Behavioral changes: diet and physical exercise. This is the first thing we do when diagnosed with type 2 diabetes. This is a good question to remember that before any drug, we must insist on changing habits. Then we would prescribe Metformin.

Behavioral changes: diet and physical exercise. This is the first thing we do when diagnosed with type 2 diabetes. This is a good question to remember that before any drug, we must insist on changing habits. [HIDDEN]

A 54-year-old man who goes for a check-up at his company. A body mass index of 32.8 kg/m2 and fasting blood glucose of 138 mg/l were detected. One month later, glycemia 13 mg/dl. Which therapeutic recommendation would you make first?

Behavioral changes. Diet and physical exercise.

Take acarbose at night, before going to bed.

[Sequential treatment with insulin glargine and metformin, and exenatide in a patient with newly diagnosed type-2 diabetes].

HISTORY AND ADMISSIONS FINDINGS: A 54-year-old man was admitted to hospital for treatment of a newly diagnosed type 2 diabetes. He had polydipsia and polyuria and had lost 11 kg in weight over four weeks. Further diagnoses were visceral obesity and arterial hypertension. Laboratory tests revealed highly elevated blood glucose parameters (HbA1c 14,9 %, fasting glucose 280 mg/dl, maximal postprandial glucose 430 mg/dl and 320 mg/dl before the meal) and triglyceride (2219 mg/dl). The patient was initially treated with a combination of insulin glargine and metformin. After a few days exenatide was added, as the patient wanted to be able to go without insulin. He was given a structured diabetes education and motivated to have five to six hours' of physical activity and a low glycemic diet. After a few days normal glucose levels had been achieved. After one month the insulin treatment was discontinued. The continuing treatment with metformin, 1000 mg twice daily, and exenatide, 5 mg twice daily, prolonged remission of beta-cell dysfunction and maintained normal blood glucose levels for seven months. After reduction of the metformin dosage (500 mg twice daily) and discontinuance of exenatide as well as a reduction of his physical activity (because of joint pain) for six months, the glucose control worsened. When exenatide was administered again, good control of postprandial blood glucose, but not of fasting glucose was achieved. Initial combination treatment with insulin glargine, metformin and exenatide may be beneficial in a subgroup of patients with newly diagnosed type 2 diabetes, markedly elevated blood glucose and free fatty acid levels (glucolipotoxicity). This should be further investigated in randomized controlled trials.

[Therapeutic behavior to follow in the following clinical case: treatment of type 2 diabetes].

A 62-year old woman with obesity, high blood pressure and type 2 diabetes mellitus (DM2) was referred to a Vascular Risk Unit of the Internal Medicine Department due to elevated HbA1C (8.1%) in spite of having taken metformin (850 mg/12h) and glipizide (10 mg/12 h) regularly. She tries to exercise daily (walking 30 min) and has lost weight (from 5 to 12 kg) several times, but always regains what she has lost. Furthermore, she monitors her glucose levels in fasting every two weeks and generally has between 120 and 160 mg/dL. Her high blood pressure is being treated with enalapril/HCTZ and she also takes aspirin 100mg/day and simvastatin 20 mg/day. It is seen in her family background that one brother died suddenly at 50 years of age. Her physical examination shows a BMI of 32.4 Kg/m(2), and she has no edemas in the lower limbs. Her BP is 154/82 mmHg and creatinine 0.9 mg/dL. She has no microalbuminuria and her liver function is normal. What treatment do you think would be the more appropriate? 1 - Add glitazones. 2 - Add incretin mimetics (GLP 1/ DPP-4). 3 - Slow acting insulin.

Short-term treatment of glucose intolerance in middle-aged subjects by diet, exercise and sulfonylurea.

