^ORIGINAL RESEARCH Troglitazone or Metformin in Combination with Sulfonylureas for Patients with Type 2 Diabetes? Julienne K. Kirk, PharmD, CDE; Kevin A. Pearce, MD, MPH; Robert Michielutte, PhD; and John H. Summerson, MS Winston-Salem, North Carolina, and Lexington, Kentucky

BACKGROUND. Combination oral therapy is often used to control the hyperglycemia of patients with type 2 diabetes. We compared the effectiveness of metformin and troglitazone when added to sulfonylurea therapy for patients with type 2 diabetes who had suboptimal blood glucose control.

METHODS. We used a randomized 2-group design to compare the efficacy, safety, and tolerability of troglita­ zone and metformin for patients with type 2 diabetes mellitus that was inadequately controlled with diet and oral sulfonylureas. Thirty-two subjects were randomized to receive either troglitazone or metformin for 14 weeks, including a 2-week drug-titration period. The primary outcome variable was mean change in the level of glycosy­ lated hemoglobin (Hb A-|C) from baseline. Secondary outcomes included mean changes from baseline in fasting plasma glucose and C-peptide levels, renal or metabolic side effects, and symptomatic tolerability.

RESULTS. The addition of either troglitazone or metformin to oral sulfonylurea therapy significantly decreased Hb A-ic levels. Both treatment regimens also significantly reduced fasting plasma glucose and C-peptide levels. We found no significant differences between the treatment arms in efficacy, metabolic side effects, or tolerability.

CONCLUSIONS. Our results demonstrate that troglitazone and metformin each significantly improved Hb A i0, fasting plasma glucose, and C-peptide levels when added to oral sulfonylurea therapy for patients with type 2 diabetes who had inadequate glucose control.

KEY WORDS. Diabetes mellitus, non-insulin-dependent; metformin; drug therapy, combination. (J Fam Pract 1999; 48:879-882)

n 1998 an estimated 9.5 million people had a diag­ Troglitazone increases the responsiveness of insulin- nosis of type 2 diabetes mellitus in the United dependent tissues through a mechanism thought to States.1 Tight control of blood glucose concentra­ involve receptors that regulate the transcription of a num­ tions to near-normal levels has been shown to ber of insulin-responsive genes.1112 It increases insulin- reduce the microvascular complications of type 2 dependent glucose disposal in skeletal muscle, enhancing Idiabetes without increasing major macrovascular compli­the effects of circulating insulin. cations.2-3 However, control of blood glucose is complex Metformin (glucophage) lowers plasma glucose by and involves multiple organ systems. Patients with type 2 decreasing hepatic glucose output through the inhibition diabetes often do not achieve desirable glucose control of gluconeogenesis and by increasing peripheral glucose despite the use of oral hypoglycemic agents or insulin. use by skeletal muscle. It is a biguanide that was intro­ Insulin resistance — the diminished ability of insulin to duced in Europe in 1957 and has been available in the exert its biological activity over a broad range of glucose United States since 1995.13-14 Metformin is indicated in levels — may contribute to the difficulty in controlling patients with type 2 diabetes as a monotherapy along with type 2 diabetes.4-5 diet; it can also be used concomitantly with a sulfonylurea Thiazolidinediones represent a newer class of drugs or insulin.16-16 The efficacy of metformin on glycemic con­ that affect insulin resistance.6-7 Troglitazone (Rezulin) is trol has been demonstrated as a monotherapy and in com­ the first drug in this class to be approved by the US Food bination with a sulfonylurea.16-17 and Drug Administration (FDA) for the treatment of type Although there are data to support the use of met­ 2 diabetes. Troglitazone can be used in combination with formin or troglitazone in combination with a sulfony­ a sulfonylurea or insulin to improve glycemic control.8-10 lurea,8-1014-16 randomized comparisons of the relative ef­ Submitted, revised, July 15, 1999. fects of these combinations on glycemic control are lack­ From the Department of Family and Community Medicine, ing. Information about the efficacy, safety, tolerability, Wake Forest University School of Medicine, Winston-Salem and cost of these combination therapies may help in (J.K.K., R.M., J.H.S.) and the Department of Family pharmacotherapy decision making. Our primary goal was Practice, University of Kentucky, Lexington (K.A.P.). to compare the effects of troglitazone with those of met­ Reprint requests should be addressed to Julienne K. Kirk, PharmD, Department of Family and Community Medicine, formin on the Hb Aic levels of patients with type 2 dia­ Wake Forest University School of Medicine, Medical Center betes who were already receiving sulfonylurea therapy. Boulevard, Winston-Salem, NC 27157. Secondary outcomes included the comparative effects of E-mail: jkirk@wfubmc. edu. these combinations on fasting plasma glucose (FPG) and

