How beneficial are thiazolidinediones for diabetes mellitus? - Clinical Inquiries - Brief Article - Statistical Data Included

Journal of Family Practice, May, 2002 by Nicole S. Culhane, Rebecca Graves

EVIDENCE-BASED ANSWER The thiazolidinediones pioglitazone (Actos) and rosiglitazone (Avandia) are effective at lowering fasting plasma glucose (FPG) and glycosylated hemoglobin (Hb [A.sub.1c]) 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 subfonylureas 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 lust-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         Control         Adjunct
dosage                         medication

Rosiglitazone
4 mg bid (2)     placebo          none
2 mg bid (3)     glyburide        none
4 mg bid
8 mg bid (4)     placebo        metformin
2 mg bid (5)     placebo      sulfonylurea
4 mg bid (6)     placebo         insulin
Pioglitazone
45 mg qd (7)     placebo          none
30 mg qd (8)     placebo      sulfonylurea
30 mg qd (9)     placebo        metformin

Drug and         Change in Hb [A.sub.1c]     Change in FPG
dosage             vs comparison             vs comparison
                      (%)                       (mg/dL)
Rosiglitazone
4 mg bid (2)         -1.5 *                     -73 *
2 mg bid (3)          0.4                         5
4 mg bid              0.2 ([dagger])            -11
8 mg bid (4)         -1.3 *                   -54.3 *
2 mg bid (5)         -1.1 *                   -43.6 *
4 mg bid (6)         -1.3 ([double dagger])   -55.8 ([double dagger])
Pioglitazone
45 mg qd (7)         -1.6 *                   -65.3 *
30 mg qd (8)         -1.3 *                   -57.9 *
30 mg qd (9)         -0.83 *                  -37.7 *

Hb [A.sub.1c] denotes glycosylated hemoglobin; FPG, fasting plasma
glucose; bid, twice a day; qd, every day.

* P < .05 versus control.

([dagger]) P = not significant.

([double dagger]) P = < .006 versus placebo plus insulin.

Find further details online at www.fpin.org.

REFERENCES

(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.