In a screening survey of women and men 47-54 years old for detection of glucose intolerance (GI), with 75 g oral glucose tolerance tests (OGTT), 25 subjects with GI were randomly selected for a therapeutic trial for normalization of the GI. A control group of 18 GI subjects was chosen randomly from the same health survey and given no treatment for 5-10 months; no significant changes in OGTT variables, body mass index, blood pressure or blood lipids were found in this group during follow-up. The treatment group was given advice concerning a low-sucrose, low-fat, high-fiber and energy-restricted (when overweight) diet and also concerning exercise - single-handed (16 subjects) or in an exercise group (9 subjects). The GI improved in the 25 treated subjects after 6 months of this therapy. Thus the total area under the glucose curve and the 1-h and the 2-h glucose values had decreased, the mean 2-h glucose value was restored to normal (less than 7.0 mmol X l-1) and 48% of the treated subjects had a normal 2-h glucose value. Body mass index, systolic blood pressure, serum cholesterol and serum triglycerides were also reduced at the follow-up. The 6-month result was similar in the subgroup of nine GI subjects who followed the dietary advice and exercised in a group for at least one hour per week during at least three months. Physical working capacity was increased, although non-significantly. Glipizide, 1.25 mg daily, was added at breakfast to ten GI-subjects who still had pathological 2-h glucose values after 6 months of dietary and exercise treatment. After a further 6 months of treatment of these 10 subjects, the total glucose area and the 2-h glucose value were reduced, while the mean 2-h glucose value had not required the normal level. Body mass index was unchanged. Another four subjects in this subgroup now showed a normal 2-h glucose value. In conclusion, the 2-h glucose value was restored to normal in totally 64% of all treated GI subjects after short-term treatment with a diet, exercise and, in some cases, added glipizide.

Acarbose vs. bedtime NPH insulin in the treatment of secondary failures to sulphonylurea-metformin therapy in type 2 diabetes mellitus.

To evaluate the efficacy of acarbose in the treatment of secondary failures to sulphonylurea-metformin therapy, its comparison against bedtime NPH insulin, and to measure the changes in postprandial metabolism resulting from both treatments. One hundred type 2 diabetic patients in a secondary failure were included. The study begun with a run-in diet period of 6 weeks, in which an isocaloric diet was prescribed. Only subjects who continued hyperglycaemic were randomly assigned to placebo and acarbose (n = 17) or bedtime NPH insulin (n = 12). Acarbose (300 mg/day) or placebo were administered using a randomized, double blind, crossover design. Treatment periods of 3 months were separated by a 3-week washout period. Insulin was administered during 3 months. At the beginning and the end of each treatment period, an i.v. glucose tolerance test and a meal test were performed. Safety tests were done every 4 weeks. Acarbose resulted in a small but significant improvement in fasting plasma glucose (13.5 +/- 2.4 vs. 11.3 +/- 3.9 mmol/l, p = 0.05), HbA1c (11.1 +/- 3.4 vs. 10.3 +/- 2.5%, P = 0.3) and in a decreased plasma glucose during the meal test. Bedtime insulin significantly decreased fasting plasma glucose (13.1 +/- 2.9 vs. 8.2 +/- 2.3 mmol/l, p < 0.01), HbA1c (11.7 +/- 2.9 vs. 9.4 +/- 2.7%, p < 0.01) and plasma cholesterol. No change in insulin secretion resulted from insulin and acarbose treatment. Acarbose decreases blood glucose in secondary failure to sulphonylurea-metformin therapy; however, the decrease is not enough to reach the desired metabolic control. Bedtime NPH insulin is, by far, a more effective alternative.

Improvement of both fasting and postprandial glycemic control by the two-step addition of miglitol and mitiglinide to basal insulin therapy: a pilot study.

Combination therapy consisting of basal insulin and oral hypoglycemic agents (OHAs) is effective for the treatment of type 2 diabetes (T2DM) that cannot be adequately controlled using OHAs alone. Though basal insulin with metformin or sulfonylurea is an effective therapy, it cannot reduce postprandial glycemia without the risk of hypoglycemia. We examined a two-step regimen consisting of the addition of postprandial hypoglycemic agents (an alpha-glucosidase inhibitor and a glinide) in patients whose T2DM was poorly controlled using basal insulin therapy. Inpatients between the ages of 30-79 years who had T2DM and an HbA1c level of more than 7.0% were recruited. The patients were treated with once-daily insulin glargine with or without metformin, depending on the patient's age and renal function. Insulin glargine was titrated to achieve a target fasting glucose level of 70-130 mg/dL as a first step (STEP0). If the 2-hour postprandial glucose (PBG) level was higher than the target of 180 mg/dL, miglitol treatment (150 mg/day) was initiated, with dose adjustments (75-225 mg) allowed depending on abdominal symptoms and the PBG (STEP1). If the PBG of the patients remained higher than the target after 3 days of treatment, mitiglinide (30 mg/day, titrated up to 60 mg) was added (STEP2). We then evaluated the proportion of patients who achieved the target PBG before and after the two-step regimen. Continuous Glucose Monitoring (CGM) was performed throughout the two-step protocol in most of the patients. Of the 16 patients who were recruited (median age, 67.0 [58.0-71.0] years; body mass index, 25.0 [22.0-27.9] kg/m(2); HbA1c level at admission, 9.1% [8.35-10.4%]), 1 patient (6.25%) achieved the target PBG at STEP 0 and 14 patients (87.5%) had achieved the target PBG at the end of the treatment protocol (P = 0.002). CGM showed a significant decrease in the glucose level at each step of the protocol. The standard deviations in the CGM glucose levels for 24 hours, MAGE, and M-value also improved. The two-step addition of postprandial hypoglycemic agents to basal insulin therapy is potentially effective and safe for decreasing both the fasting and postprandial glucose levels.

Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial.

Compared with other insulin regimens, combination therapy with oral hypoglycemic agents and bedtime insulin produces similar improvement in glycemic control but induces less weight gain. To determine whether bedtime insulin regimens differ with respect to their effects on weight gain in patients with type 2 diabetes. Randomized, controlled trial. Four outpatient clinics at central hospitals. 96 patients (mean age, 58 +/- 1 years; mean body mass index, 29 +/- 1 kg/m2) whose type 2 diabetes was poorly controlled with sulfonylurea therapy (mean glycosylated hemoglobin value, 9.9% +/- 0.2%; mean fasting plasma glucose level, 11.9 +/- 0.3 mmol/L [214 +/- 5 mg/dL]). Random assignment to 1 year of treatment with bedtime intermediate-acting insulin plus glyburide (10.5 mg) and placebo, metformin (2 g) and placebo, glyburide and metformin, or a second injection of intermediate-acting insulin in the morning. Patients were taught to adjust the bedtime insulin dose on the basis of fasting glucose measurements. Body weight, biochemical and symptomatic hypoglycemias, and indices of glycemic control. At 1 year, body weight remained unchanged in patients receiving bedtime insulin plus metformin (mean change, 0.9 +/- 1.2 kg; P < 0.001 compared with all other groups) but increased by 3.9 +/- 0.7 kg, 3.6 +/- 1.2 kg, and 4.6 +/- 1.0 kg in patients receiving bedtime insulin plus glyburide, those receiving bedtime insulin plus both oral drugs, and those receiving bedtime and morning insulin, respectively. The greatest decrease in the glycosylated hemoglobin value was observed in the bedtime insulin and metformin group (from 9.7% +/- 0.4% to 7.2% +/- 0.2% [difference, -2.5 +/- 0.4 percentage points] at 1 year; P < 0.001 compared with 0 months and P < 0.05 compared with other groups). This group also had significantly fewer symptomatic and biochemical cases of hypoglycemia (P < 0.05) than the other groups. Combination therapy with bedtime insulin plus metformin prevents weight gain. This regimen also seems superior to other bedtime insulin regimens with respect to improvement in glycemic control and frequency of hypoglycemia.

Prevention of diabetes in family medicine.