1999 Dowden Publishing Co/ISSN 0094-3509 The Journal of Family Practice, Vol. 48, No. 11 (Nov), 1999 879 TROGLITAZONE OR METFORMIN FOR PATIENTS WITH TYPE 2 DIABETES?

C-peptide levels. We also compared safety, tolerability, and before breakfast and at bedtime. We validated blood glu­ cost of the 2 drugs. cose monitors for accuracy by checking control solutions and performing check strip tests at study visits. Patients METHODS received standardized information about diabetes from a certified diabetes educator consisting of a general Study Subjects overview of diabetes mellitus, a medication review, We studied 32 patients (20 men, 12 women) with type 2 instructions for blood glucose monitoring, a review of diabetes who were already taking a sulfonylurea. We ran­ complications associated with diabetes, and nutritional domly screened individuals found in a database of family advice. Each patient was given the same written informa­ medicine patients who had been given a diagnosis of type tion about diabetes and counseled on the signs and symp­ 2 diabetes mellitus. Patients were eligible if they were aged toms of high and low blood glucose. No patient enrolled in 30 to 75 years, had poorly controlled diabetes defined by this trial reported problems reading or understanding writ­ an Hb Aic level between 8.5% and 16% at the screening ten instructions. We assessed compliance using pill counts visit, and were able to give informed consent. We exclud­ during each scheduled follow-up visit. We asked patients ed women of childbearing potential. The other exclusion about adverse events at each visit after beginning drug criteria were: a history or laboratory evidence of renal or therapy; any reported events were recorded. hepatic insufficiency; a history of alcohol abuse (including binge drinking within the past year); concomitant treat­ Statistical Analysis ment with insulin, cholestyramine, potentially nephrotox­ We performed an analysis of efficacy by intention to treat. ic drugs, or glucocorticoids (except topical or inhaled glu­ We included all patients who received at least one dose of cocorticoids); plans for radiographic studies involving the troglitazone or metformin, and selected a sample size ade­ use of intravenous iodinated contrast during the course of quate for detecting clinically meaningful differences in our study; and known intolerance or sensitivity to a treatment effects. A sample of 16 patients in each group biguanide or troglitazone. The protocol was approved by allowed detection of a mean absolute difference in Hb Aic the institutional review board at Wake Forest University level reduction between groups from a baseline of 1.2% Baptist Medical Center. (±0.2%) with a power greater than 0.80 (a = 0.05, 2-tailed test). We evaluated baseline differences between treat­ Study Design ment groups using analysis of variance and chi-square pro­ At baseline we randomized the patients to receive either cedures. Paired t tests were used to examine changes in metformin or troglitazone for a 14-week period. The study variables over time. Analyses were performed using the was divided into 2 phases: a 2-week dose-titration period Statistical Package for the Social Sciences for Personal and a 12-week open-label comparison of metformin and Computers (Version 8.0, SPSS, Inc, Chicago, 111). troglitazone. If randomized to metformin, the patient took 500 mg with the evening meal for 2 days, then 500 mg twice RESULTS daily with the morning and evening meals for 5 days. During the second week of the study, the patient took 500 The baseline demographic and disease-related character­ mg with the morning meal and 1000 mg with the evening istics of the participants are outlined in Table 1. There meal. After week 2, all patients randomized to metformin were no significant differences at baseline between treat­ therapy were taking 1000 mg with the morning and ment groups with respect to age; body mass index (BMI); evening meals. Patients randomized to troglitazone took Hb Aic, FPG, or C-peptide levels; or the duration of dia­ 200 mg daily with the evening meal for 2 weeks and then betes. Ninety-seven percent of the patients took their 400 mg daily for the remaining 12 weeks of the study. If at assigned medication for the 14 weeks of the study. All any time during the study a patient experienced a FPG of patients were receiving an oral sulfonylurea, with 85% tak­ less than 80 mg/dL, the oral sulfonylurea was decreased by ing glipizide (Glucotrol XL) 10 mg to 20 mg per day, 9% tak­ one half of the original dose and then discontinued if fur­ ing glimepiride (Amaryl) 4 to 8 mg per day, and 6% taking ther blood glucose readings were less than 80 mg/dL on glyburide (generic or DiaBeta) 10 to 20 mg per day. more than one occasion. Table 2 contains the changes in glycemic control para­ Patients were required to make a screening visit at least meters observed in each treatment group. At the end of a 1 week before entry into the trial. We obtained a past med­ 3-month treatment period, Hb Aic values decreased signif­ ical history, body weight and height, and blood tests icantly for each group when compared with the values (serum creatinine, serum bicarbonate, liver enzymes, Hb obtained at baseline. The mean Hb Aic level among those Aic, FPG, and C-peptide levels). We recorded body weight receiving metformin fell from 9.9% ±1.6 to 7.8% ±1.3 (P and repeated blood tests 6 to 8 weeks after randomization •c.001). Among patients in the troglitazone treatment and at the end of the study period (14 weeks). In addition, group, the mean Hb Aic level fell from 10% ±1.6 to 7.4% participants randomized to troglitazone had monthly liver ±1.7 (P <.001). The mean FPG level fell from 229 mg/dL enzyme tests. We also instructed patients to perform home ±75 to 138 mg/dL ±36 (P c.001) in the patients receiving blood glucose monitoring twice daily, in the morning metformin and from 210 mg/dL ±79 to 127 mg/dL ±33 (P

