Exp Clin Endocrinol Diabetes 2000; Vol. 108: 256-266
DOI: 10.1055/s-2000-8528
© Johann Ambrosius Barth

Combining pioglitazone with a sulphonylurea or metformin in the management of type 2 diabetes

M. Hanefeld, B. Göke
  • Institute and Outpatient Clinic of Metabolic Research, Technical University of Dresden, Germany; Department of Internal Medicine, University of Bern, Switzerland
Further Information

Publication History

Publication Date:
31 December 2000 (online)

Summary:

Evidence suggests that strict control of both fasting and postprandial hyperglycaemia is essential to prevent chronic progression of diabetes and its complications. The UKPDS authors concluded that this goal may be achieved by using combination therapy rather than monotherapy after failure of dietary and lifestyle changes. This paper focuses on the role of pioglitazone in combination with other oral antihyperglycaemic agents in the treatment of type 2 diabetes. New long-term data from an interim analysis with respect to efficacy and safety of these combinations are also discussed. Sulphonylureas (SUs) are suitable for combination with pioglitazone based on their complementary mechanisms of action, while adding pioglitazone to metformin provides a useful synergistic combination when glucose levels are insufficiently controlled with monotherapy. Long-term combination therapy for up to 40 weeks with pioglitazone and an SU or metformin resulted in continued metabolic improvement. As an important adjunctive effect of pioglitazone combination therapy, a sustained improvement in the lipid profile was reported. Pioglitazone, in combination with either an SU or metformin, thus enhances glycaemic control and favourably affects the lipid profile in patients with type 2 diabetes. All effects are maintained over the long term. Combination therapy with an SU or metformin was well tolerated and did not show any drug-related hepatotoxicity. The continued improvement in glycaemic control was associated with weight gain of 3-4 kg over the 40-week study period.