none declared. The incidence of diabetes type 2 (diabetes mellitus type 2 - DM 2) is rapidly increasing worldwide. Physical inactivity and obesity are the major determinants of the disease. Primary prevention of DM 2 entails health monitoring of people at risk category. People with impaired glycemic control are at high risk for development of DM 2 and enter the intensive supervision program for primary and secondary prevention. To evaluate the impact of metformin and lifestyle modification on glycemia and obesity in patients with prediabetes. The study was conducted on three groups of 20 patients each (total of 60 patients) aged from 45 to 80, with an abnormal glycoregulation and prediabetes. The study did not include patients who already met the diagnostic criteria for the diagnosis of diabetes. During the study period of 6 months, one group was extensively educated on changing lifestyle (healthy nutrition and increased physical activity), the second group was treated with 500 mg metformin twice a day, while the control group was advised about diet and physical activities but different from the first two groups. At beginning of the study, all patients were measured initial levels of blood glucose, HbA1C, BMI (Body Mass Index), body weight and height and waist size. Also the same measurements were taken at the end of the conducted research, 6 months later. For the assessment of diabetes control was conducted fasting plasma glucose (FPG) test and 2 hours after a glucose load, and HbA1C. At the beginning of the study the average HbA1C (%) values in three different groups according to the type of intervention (lifestyle changes, metformin, control group) were as follows: (6.4 ± 0.5 mmol / l), (6.5 ± 1.2 mmol / l), (6.7 ± 0.5 mmol / l). At the end of the research, the average HbA1C values were: 6.2 ± 0.3 mmol / l, 6.33 ± 0.5 mmol / l and 6.7 ± 1.4 mmol / l. In the group of patients who received intensive training on changing lifestyle or group that was treated with metformin, the average reduction in blood glucose and HbA1C remained within the reference range and there were no criteria for the diagnosis of diabetes. Unlike the control group, a group that was well educated on changing habits decreased average body weight by 4.25 kg, BMI by 1.3 and waist size by 2.5 cm. Metformin therapy led to a reduction in the average weight of 3.83 kg, BMI of 1.33 and 3.27 for waist size. Changing lifestyle (healthy diet and increased physical activity) has led to a reduction in total body weight in 60% of patients, BMI in 65% of patients, whereas metformin therapy led to a reduction of the total body weight in 50%, BMI in 45% of patients. In the control group, the overall reduction in body weight was observed in 25%, and BMI in 15% of patients. Modification of lifestyle, such as diet and increased physical activity or use of metformin may improve glycemic regulation, reduce obesity and prevent or delay the onset of developing DM 2.

Diet in diabetes

Timing of meals For people with diabetes, healthy eating is not simply a matter of what one eats, but also when one eats. For insulin dependent diabetics, when they eat depends on their blood sugar level and the type of insulin they take (i.e.: long-, medium- or quick-acting insulin). If patients check their blood glucose at bedtime and find that it is low, for example below 6 millimoles per liter (108 mg/dL), it is advisable that they take some long-acting carbohydrate before retiring to bed to prevent night-time hypoglycemia. Night sweats, headaches, restless sleep, and nightmares can be a sign of nocturnal hypoglycemia, and patients should consult their doctor for adjustments to their insulin routine if they find that this is the case. Another possible sign of nocturnal hypoglycemia is morning hyperglycemia, which actually occurs in response to blood sugar getting too low at night. This is called the Somogyi effect.

[Short-term Glucose Lowering Effects of Sodium-glucose Cotransporter 2 Inhibitors Confirmed by Flash Glucose Monitoring in Two Outpatients with Type 1 Diabetes].

Case 1 was a 41-year-old man with type 1 diabetes. He presented with poor glycemic control [hemoglobin A1c (HbA1c) of 8-9%] despite treatment with more than 20 units/day of insulin and 150 mg of miglitol. Before administration of sodium glucose cotransporter 2 (SGLT2) inhibitor, hyperglycemia was noted mainly at night by Flash Glucose Monitoring (FGM). Administration of ipragliflozin at 50 mg improved the hyperglycemia mainly at night (mean blood glucose, before administration: 205 mg/dl, day 6 of treatment: 119 mg/dl). Two months later, the HbA1c improved to 7.2% without hypoglycemia or ketosis. Case 2 was a 46-year-old woman with type 1 diabetes. She was morbidly obese and presented with poor glycemic control (HbA1c: 9-11%) although she was being treated with more than 50 units/day of insulin and 2,250 mg of metformin. Before administration of SGLT2 inhibitor, hyperglycemia was noted to be mainly nocturnal by FGM. Administration of dapagliflozin at 5 mg improved the hyperglycemia mainly at night on day 2 with improvement in the mean blood glucose level from 188 mg/dl before administration to 128 mg/dl on day 5. Four months later, the HbA1c improved to 8.0% without hypoglycemia and ketosis, and her body weight decreased from 92.1 to 89.8 kg. The hypoglycemic effect of SGLT2 inhibitors is independent of insulin. These agents also have various other effects, including weight loss, improvement of blood pressure and lipid metabolism. Here we report the short-term glucose lowering effects of two SGLT2 inhibitors, as confirmed by FGM, in two outpatients with type 1 diabetes.

Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study.