880 The Journal of Family Practice, Vol. 48, No. 11 (Nov), 1999 TROGLITAZONE OR METFORMIN FOR PATIENTS WITH TYPE 2 DIABETES?

TABLE 1 adverse effects were ascribed Baseline Characteristics of Study Participants Before Randomization to the study medications.

Characteristics* Troglitazone (n = 16) Metformin (n = 16) DISCUSSION

Age, years 54.5 ± 9 .1 50.5 ± 10.9 There has been much interest in Sex combined pharmacologic thera­ Men 5 9 py for type 2 diabetes, especially 6 W om en 11 when target Hb Aic levels are Race not achieved with monotherapy. African American 8 4 W hite 8 12 The American Diabetes Asso­ W eight, kg 96 .8 ± 21 92.7 ± 22 ciation recommends that the Body mass index, kg/m2 34.1 ± 5.8 32 ± 7.1 goal of treatment in type 2 dia­ Fasting plasma glucose, mg/dL* 210 ± 7 9 229 ± 75 betes is an Hb Aic level of less Hb A ic, % t 10 ± 1.6 9.9 ± 1.6 than 7%, with additional action Fasting C-peptide, ng/m Lf 6.5 ± 3 .9 6 .9 ± 2.3 suggested at values greater than Duration of diabetes, years 5.3 ± 3.6 4.7 ± 2 .6 8%.1S This small study addressed patients with type 2 diabetes Note: No baseline data characteristics were statistically different between the 2 treatment groups at P <.05. who were already receiving *Normal range = 65 mg/dL to 115 mg/dL. {Normal range = 4.2% to 5.9%. treatment with moderate to {Normal range = 0.9 ng/mL to 4.0 ng/dL. maximum doses of a sulfony­ lurea. The patients in this study <.001), in those receiving troglitazone. For each treatment were obese (mean BMI; 33 kg/m2) and had uncontrolled group this amounts to a 60% reduction in FPG levels. For diabetes as evidenced by baseline Hb Aic levels. Our those patients receiving metformin, fasting C-peptide lev­ results show that metformin and troglitazone had very els fell from 6.9 ng/mL ±2.3 to 4.7 ng/mL ±1.6 (P <.001), and similar efficacy for those patients in terms of reductions in troglitazone-treated patients, it fell from 6.5 ng/mL ±3.9 in Hb Aic, FPG, and C-peptide levels when used in com­ to 4.5 ng/mL ±2.3 (P = .004). Although both troglitazone bination with a sulfonylurea. Furthermore, safety and and metformin significantly improved glycemic control, tolerability in terms of symptomatic adverse events, there was no significant difference between the 2 groups in hypoglycemia, changes in serum creatinine, and changes any treatment effect measured. In addition, BMI did not in liver enzymes were good for both combinations dur­ significantly change from baseline to the end of the study ing the 14 weeks of this clinical trial. Previous stud­ in either treatment group. ies910,14,16 have shown these combinations effective, but Safety was assessed on the basis of the results of those studies did not directly compare them in a con­ serum FPG levels, creatinine and liver function tests, and trolled fashion. Troglitazone and metformin are both home glucose monitoring. There were no elevations in approved by the FDA for combination therapy with a sul­ liver enzymes or serum creatinine in those individuals fonylurea. Although metformin is also FDA approved as receiving either troglitazone or metformin. No patient reported TABLE 2 hypoglycemic symptoms or Pretreatment and Posttreatment Differences in Hb Aic, FPG, and C-Peptide Levels blood glucose values of less than 70 mg/dL on more than Mean one occasion. Tolerability was Values Mean Values Mean evaluated using a questionnaire Measurement Baseline at 3 Months Difference (SD) 95% Cl P of potential side effects that was answered during each H b Ac, % study visit. There was one M etform in 9.9 7.8 2.2 (1.1) 1.7, 2.8 <.001 <.001 dropout from the trial in the Troglitazone 10.0 7.4 2.6 (1.1) 2.0, 3.2 metformin treatment arm, FPG, m q /d L 91 (54) 58, 123 <.001 which was attributed to moder­ M etform in 229 138 127 8 3 (6 1 ) 54, 112 <.001 ate nausea and diarrhea after 1 Troglitazone 210 C-peptide, ng/mL month of treatment. Six addi­ <.001 M etform in 6.9 4.7 2 .2 (2.4) 1.2, 31 tional participants in the met­ .004 Troglitazone 6.5 4.5 2.0 (1.8) 0.8, 3.3 formin group reported mild nausea and bloating in the first Hb A i0 denotes glycosolated hemoglobin; FPG, fasting plasma glucose; SD, standard deviation; 2 weeks of treatment with met­ Cl, confidence interval. formin; however, no other

