roxisaes er: 07.02.95 PU04442ENGO oureuszive. Diabetes Research od Clinical Practice, 1(1991)S19-882 f 1901 Fleer Science Publishers B.V_0168:227/91/S03.50 879 DIABET 00556 Evaluation of the efficacy and safety of Diamicron® in non-insulin-dependent diabetic patients C. Kilo, J. Dudley and B. Kalb Kilo Diabetes and Vascular Disease Research Fond 1, Loui, Misour, US.A Summary ‘The efficacy and safety of gliclazide (Diamicron®) were studied in 29 NIDDM patients (19 men and 10 women aged 25-68 years) who failed to improve with diet or with diet plus a sulfonylurea. All patients were overweight and had fasting blood glucose levels consistently above 150 mg/dl (8.24 mmoi/I). After ‘withdrawal of oral hypogiycemics where applicable, they received 40 mg Diamicron® three times daily ‘with meals, The dose was increased by 40-80 mg/day until optimum control was obtained or up 10 @ ‘maximum of 320 mg/day. Treatment lasted for 12 months, At the end of this period the mean fasting blood glucose level had fallen by 35% from 238 to 154 mg/dl and the mean 2-n postprandial Llovd glucose level had fallen by 28% [tom 237.7 to 195 mg/dl. The mean glycosylated hemoglobin level also fell by 30% from 10.10 to 7.02%, ie. within the normal range. In addition, there was a 199% fall in Itiglyceride and a 10% fallin cholestero! levels, with no change in body weight. No changes were observed. for serum insulin, C-peptide and glucagon levels, thyroid function tests, blood counts, liver and kidney function tests, uric acid, electrolytes, blood pressure or heart rate, No clinical or ECG abnormalities ‘were observed in patients with or without cardiovascular disease. There were two presumptive hypoglycemic reactions, but these did not require treatment. Adverse effects were reported by 22 patients, including dizziness and light-headedness, diarrhea, nausea, palpitations and pruritus, but none required modification ‘of Diamieron® therapy. The results therefore show that Diamicron® is safe, effective and weil tolerated in suitably selected NIDDM patients. {Introduction perglycemia, involve the conversion of glucose to sorbitol fructose, which results in complications Diabetes mellitus is a chronic metabolic disease caused by an absolute or relative lack of insulin which results in hyperglycemia and abnormalities in carbohydrate, protein and fat metabolism. Polyol pathway metabolic changes, a consequence of hy- Cormapondence to: C. Kil, Kil Diabetes and Vascular Ditese Research Foundation, St Lous, MO,US.A, which involve the skin and all the organ systems contained within it. This includes the microvaseu- lar, macrovascular and neurological systems. Di- abetic patients are categorized on the basis of insulin dependence, The two main groups of di- abetic patients are: Insulin-dependent diabetes mellitus (IDDM) pa~ tients, who have an absolute deficiency (insul ‘openia) in the insulinogenic capacity of the pan-S80 creatic 6 cells. These individuals have antibodies against their own fcels years before hyperglycemia ‘occurs, IDDM patients are usually non-obese. ketosis-prone individuals in whom the onset of diabetes almost always occurs at an carly age {usually under 30 years). Neither diet nor oral bbypoglycemics satisfactorily control hyperglycemia or its acute or chronic complications. Multiple daily injections of exogenous insulin are the mainstay of treatment, coupled with an appropriate diabetic real plan designed to achieve normal growth and development and an exercise program. The goal of diabetes therapy is to normalize blood glucose levels before each meal and bedtime resulting in normal glycosylated hemoglobin levels, The control ‘of eardiovascular risk factors, which include hyper- tension, cholesterol, triglycerides, cigarette smok- ing and obesity, is also our goal. Non-insulin-dependent diabetes mellitus, (NIDDM) patients have below normal, normal or above normal basal insulin levels. Approximate- ly 80-85% of all NIDDM patients are obese. There {s also a strong hereditary component to the de velopment of NIDDM. There is a defect in B-cell insulin secretion, insulin resistance and increased hepatic glucose production. Onset of symptoms and diagnosis of NIDDM almost always occur in adult hood, The goal of therapy must be the normal zation of blood glucose and control of cardiovas- cular tisk factors [1,2]. Diabetic meal plans designed to achieve desirable body weight and exercise programs are the cornerstones of therapy ‘When fasting and postprandial blood glucose levels remain elevated, an oral hypoglycemic agent ‘and/or insulin in multiple injections must be pre~ scribed. Study design ‘The present study was designed to determine the efficacy and safety of Diamicron® (gliclazide) in NIDDM patients who failed either on dietary therapy or on dietary plus sulfonylurea therapy. Emicacy ‘The efficacy of Diamicron® was evaluated on the basis of reduction in fasting and postprandial blood lucose levels and measurement of glycosylated hemoglobin levels. Patient exclusions Patients were excluded for the following reasons: pregnaney or the potential to became pregnant history of severe hepatic or renal disease; antici- pation of major surgery: history of allergy or hypersensitivity to sulla drugs or sulfonylurea ‘agents; taking drugs known to affect glucose me- tabolism; history of poor compliance to drug, diet therapy or office visits Safety The safety of Diamicron® therapy was assessed by evaluating clinical and laboratory data. Patient selection ‘Two fasting blood glucose valnes of greater than 150 mg/dl (8.24 mmol/!) taken one week apart while on a diabetic diet for one month without prior sulfonylurea therapy and an exercise program were required