebo | sulfonylurea | -1.1* | -43.6* |
| 4 mg bid6 | placebo | insulin | -1.3‡ | -55.8‡ |
| Pioglitazone | ||||
| 45 mg qd7 | placebo | none | -1.6* | -65.3* |
| 30 mg qd8 | placebo | sulfonylurea | -1.3* | -57.9* |
| 30 mg qd9 | placebo | metformin | -0.83* | -37.7* |
| Hb A1cdenotes glycosylated hemoglobin; FPG, fasting plasma glucose; bid, twice a day; qd, every day. | ||||
| *P < .05 versus control. | ||||
| †P= not significant. | ||||
| ‡P= < .006 versus placebo plus insulin. | ||||
| Find further details online at www.fpin.org. | ||||
Read a clinical commentary by Steven Zweig, MD, at www.fpin.org
1. The American Association of Clinical Endocrinologists. Endocrin Pract 2000;
2. Lebovitz HE, Dole JF, Patwardhan R, et al. J Clin Endocrinol Metab 2001;86:280-8.
3. Charbonnel B, Lonnqvist F, Jones N, et al. Diabetes 1999;48 (suppl 1):A114.-
4. Fonseca V, Rosenstock J, Patwardhan R, et al. JAMA 2000;283:1695-702.
5. Wolffenbuttel BH, Gomist R, Squatrito S, et al. Diabet Med 2000;17:40-7.
6. Raskin P, Rendell M, Riddle MC, et al. Diabetes Care 2001;24:1226-32.
7. Aronoff S, Rosenblatt S, Braithwaite S, et al. Diabetes Care 2000;23:1605-11.
8. Kipnes MS, Krosnick A, Rendell MS, et al. Am J Med 2001;111:10-7.
9. Einhorn D, Rendell M, Rosenzweig J, et al. Clin Ther 2000;22:1395-409.
10. Thomas ML, Lloyd SJ. Ann Pharmacother 2001;35:123-4.
11. Al-Salman J, Arjomand H, Kemp DG, et al. Ann Intern Med 2000;132:121-4.
12. Forman LM, Simmons DA, Diamond RH. Ann Intern Med 2000;132:118-20.
13. The American Diabetes Association. Diabetes 2001;(suppl 1):S1-S133.
14. Holmboe ES. Clinical applications. JAMA 2002;287:373-6.
15. Inzucchi SE. Scientific review. JAMA 2002;287:360-72.
1. The American Association of Clinical Endocrinologists. Endocrin Pract 2000;
2. Lebovitz HE, Dole JF, Patwardhan R, et al. J Clin Endocrinol Metab 2001;86:280-8.
3. Charbonnel B, Lonnqvist F, Jones N, et al. Diabetes 1999;48 (suppl 1):A114.-
4. Fonseca V, Rosenstock J, Patwardhan R, et al. JAMA 2000;283:1695-702.
5. Wolffenbuttel BH, Gomist R, Squatrito S, et al. Diabet Med 2000;17:40-7.
6. Raskin P, Rendell M, Riddle MC, et al. Diabetes Care 2001;24:1226-32.
7. Aronoff S, Rosenblatt S, Braithwaite S, et al. Diabetes Care 2000;23:1605-11.
8. Kipnes MS, Krosnick A, Rendell MS, et al. Am J Med 2001;111:10-7.
9. Einhorn D, Rendell M, Rosenzweig J, et al. Clin Ther 2000;22:1395-409.
10. Thomas ML, Lloyd SJ. Ann Pharmacother 2001;35:123-4.
11. Al-Salman J, Arjomand H, Kemp DG, et al. Ann Intern Med 2000;132:121-4.
12. Forman LM, Simmons DA, Diamond RH. Ann Intern Med 2000;132:118-20.
13. The American Diabetes Association. Diabetes 2001;(suppl 1):S1-S133.
14. Holmboe ES. Clinical applications. JAMA 2002;287:373-6.
15. Inzucchi SE. Scientific review. JAMA 2002;287:360-72.
Evidence-based answers from the Family Physicians Inquiries Network