The Journal of Family Practice, Vol. 48, No. 11 (Nov), 1999 881 TROGLITAZONE OR METFORMIN FOR PATIENTS WITH TYPE 2 DIABETES?

a monotherapy, it is common practice to start with a sul­ from large clinical trials of sufficient duration that assess fonylurea when type 2 diabetes is diagnosed. their effects on diabetes-related morbidity and mortality. The United Kingdom Prospective Diabetes Study (UKPDS) showed metformin to be beneficial as a REFERENCES 1. Harris MI. Diabetes in America: epidemiology and scope of the monotherapy for obese patients with type 2 diabetes, but problem. Diabetes Care 1998:21(suppl 3);C114. raised concern about combination sulfonylurea/metformin 2. UK Prospective Diabetes Study Group. Intensive blood-glucose therapy.19 In the UKPDS, metformin was shown to reduce control with sulphonylureas or insulin compared with conven­ overall mortality in obese patients with serum creatinine tional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:833-53. levels less than 1.5 mg/dL, but increased mortality was 3. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin thera­ associated with the addition of metformin to sulfonylurea py prevents the progression of diabetic microvascular compli­ therapy. The baseline differences between patients treat­ cations in Japanese patients with non-insulin dependent dia­ betes mellitus: a randomized prospective 6 year study. Diab Res ed with metformin alone and those for whom metformin Clin Prac 1995; 28:103-17. was added to a sulfonyurea (plus the small number of 4. Iwamoto Y, Koska K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko deaths overall) led the UKPDS investigators to question T. Effects of troglitazone. Diabetes Care 1996; 19:151-6. 5. Polonsky K, Stiuis J, Bell GI. Non-insulin-dependent diabetes the validity of this observation. Special precautions are mellitus — a genetically programmed failure of the beta cell to recommended when prescribing metformin,29 mainly compensate for insulin resistance. N Engl J Med 1996; 334:777- because of potential problems with severe lactic acidosis 83. 6. Nolan JJ, Ludvic B, Beerdsen P, Joyce M, Olefsky J. observed in the past with another biguanide (phenformin). Improvement in glucose tolerance and insulin resistance in Accordingly, metformin is contraindicated in congestive obese subjects treated with troglitazone. N Engl J Med 1994; heart failure, in the presence of renal or hepatic insuffi­ 331:1188-93. 7. Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton ciency, during periods of hypoxemia or dehydration, and V, Shulman GI. Efficacy and metabolic effects of metformin for heavy alcohol drinkers. It should also be withheld and troglitazone in type II diabetes mellitus. N Engl J Med 1998; before, during, and after the administration of iodinated 338:867-72. 8. Schwartz S, Raskin P, Fonseca V, Graveline JF. Effect of trogli­ intravenous contrast. Tolerability of metformin can be tazone in insulin-treated patients with type II diabetes mellitus. problematic during the dose-titration phase for some N Engl J Med 1998; 338:861-6. patients because of gastrointestinal side effects, but adher­ 9. Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T. Effect of combination therapy of troglitazone and sulphony­ ence to treatment can be optimized by educating patients lureas in patients with type 2 diabetes who were poorly con­ that this is usually a transient side effect. trolled by sulfonylurea therapy alone. Diabetic Med 1996; Troglitazone has been associated with elevated hepatic 13:365-70. 