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European Association for the Study of Diabetes Annual Meeting, 1999 Treatment Modalities

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European Association for the Study of Diabetes Annual Meeting, 1999 Treatment Modalities Reviews/Commentaries/Position Statements PERSPECTIVES ON THE NEWS European Association for the Study of Diabetes Annual Meeting, 1999 Treatment modalities ZACHARY T. BLOOMGARDEN, MD patients who received metformin (1.5 g daily), pentoxifylline (1.2 g daily), and nic- otinamide (1.5 g daily) with 13 patients who received none of these drugs. Higher levels of C-peptide and lower insulin his is the first of three reports on the rently treated with metformin may have requirements in the treated group sug- 35th Annual Meeting of the European contraindications to its use. gested improvement of islet engraftment. TAssociation for the Study of Diabetes Davis et al. (abstract 845) showed sig- Standl et al. (abstract 839) assessed (EASD) held in Brussels in September nificant and independent associations of 154 patients treated with glyburide (7–20 1999. It covers topics related to the diag- BMI, plasma glucose, lower HbA1c, serum mg daily) and metformin (500–850 mg nosis and treatment of diabetes. creatinine Ͼ125 µmol/l, and metformin daily) randomized to miglitol (100 mg Ͼ dose 1,500 mg daily with fasting plasma daily) or placebo for 24 weeks. HbA1c was Oral Agents in the Treatment of lactate levels in 184 metformin-treated 8.3 and 8.6%, and 1-h glucose was 242 Hyperglycemia patients. Lactate was Ͻ2 mmol/l in 59%, and 277 mg/dl, respectively. In a similar Melander et al. (abstract 1) reported on a between 2 and 3 mmol/l in 34%, 3–4 study, Maislos et al. (abstract 838) assessed study of people with diabetes identified in 2 mmol/l in 5%, and Ͼ4 mmol/l in 1% of the 153 patients treated with metformin Swedish municipalities from 1984 to 1994 patients. The authors suggest that regular (1,500–2,550 mg daily) randomized to comparing 171 patients treated with both monitoring of plasma lactate may be useful miglitol (100 mg daily) or placebo for 28 sulfonylureas and metformin with 872 with metformin treatment. weeks. HbA1c was 8.3 and 8.7%, and 1-h patients treated with sulfonylureas alone. Tsaglis et al. (abstract 842) reported a glucose 249 and 284 mg/dl, respectively. In Total, coronary-disease, and stroke mortal- fall in vitamin B12 levels from 689 to 370 the two studies, 10% and 8% of patients ity levels through 1996 were increased by pmol/l and an increase in MCV (mean cor- had adverse gastrointestinal effects. 77, 95, and 116%, respectively, adjusted for puscular volume) from 90 to 92 fl after Simpson et al. (abstract 836) random- age, sex, duration of diabetes, municipality, 3 months in 24 overweight, newly diag- ized 154 insulin-treated patients to acarbose year of inclusion, and fasting blood glucose nosed type 2 diabetic patients treated with (100 mg three times daily) or matching at inclusion. This supports the U.K. metformin 850 mg once or twice daily. placebo for 26 weeks. Of those treated with Prospective Diabetes Study (UKPDS) find- They concluded that regular monitoring of acarbose, 48% withdrew prematurely ing of greater mortality among patients serum B12 levels may be advisable with because of gastrointestinal side effects, com- treated with the combination than among metformin treatment. pared with only 9% in the placebo group. those treated with sulfonylureas alone. Two studies suggest roles of metformin Hypoglycemia was not increased. HbA1c Emslie-Smith et al. (abstract 4) ana- treatment in patients with type 1 diabetes. decreased 0.3% versus an increase of 0.3% lyzed a database of 7,885 patients with dia- Meyer et al. (abstract 849) randomized 62 on intention-to-treat analysis. betes in Tayside, U.K., 1,847 of whom were patients with type 1 diabetes treated with Kristensen et al. (abstract 6) reported treated with metformin. Of those treated continuous subcutaneous insulin infusion the 1-year frequency of severe hypoglycemia with metformin, 65 were admitted with to metformin (850 mg twice daily) or to be 1.3% in 761 patients treated with myocardial infarction (MI) and 77 were placebo for 6 months. Respectively, the two repaglinide versus 3.3% in 205, 73, and 89 admitted with congestive heart failure groups showed an 8% decrease and a 2% patients treated with the sulfonylureas glip- (CHF), but only 20% and 18% stopped increase in insulin dose, with 2.4 and 3.3 izide, glyburide, and gliclazide, respectively. metformin after admission for the respec- hypoglycemic events per patient per The glucose level during hypoglycemia was tive conditions. Another 388 were treated month. In a study of type 1 diabetes Ͻ2.5 mmol/l during 7% of the episodes in for CHF as outpatients, and 87 had renal patients undergoing islet transplantation, the repaglinide group versus 20% of the insufficiency. Thus, 25% of patients cur- Maffi et al. (abstract 119) compared 6 episodes in the sulfonylurea group. HbA1c levels were similar at 7.1–7.5%. Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with Thiazolidinediones the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York. Abbreviations: ADA, American Diabetes Association; CHD, coronary heart disease; CHF, congestive heart The mechanism of action of the thiazo- failure; CVD, cardiovascular disease; DCCT, Diabetes Control and Complications Trial; DPP-IV, dipeptidyl lidinediones (TZDs) remains uncertain. peptidase IV; EASD, European Association for the Study of Diabetes; MAGE, mean amplitude of glycemic Kubota et al. (abstract 49) studied mice excursion; MI, myocardial infarction; PPAR␥, peroxisome proliferator–activated receptor gamma; QOL, qual- bred for deletion of the peroxisome prolif- ity of life; TZD, thiazolidinedione; UAE, urinary albumin excretion; UKPDS, U.K. Prospective Diabetes Study; ␥ WHO, World Health Organization. erator–activated receptor gamma (PPAR ) A table elsewhere in this issue shows conventional and Système International (SI) units and conversion to assess its biological role. Homozygotes factors for many substances. did not survive beyond mid-embryonic 1012 DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000 Bloomgarden life. Heterozygotes fed a high-fat diet (titrated to maximal glucose-lowering effi- rosiglitazone daily or placebo. HbA1c showed a 30% decrease in weight gain, cacy) for 12 months, showing similar reduc- (8.6–8.9% at baseline) decreased 0.6 and with decreased food intake and less devel- tions in HbA1c and hypoglycemia in 1, 2, 0.8% in the rosiglitazone group and opment of insulin resistance than mice with and 12%, respectively. increased 0.5% with placebo. Fasting glu- normal PPAR␥. The capacity of embryonic Mathisen et al. (abstract 853) treated cose (11.9–12.2 mmol/l at baseline) fibroblasts from heterozygotes to differenti- 197 patients with pioglitazone (30 mg decreased 1.8 and 2.5 mmol/l with the ate into adipocytes was impaired, with daily) or placebo. Their data showed a fall in addition of rosiglitazone and increased 0.3 pioglitazone restoring this to the level of HbA1c from 10.5 to 9.9% versus an increase mmol/l with placebo. Finally, Freed et al. cells with normal PPAR␥. from 10.3 to 11.0%, a fall in fasting glucose (abstract 866) compared urinary albumin Jacob et al. (abstract 161) studied 12 from 273 to 223 mg/dl versus an increase excretion in 212 patients treated with offspring of patients with type 2 diabetes from 270 to 278 mg/dl, a fall in triglyceride rosiglitazone and 57 patients receiving homozygous for the PPAR␥2 amino acid from 400 to 297 mg/dl versus 335 to 317 placebo who had microalbuminuria at polymorphism of alanine for proline at mg/dl, and an increase in HDL cholesterol baseline, showing 19–28% reductions. position 12. Insulin sensitivity was 30% from 38 to 43 mg/dl versus from 39 to 40 higher in individuals who carried the poly- mg/dl. LDL cholesterol did not increase. Fasting Versus Postprandial Glucose morphism. Thus, in two entirely different Two of the studies used pooled data for Diagnosis and Treatment of settings, a deficiency in PPAR␥, perhaps on monotherapy. Goldstein and Salzman Diabetes leading to a decrease in intracellular lipid (abstract 861) evaluated the efficacy of de Courten et al. (abstract 406) screened content, has been associated with increased rosiglitazone (4 or 8 mg daily) versus 6,294 individuals for diabetes with an oral insulin sensitivity, contrasting with the role placebo in data from three multicenter glucose tolerance test. Their results showed of the PPAR␥-agonist thiazolidinediones as studies of a total of 2,090 patients, show- an average 20% increase in diabetes preva- insulin sensitizers. ing placebo-corrected falls in HbA1c of lence when fasting and 2-h glucose were Ide et al. (abstract 50) treated insulin- 1.1–1.8% and in fasting glucose of 29–67 used together in an either/or fashion rather resistant ZDF rats with KRP-297, a TZD mg/dl. Cranmer et al. (abstract 856) used than using either test alone for diabetes that binds to both PPAR␣ and PPAR␥, pooled data from three multicenter studies classification. Shaw et al. (abstract 156) increasing oxidation of palmitic acid to nor- of a total of 1,985 patients. The data showed reported on the 5- to 12-year follow-up of mal levels in liver and skeletal muscle. Oxi- that among patients with BMI Ն27 kg/m2, 595 people with previously diagnosed dia- dation of short-chain fatty acids was not rosiglitazone (4 and 8 mg/day) led to falls in betes and 799 with newly diagnosed dia- impaired and showed no change with treat- fasting glucose of 36 and 52 mg/dl, while betes, of whom 243 had normal fasting ment. Because long-chain, but not short- among patients with BMI Ͻ27 the falls were glucose with 2-h glucose Ն200 mg/dl.
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