To assess and compare the therapeutic efficacy and safety of metformin (M) and sulfonylurea (glyburide, G), alone and in various combinations, in patients with non-insulin-dependent diabetes mellitus (NIDDM). Of 165 patients (fasting blood glucose [FBG] > or = 6.7 mmol/l) initially treated with diet alone, 144 (FBG still > or = 6.7 mmol/l) were randomized to double-blind, double-dummy controlled treatment with M, G, or primary combination therapy (MG). The dose was titrated, with FBG < 6.7 mmol/l as target, using, at most, six dose levels. The first three dose levels comprised increasing single-drug therapy (M or G) or primary combination at increasing but low dosage (MGL), and the second three levels were composed of various high-dose combinations, i.e., add-on therapy (M/G or G/M) and primary combination escalated to high dosage (MGH). Medication was maintained for 6 months after completed dose titration. The FBG target was achieved in 9% of patients after diet alone. Single-drug therapy was insufficient in 36% and MGL in 25% (NS) of the randomized patients. There was further improvement in glucose control by the high-dose combinations. Mean FBG +/- SE was reduced (P = 0.001) from 9.1 +/- 0.4 to 7.0 +/- 0.2 mmol/l in those maintained on single-drug treatment or low-dose primary combination. Those treated with different high-dose combinations had a large mean FBG reduction, from 13.3 +/- 0.8 to 7.8 +/- 0.6 mmol/l. HbA1c levels showed corresponding reductions, and glycemic levels rose after drug discontinuation. Fasting C-peptide rose during treatment with G and MGL but not with M, while fasting insulin was not significantly changed. Meal-stimulated C-peptide and insulin levels were unchanged by M but increased by G and, to a lesser extent, by MGL. There were no significant insulin or C-peptide differences between the different high-dose combinations (M/G, G/M, and MGH). Body weight did not change following treatment with M or combination but increased by 2.8 +/- 0.7 kg following G alone. Blood pressure was unchanged. Overall effects on plasma lipids were small, with no significant differences between groups. Drug safety was satisfactory, even if the reporting of (usually modest) adverse events was high; the profile, but not the frequency, differed between groups. Dose-effect titrated treatment with either metformin or glyburide promotes equal degrees of glycemic control. The former, but not the latter, is able to achieve this control without increasing body weight or hyperinsulinemia. Near-normal glycemia can be obtained by a combination of metformin and sulfonylurea, even in advanced NIDDM.

Type 1 diabetes

The mainstay of type 1 diabetes treatment is the regular injection of insulin to manage hyperglycemia. Injections of insulin – via subcutaneous injection using either a syringe or an insulin pump – are necessary multiple times per day, adjusting dosages to account for food intake, blood glucose levels and physical activity. The goal of treatment is to maintain blood sugar in a normal range – 80–130 mg/dL before a meal; <180 mg/dL after – as often as possible. To achieve this, people with diabetes often monitor their blood glucose levels at home. Around 83% of type 1 diabetics monitor their blood glucose by capillary blood testing – pricking the finger to draw a drop of blood, and determining blood glucose with a glucose meter. The American Diabetes Association recommends testing blood glucose around 6–10 times per day: before each meal, before exercise, at bedtime, occasionally after a meal, and any time someone feels the symptoms of hypoglycemia. Around 17% of people with type 1

Richard K. Bernstein

Diabetes treatment Bernstein's diet is extremely low-carbohydrate in that it completely eliminates all simple sugars and starches, and restricts other carbohydrates to 30 grams a day spread out over 3 small meals (6g at breakfast, 12g at lunch and 12g at dinner), with gaps of around 4 hours between meals to enable more accurate postprandial blood glucose tracking. This diet is combined with exercise with an emphasis on resistance-based muscle-building exercise, and supported by medication if needed. For insulin-dependent diabetics, he advocates taking insulin as small doses before each meal, to exactly cover that meal. The goal of the program is to simulate the blood sugars of non-diabetics, which according to Bernstein are close to 83 mg/dl or 4.6 mmol/l most of the time. If this goal can be reached and maintained, further complications due to high blood sugar would stop, though earlier damage cannot be reversed. Diabetes is perfectly controlled, in effect "cured". (Bernstein 2011)

NIDDM: new once-daily intervention for type 2 diabetes mellitus: Diaprel MR.