for the patient to enter the study. Ifthe individual was on an oral hypoglycemic agent, it was discontinued for two weeks and the patient ‘was continued on his/her diabetic meal plan and ‘exercise program. Afler two weeks, two successive fasting blood glucose values were obtained one ‘week apart, Ifthe blood glucose values were equal to of greater than 150 mg/dl or 8.24 mmol/I, they were eligible for enrollment into the study. The patient signed an informed consent form after meeting the criteria for acceptance into the study.Demography Twenty-nine patients were studied, Sex: 19 males and 10 females; age: mean 56.1 years, range 25- 68; overweight (9): mean 42.8, range 4-95; duration of diabetes: years, 8.03, range 9 months ~ 26 years. ‘Treatment prior to Diamicron® One newly diagnosed; two dietary therapy; 26 prior sulfonylurea therapy including tolbutamide (Ori- nase®), tolazamide (Tolinase®), chlorpropamide (DiabineseS), glipizide (Glucotrol®), CCinical and laboratory studies At entrance into the study, patient histories were taken and all patients had physical examinations; blood pressure and body weight were measured and urinalysis, electrocardiogram, and the following blood tests were done: complete blood count, fasting blood glucose, 2-h postprandial blood glu- cose, fasting insulin, C-peptide, glucagon, glyco sylated hemoglobin, lipid profile, thyroid panel, blood urea nitrogen, creatinine, electrolytes, liver function test and urie acid. At monthly intervals, patients were evaluated for body weight, blood pressure, urinalysis, fasting and postprandial blood glucose. Diet, medication com- pliance and adverse events were evaluated and recorded. Fasting glycosylated hemoglobin and lipid profile was repeated every three months. Fasting insulin and glucagon levels were repeated every six months. Fasting C-peptide and all baseline studies were repeated at twelve months. ‘Study dropouts Patients were dropped from the study if they exhib- ited: drug allergy; significant hypoglycemic reac- tions or hyperglycemia; ketoacidosis; major illness; severe drug related symptoms; poor compliance. ‘There were no dropouts because of the above sat teasons. Two patients discontinued the study for the following reasons: one patient moved out of the area and another could not keep his appoint- ments because of changes in his working hours. Medication Diamicron® was prescribed at a dose of 40 mg. per day with breakfast and lunch or dinner. The dose was increased by 40 to 80 mg per day until ‘optimal control was achieved. The maximal dose ‘was 320 mg per day. The daily dose range was 80 to 320 mg per day. Results The baseline indicators of hyperglycemia were as follows: fasting blood glucose (238.0 14 me/al), 2h postrandial blood slvcose (297.7£20°5 mw A lycoeylated hemoglobin (10.10-0.44%, nor imal 3.5 to 8.5%). Efficacy of Diamicron® therapy ‘Twelve months of Diamicron® therapy resulted in 4 reduction in mean fasting blood glucose to 154 mg/dl ~ a 38% reduction in mean fasting blood glucose (Fig. 1), The mean 2-h postprandial blood (Boos sxucose] ais oo porn Fig 1. Significant fal in fasting (-34%) and postprandial blood lucose(-29%) were achieved throughout the study (PC 0.01),82 ~paees ‘ Fig. 2. Progese fallin HOA, to 2.0% at 12 montis (coo. [senonuros] mold! *ROLYCERDES me = ' zo. ! im. mo Fig 5. Significant rations of serum tglyoerides (P<0.01) and chofsterol (P08) occured with no changes in lipoprotein profit glucose at twelve months was 195 mg/dl, a 28% reduction in mean 2-h postprandial blood glucose (Fig. 1). The mean glycosylated hemoglobin at twelve months was 7.02%, a 30% reduction in lyeosylated hemoglobin level (normal range 3.5 to 8.5%: Fig, 2). There was @ 19% reduction in triglyceride and 10% reduction in cholesterol levels (Eig. 3). There was no significant change in body weight, This observation strongly attributes the reduction in blood glucose, glycosylated hemogio- bin, triglyceride and cholesterol levels to Diam cron® therapy, There were no clinical or electro: cardiogram abnormalities observed in patients with of without cardiovascular disease in this one year study. No changes were observed in diabetic mi roangioputhy ut seurupathy. There were no nificant changes in serum insulin, C-peptide and glucagon levels, thyroid panel, complete blood count, liver funetion tests, urie acid, renal panel or electrolytes. The systolic, diastolic blood pres- ‘sure and heart rate per minute showed no significant ‘changes. Two hypoglycemic reactions were suspect- ed but not confirmed by a blood glucose measu- rement. Treatment was sot required. The Diami- ccron® dose was not reduced. [Adverse symptoms were reported in 22 patients. ‘The symptoms possibly related to Diamicron® occurred in the following systems: Central nervous system (6); lightheaded, dizzy; gastrointestinal (8) diarrhea or nausea: cardiovascular (1): palpitations musculoskeletal (0); skin (3) itching. Most patients were polymedicated. There was no change in Dia~ micron® therapy, Conclusion “The significant lowering of fasting (35%) and post prandial blood glucose (28%) glycosylated hemo- slobin levels (304) to normal range and improve ‘ment in triglycerides (19%) and cholesterol (10%) ‘are especially important since hyperglycemia and hyperlipidemia are risk factors for microvascular, macrovascular disease and neurological defects. Diamicron® therapy is safe, effective and well tol- crated in properly selected NIDDM patients. References 1 Rilo, C, (1985) Value of glucose contol in preventing omplcations of diabetes Am. J. Med. 9, 33-7 2 Willamson, JR. and Kilo, C. (1980) New evidence that controling the hyperaivemia of diabetes ssmportant. Med. Times 15, §3-92