References

  • 1 Austin M A, Hokanson J E, Edwards K L. Hypertriglyceridemia as a cardiovascular risk factor.  Am J Cardiol. 81(4A) 7B-12B 1998; 
  • 2 Bailey C J, Turner R C. Metformin.  N Engl J Med. 334 574-579 1996; 
  • 3 Ban J, Miyajima T, Tsumura Y, Inoue T, Nakamura T, Imamura R, Oe M. Concomitant administration of an insulin-resistance improving drug, AD-4833, with SU drugs: influence on the serum concentrations of SU drugs.  Jpn J Clin Exp Med. 74 1217-1226 1997; 
  • 4 Belcher G, Matthews D. Safety and tolerability of pioglitazone.  Exper Clin Endocrinol Diabetes. 108 (Suppl 2) S 267-S 273 2000; 
  • 5 Bloomgarden Z T. International diabetes federation meeting, 1997: Issues in the treatment of type 2 diabetes; sulfonylureas, metformin, and troglitazone.  Diabetes Care. 21 1024-1026 1997; 
  • 6 Buse J. Combining insulin and oral agents.  Am J Med 108 ((Suppl 6a)) 23S-32S 2000; 
  • 7 Ceriello A, Giugliano D, Quatraro A, Consoli G, Stante A, Dello Russo P, D'Onofrio F. Induced hyperglycemia alters antithrombin III activity but not its plasma concentration in healthy normal subjects.  Diabetes. 36 320-323 1987; 
  • 8 Ceriello A, Quatraro A, Giugliano D. Diabetes mellitus and hypertension. The possible role of hyperglycaemia through oxidative stress.  Diabetologia. 36 265-266 1993; 
  • 9 Ceriello A. Acute hyperglycaemia and oxidative stress generation.  Diabetic Med. 14 S45-S49 1997; 
  • 10 Criqui M H, Golomb B A. Epidemiologic aspects of lipid abnormalities.  Am J Med. 105 48S-57S 1998; 
  • 11 DeFronzo R A, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease.  Diabetes Care. 14 173-194 1991; 
  • 12 DeFronzo R A. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis.  Neth J Med. 50 191-197 1997; 
  • 13 Donnelly R, Qu X. Mechanisms of insulin resistance and new pharmacological approaches to metabolism and diabetic complications.  Clin Exp Pharmacol Physiol. 25 79-87 1998; 
  • 14 Editorial . A desktop guide to Type 2 diabetes mellitus. European Diabetes Policy Group 1999.  Diabetic Med. 16 716-730 1999; 
  • 15 Einhorn D, Rendell M, Rosenzweig J, Egan J W, Mathisen A L, Schneider R L. Pioglitazone hydrochloride in combination with metformin therapy improves glycemic control in the treatment of patients with type 2 diabetes mellitus: a randomised placebo-controlled study.  Clinical Therapeutics. 22(12) in press, 2000; 
  • 16 Emoto M, Nishizawa Y, Maekawa K, Hiura Y, Kanda H, Kawagishi T, Shoji T, Okuno Y, Morii H. Homeostasis model assessment as a clinical index of insulin resistance in type 2 diabetic patients treated with sulfonylureas.  Diabetes Care. 22 818-822 1999; 
  • 17 Evans A, Krentz A J. Benefits and risks of transfer from oral agents to insulin in type 2 diabetes mellitus.  Drug Saf. 21 7-22 1999; 
  • 18 Feinglos M N, Bethel M A. Treatment of type 2 diabetes mellitus.  Med Clin North Am. 82 757-790 1998; 
  • 19 Frick M H, Elo O, Haapa K, Heinonen O P, Heinsalmi P, Helo P, Huttunen J K, Kaitaniemi P, Koskinen P, Manninen V. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.  N Engl J Med. 317(20) 1237-1245 1987; 
  • 20 Frick M H, Heinonen O P, Huttunen J K, Koskinen P, Manttari M, Manninen V. Efficacy of gemfibrozil in dyslipidaemic subjects with suspected heart disease. An ancillary study in the Helsinki Heart Study frame population.  Ann Med. 25(1) 41-45 1993; 
  • 21 Ginsberg H, Plutzky J, Sobel B E. A review of metabolic and cardiovascular effects of oral antidiabetic agents: Beyond glucose-level lowering.  J Cardiovasc Risk. 6 337-346 1999; 
  • 22 Haffner S M, Miettinen H, Stern M P. The homeostasis model in the San Antonio Heart Study.  Diabetes Care. 20 1087-1092 1997; 
  • 23 Haffner S M, Valdez R A, Hazuda H P, Mitchell B D, Morales P A, Stern M P. Prospective analysis of the insulin resistance syndrome (Syndrome X).  Diabetes. 41 715-722 1992; 
  • 24 Hanefeld M, Leonhardt W. Das metabolische Syndrom.  Dt. Gesundh Wesen. 36 545-551 1981; 
  • 25 Hanefeld M, Koehler C, Schaper F, Fuecker K, Henkel E, Temelkova-Kurktschiev T. Postprandial plasma glucose is an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals.  Atherosclerosis. 144 229-235 1999; 
  • 26 Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch H J, Lindner J. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up.  Diabetologia. 39 1577-1583 1996; 
  • 27 Howard B V, Robbins D C, Sievers M L, Lee E T, Rhoades D, Devereux R B, Cowan L D, Gray R S, Welty T K, Go O T, Howard W J. LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: The Strong Heart Study.  Arterioscler Thromb Vasc Biol. 20(3) 830-835 2000; 
  • 28 Hunt A E, Paradisi G, Steinberg H O, Hook G, Mather K J. Using the Homeostasis Model (HOMA-IR) to measure therapeutically induced alterations in insulin sensitivity.  Diabetes 49 ((Suppl 1)) A91 2000; 
  • 29 Kaneko T, Baba S, Toyota T, Akanuma Y, Sakamoto N, Shigeta Y, Shichiri M. Dose finding study of AD-4833 in NIDDM patients on treatment with a sulphonylurea drug.  Jpn J Clin Exper Med. 74 1278-1306 1997a; 