Pharmacological treatment of hyperglycemia should address to both abnormalities in T2DM treatment, that is reduction of insulin resistance and restoration of normal insulin secretion. Gliclazide is a sulfonylurea compound oral hypoglycemic drug that has a unique feature of restoring the first-phase insulin secretion, which is lost in T2DM being one of the early features of disease. Laboratoires Servier conducted in Romania a an open non randomized surveillance on the efficacy and safety of Diaprel MR in type 2 diabetic patients. 199 patients in 14 treatment centers were enrolled. Eligibility criteria were as it follows: men and women with diabetes, previously on diet alone and not treated with other OAD, over 35 years old with FPG (mg/dl) at enrollment between 126 and 180. The clinical trial lasted for 16 weeks. During this period the doctors examined the patients 6 times. First visits were at a 2 weeks interval and the last two visits at a 4 weeks interval. At each visit the doctor renewed the prescription for the subsequent period according to the following protocol: the starting dose was 30 mg Diaprel MR/day, if the FPG (mg/dl) was over 140 (at the next visit) the dosage was increased with 30 mg Diaprel MR/day, if the FPG (mg/dl) was under 140 the dosage remained the same as the previous dosage. The maximum dosage was 120 mg Diaprel MR/day. The following parameters were measured on first and last (seventh) visit: blood pressure (systolic and diastolic), heart rate (bpm), body mass index-BMI (kg/m2), fasting plasma glucose FPG (mg/dl and mmol/l), glycated hemoglobin HbA1c (%) and Hb-Hct (mg/dl-%), creatinine (mg/dl), SGPT (UI/I), cholesterol (mg/dl) and triglycerides (mg/dl). Blood pressure (systolic and diastolic), heart rate, BMI and FPG were measured from the second to sixth visit also. On each visit there was registered other data such as: associated illnesses, concomitant medication and adverse events. Primary end points. The average values of end points HbA1c (%) and PFG (mg/dl) registered a significant decrease during the 16 weeks of medication, from the enrollment moment (S0) to the last week (S16). The decrease was significant on the total sample of the main analysis group but also on subsamples of age, gender and BMI. HbA1c (%) average values decreased in the main analysis group (S16 compared to S0): with 22% on the total sample (from 7.7 to 6.0); p < 0.05. FPG (mg/dl) average values decreased in the main analysis group (S16 compared to S0): with 21% on the total sample (from 159 to 126); p < 0.05. Secondary end points. There were no significant changes registered in the average level of cholesterol and triglycerides, BMI, diastolic blood pressure, heart rate, creatinine, SGPT. A significant decline of the average systolic blood pressure was registered. Diaprel MR can be used safely in diabetic patients newly diagnosed, uncontrolled on diet or other oral antidiabetic drugs, overweight, safely in those with cardio-vascular disease, or in patients with creatinine clearance 50-80 ml/min.

Diabetes and pregnancy

Cut down sweets, eats three small meals and one to three snacks a day, maintain proper mealtimes, and include balanced fiber intake in the form of fruits, vegetables and whole-grains. Increased physical activity - walking, swimming/aquaerobics, etc. Monitor blood sugar level frequently, doctors may ask to check the blood glucose more often than usual. The blood sugar level should be below 95 mg/dl (5.3 mmol/l) on awakening, below 140 mg/dl (7.8 mmol/l) one hour after a meal and below 120 mg/dl (6.7 mmol/l) two hours after a meal. Each time when checking the blood sugar level, keep a proper record of the results and present to the health care team for evaluation and modification of the treatment. If blood sugar levels are above targets, a perinatal diabetes management team may suggest ways to achieve targets. Many may need extra insulin during pregnancy to reach their blood sugar target. Insulin is not harmful for the baby.

Unrecognized hypo- and hyperglycemia in well-controlled patients with type 2 diabetes mellitus: the results of continuous glucose monitoring.