10. Horton ES, Whitehouse F, Ghazzi MN, Venable TC, Whitcomb enzymes in approximately 2% of patients in clinical trials; RW. Troglitazone in combination with sulfonylurea restores very rare severe or fatal hepatic dysfunction has also been glycemic control in patients with type 2 diabetes. Diabetes Care reported.21 Accordingly, the manufacturer recommends 1998; 21:1462-9. 11. Prigeon RL, Kahn SE, Porte D. Effect of troglitazone on B cell periodic assay of serum alanine aminotransferase levels function, insulin sensitivity, and glycemic control in subjects (baseline and monthly for the first year of therapy, then with type 2 diabetes mellitus. J Clin Endocrinol Metab 1998; quarterly).22 Similar laboratory monitoring is not required 83:819-23. 12. Sparano N, Seaton TL. Troglitazone in type II diabetes mellitus. for metformin. Pharmacotherapy 1998; 18:53948. Simplicity of a prescribed drug regimen is a considera­ 13. Bailey CJ, Path MRC, Himer RC. Metformin. N Engl J Med tion for patients, especially with regard to compliance. 1996; 334:574-9. 14. DeFronzo RA, Goodman AM, Multicenter Metformin Group. Metformin requires at least twice-daily administration; Efficacy of metformin in patients with non-insulin-dependent troglitazone can be taken once per day. Comparative drug diabetes mellitus. N Engl J Med 1995; 333:541-9. costs are also important to consider. As of 1999, the aver­ 15. Daniel JR, Hagmeyer KO. Metformin and insulin: is there a role for combination therapy? Ann Pharmacother 1997; 31:474-80. age wholesale cost in the United States for a 1-month sup­ 16. Herman LS, Schersten B, Bitzen PO, Kjellstrom T, Lindgarde F, ply of the doses in our study is approximately $142 for Melander A. Therapeutic comparison of metformin and sul­ troglitazone and $75 for metformin.23 Newer thiazolidine- fonylurea, alone and in various combinations. Diabetes Care 1994; 17:1100-9. diones, such as rosiglitazone and pioglitazone, will add 17. Jhansen K. Efficacy of metformin in the treatment of NIDDM. competition and continued scrutiny to the efficacy, safety, Diabetes Care 1999; 22:33-7. and costs of this drug class. 18. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 1999; (supp 1):S3241. CONCLUSIONS 19. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet Metformin and troglitazone improved glycemic profiles and 1998; 352:854-65. C-peptide levels with equal success with no significant dif­ 20. Sulkin TV, Bosnian D, Krentz A. Contraindications to met­ ferences in safety or tolerability. Although our study had formin in patients with NIDDM. Diabetes Care 1997; 20:925-8. 21. Watkins PB, Whitcomb RW. Hepatic dysfunction associated sufficient power to detect a clinically meaningful difference with troglitazone. N Engl J Med 1998; 338:916-7. in Hb Aic reduction, it was based on a small number of 22. Parke-Davis Pharmaceuticals. TVoglitazone package insert. patients and a short study duration. The true test of the Morris Plains, NJ: Parke-Davis Pharmaceuticals, 1999. 23. Medical Economics Co. Drug topic redbook. Montvale, NJ: effectiveness of these combination therapies must come Medical Economics Co, Inc, 1999:18.

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