  • 30 Kaneko T, Baba S, Toyota T, Akanuma Y, Sakamoto N, Shigeta Y, Shichiri M. Clinical usefulness of long-term treatment with AD-4833 in patients with non-insulin-dependent diabetes mellitus (NIDDM).  Jpn J Clin Exper Med. 74 1589-1613 1998; 
  • 31 Kaneko T, Baba S, Toyota T, Akanuma Y, Sakamoto N, Shigeta Y, Shichiri M, Nakano S. Clinical evaluation of an insulin resistance improving agent, AD-4833, in patients with non-insulin-dependent diabetes mellitus (NIDDM) on treatment with an SU drug.  Jpn J Clin Exper Med. 74 1515-1539 1997b; 
  • 32 Kemnitz J W, Elson D F, Roecker E B, Baum S T, Bergman R N, Meglasson M D. Pioglitazone increases insulin sensitivity, reduces blood glucose, insulin, and lipid levels, and lowers blood pressure, in obese, insulin-resistant rhesus monkeys.  Diabetes. 43 204-211 1994; 
  • 33 Kipnes M, Krosnick A, Rendell M, Egan J W, Mathisen A L, Schneider R L. Pioglitazone hydrochloride in combination with SU therapy improves glycemic control in the treatment of patients with type 2 diabetes mellitus: a randomised placebo-controlled study.  Submitted for publication.
  • 34 Luna B, Hughes A TD, Feinglos M N. The use of insulin secretagogues in the treatment of type 2 diabetes.  Primary Care - Clinics In Office Practice. 26 895-915 1999; 
  • 35 McCormack J, Greenhalgh T. Seeing what you want to see in randomised controlled trials: versions and perversions of UKPDS data.  Br Med J. 320 1720-1723 2000; 
  • 36 Mathisen A, Egan J, Schneider R. Pioglitazone 010 Study Group . The effect of combination therapy with pioglitazone and sulfonylurea on the lipid profile in patients with type 2 diabetes.  Diabetes 48 ((Suppl 1)) A106 1999; 
  • 37 Matthews D R, Hosker J P, Rudenski A S, Naylor B A, Treacher D F, Turner R C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 28 412-419 1985; 
  • 38 Meltzer S, Leiter L, Daneman D, Gerstein H C, Lau D, Ludwig S, Yale J F, Zinman B, Lillie D. 1998 clinical practice guidelines for the management of diabetes in Canada. Canadian Diabetes Association.  Can Med Assoc J 159 ((Suppl 8)) S1-S29 1998; 
  • 39 Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Cusi K, Mandarino L, DeFronzo R A. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM).  Diabetes 49 ((Suppl 1)) A299 2000; 
  • 40 Mooradian A D. Drug therapy of non-insulin-dependent diabetes mellitus in the elderly.  Drugs. 51 931-941 1996; 
  • 41 Nathan D M. Some answers, more controversy, from UKPDS. United Kingdom Prospective Diabetes Study.  Lancet. 352 832-833 1998; 
  • 42 Reaven G M. Banting Lecture 1988. Role of insulin resistance in human disease.  Diabetes. 37 1595-1607 1988; 
  • 43 Riddle M. Combining sulfonylureas and other oral agents.  Am J Med. 108 15S-22S 2000; 
  • 44 Rosenstock J. Improved insulin sensitivity and beta cell responsivity suggested by HOMA analysis of pioglitazone therapy.  Diabetologia 43 ((Suppl 1)) A-192, Abstract 738 2000; 
  • 45 Rosetti L. Glucose toxicity: the implications of hyperglycaemia in the pathophysiology of diabetes mellitus.  J Clin Invest. 18 255-260 1995; 
  • 46 Rubins H B, Robins S J, Collins D, Fye C L, Anderson J W, Elam M B, Faas F H, Linares E, Schaefer E J, Schectman G, Wilt T J, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.  New Engl J Med.. 341(6) 410-418 1999; 
  • 47 Scheen A J, Lefebvre P J. Oral antidiabetic agents. A guide to selection.  Drugs. 55 225-236 1998; 
  • 48 Schneider R, Egan J, Houser V. Combination therapy with pioglitazone and sulfonylurea in patients with type 2 diabetes.  Diabetes 48 ((Suppl 1)) A106 1999; 
  • 49 Temelkova-Kurktschiev T S, Koehler C, Leonhardt W, Schaper F, Henkel E, Siegert G, Hanefeld M. Increased intimal-medial thickness in newly detected type 2 diabetes: risk factors.  Diabetes Care. 22 333-338 1999; 
  • 50 Turner R C, Millns H, Neil H A, Stratton I M, Manley S E, Matthews D R, Holman R R. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study.  Br Med J. 823-828 316 1998; 
  • 51 University Group Diabetes Program . A study of the effects of hypoglycaemic agents on vascular complications in patients with adult-onset diabetes. V. Evaluation of phenformin therapy.  Diabetes 24 ((Suppl 1)) 65-184 1975; 
  • 52 UK Prospective Diabetes Study Group . Overview of 6 years' therapy of type II diabetes: a progressive disease.  Diabetes. 44 1249-1258 1995; 
  • 53 UK Prospective Diabetes Study (UKPDS) Group . Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).  Lancet. 352 837-853 1998a; 
  • 54 UK Prospective Diabetes Study (UKPDS) Group . Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).  Lancet. 352 854-865 1998b; 
  • 55 Zimmet P, Collier G. Clinical efficacy of metformin against insulin resistance parameters: sinking the iceberg.  Drugs. 58 1-8 1999; 

Prof. Dr. med. habil. Markolf Hanefeld

Institute and Outpatient Clinic of Metabolic Research

Medical Faculty C. G. Carus

Technical University of Dresden

Germany

Phone: 49-351-458-3310

Fax: 49-351-458-4342

Email: hanefeld@rcs1.urz.tu-dresden.de

    >