The aim of this study was to determine the prevalence and extent of glycemic excursions (hypo- and hyperglycemic) in elderly patients with well-controlled type 2 diabetes using a Continuous Glucose Monitor System (CGMS) (Medtronic MiniMed). Elderly patients (>65 years old) with type 2 diabetes were recruited if their glycosylated hemoglobin (HbA1c) was <7.5% and if their oral hypoglycemic therapy included a sulfonylurea. Patients were asked to undergo two consecutive 72-h periods of continuous glucose monitoring at baseline and then again at 1 month (total 288 h). Patients were asked to record four self-monitored capillary blood glucose levels each day for calibration of the monitor and also to record meal times, exercise, and symptoms of hypoglycemia. The number of hyperglycemic (>144 mg/dL), hypoglycemic (<50 mg/dL), and borderline-hypoglycemic (50-65 mg/dL) events were determined (an event was defined as a glucose value that persisted for at least 15 min with or without symptoms). Twenty-five patients (21 men, four women) 73.9 +/- 4.4 years old with an HbA1c of 6.2 +/- 0.8% were each monitored for an average of 187.57 h. The mean glucose values were: fasting, 139 +/- 40 mg/dL; 2 h post-breakfast, 167 +/- 58 mg/dL; 2 h post-lunch, 157 +/- 53 mg/dL; and 2 h post-dinner, 149 +/- 49 mg/dL. Twenty patients (80%) experienced a total of 103 hypoglycemic events, and 14 of these patients experienced 54 events where the glucose levels were </=40 mg/dL. Twenty-four patients (96%) experienced borderline-hypoglycemia (n = 229 events). Patients experienced a mean of 0.62 +/- 0.72 episodes of hypoglycemia (interstitial glucose <50 mg/dL) per day (four to five episodes overall), 0.35 +/- 0.6 episodes per day where the interstitial glucose was </=40 mg/dL (two to three episodes overall), and 1.37 +/- 1.22 episodes of borderline-hypoglycemia (nine to 10 episodes overall). Each episode of hypoglycemia persisted for 78 +/- 73 min, and borderline-hypoglycemia for 45 +/- 11 min. Patients were hypoglycemic 3.3% of the time and borderline-hypoglycemic 3.7% of the time. No episode of hypoglycemia was recorded by any patient in his or her daily diary. High postprandial glucose values (>144 mg/dL 2 h postprandial) were recorded after 57% of all meals (breakfast 60%, lunch 57.5%, dinner 55.2%). The CGMS was generally well tolerated, but 52% of patients could not be studied for the full 12 days of monitoring. Thus hypoglycemia and excessive postprandial glycemic excursions are common in well-controlled patients with type 2 diabetes treated with a sulfonylurea with or without metformin. The CGMS is a useful research and clinical tool to assess glycemia in patients with type 2 diabetes but is not tolerated by all subjects.

Pharmacology_Katzung

A 66-year-old obese Caucasian man presented to an academic Diabetes Center for advice regarding his diabetes treatment. His diabetes was diagnosed 10 years previously on routine testing. He was initially given metformin but when his control deteriorated, the metformin was stopped and insulin treatment initiated. The patient was taking 50 units of insulin glargine and an average of 25 units of insulin aspartate pre-meals. He had never seen a diabetes educator or a dietitian. He was checking his glucose levels 4 times a day. He was smoking half a pack of cigarettes a day. On examination, his weight was 132 kg (BMI 39.5); blood pressure 145/71; and signs of mild peripheral neuropathy were present. Laboratory tests noted an HbA1c value of 8.1%, urine albumin 3007 mg/g creatinine (normal <30), serum creatinine 0.86 mg/dL (0.61–1.24), total choles-terol 128 mg/dL, triglycerides 86 mg/dL, HDL cholesterol 38 mg/dL, and LDL cholesterol 73 mg/dL (on atorvastatin 40 mg daily). How would you

Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group.

Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown. To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. Outpatient diabetes clinics in 15 UK hospitals. A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. Fasting plasma glucose and HbA1c levels, and the proportion of patients who achieved target levels below 7% HbA1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.

[Starting insulin or not? And if so, which basal insulin?]

A 55-year-old patient with a BMI of 30 kg/m2 is referred for uncontrolled type 2 diabetes mellitus. His HbA1c-concentration is 71 mmol/mol, despite an initial 8% weight loss and treatment with metformin and glimepiride. The general practitioner proposes to start with insulin, but the patient refuses. We discuss whether there is a good alternative for insulin such as more weight loss and the addition of more drugs. Our patient then changes his mind and agrees to start insulin treatment. Basal insulin is usually recommended in cases like this.Since there are no significant differences between different types of available basal insulin, it seems reasonable to take price into account. Our patient achieved reasonable glucose control without weight gain using a combination of basal insulin and a GLP-1 receptor agonist.

Reactive Hypoglycemia From Metformin Immediate-Release Monotherapy Resolved by a Switch to Metformin Extended-Release: Conceptualizing Their Concentration-Time Curves.

Metformin rarely, if ever, causes hypoglycemia when it is used as labeled. A 55-year-old woman presented to the medicine ward with an altered level of consciousness. She had been reviewed in an outpatient department three days earlier and prescribed 500 mg two times per day of metformin immediate-release (Met IR) for newly diagnosed type 2 diabetes mellitus (T2DM), to which she had been adherent; however, she had been experiencing intermittent episodes of hypoglycemia after taking the medication prescribed to treat her T2DM. On physical examination, she was diaphoretic and disoriented but responsive to sensory stimuli. In the ward, she received 25 ml of intravenous dextrose as the initial blood glucose reading was low at 54 mg/dl, and 4 ounces of apple juice additionally two hours later as her blood glucose level fell below 70 mg/dl again. She was no longer hypoglycemic a few hours later, and there was a significant neurological improvement. The remainder of the laboratory results, including serum renal and liver function tests, were normal. Met IR was discontinued, and metformin extended-release (Met XR) 500 mg/day was initiated at discharge. The patient's hypoglycemic episodes resolved within days after the initiation of Met XR. Hypoglycemia is rarely associated with accidental or suicidal overdose of metformin, metabolic dysfunction (e.g., renal insufficiency), exercise, missed meal, acute illness, or the initiation of additional antidiabetic medication. Albeit even uncommon, metformin-associated hypoglycemia may occur with no obvious trigger. In this context, we determine to what extent Met IR may contribute to the development of hypoglycemia in an individual case, but also that the risk could be mitigated by a switch to Met XR. In a preferred embodiment, the Met XR dosage form can be administered once a day, ideally with or after a meal, preferably with or after the evening meal, and it provides therapeutic levels of the drug throughout the day with peak plasma levels being obtained between four to eight hours after the administration (T<submax</sub).

Glycaemic control without weight gain in insulin requiring type 2 diabetes: 1-year results of the GAME regimen.

Weight gain appears to be unavoidable in patients with type 2 diabetes who are switched from oral agents to insulin therapy. Peripheral hyperinsulinism induced by the use of long-acting insulin may be the key to explain this adverse effect. The aim of this study was to investigate whether a regimen free of long-acting insulin can provide long-term glycaemic control without causing weight gain. This is an uncontrolled, 1-year study comprising 58 patients with type 2 diabetes and secondary failure, age 30-75 years, BMI 25-35 kg/m(2), HbA1c > 7.5% and fasting C-peptide level > 0.3 mmol/l. All patients were treated with the GAME regimen, a combination of glimepiride administered at 20:00 hours for nocturnal glycaemic control, insulin aspart three times daily for meal-related glucose control and metformin. Seventy-one per cent of the patients were considered evaluable. HbA1c decreased from 10.0 +/- 0.3 to 7.4 +/- 0.1% (p < 0.001). Fifty-nine per cent reached HbA1c levels <or= 7.5%. Symptomatic nocturnal hypoglycaemia was not reported. Body weight tended to decrease during the first 3 months (-1.0 +/- 0.5 kg, p = 0.06), but then gradually rose to a value 0.8 +/- 0.5 kg higher than at baseline (p = 0.12). This is 4.4 +/- 0.6 kg less than predicted for conventional regimens employing long-acting insulin (p < 0.001). The GAME regimen provides long-term glycaemic control as well as stabilization of body weight in about 60% of type 2 patients presenting with secondary failure.

Effect of acarbose on glycemic control, serum lipids and lipoproteins in type 2 diabetes.

To assess the efficacy of acarbose monotherapy during 12-weeks treatment on the fasting glycemic level, lipid and lipoproteins profiles, in patients with type 2 diabetes mellitus. Type 2 diabetics were selected from out patient department of Baqai Diabetes and Endocrine Centre, and one other diabetic clinic of Karachi, during 1996-97. A prospective intervention trial, and a 10 days screening period with a follow-up of 12 weeks. Forty-four patients (36 men and 8 women, mean age 55.09 +/- 1.72 years) were included of whom 25 (56.81%) patients were previously treated with diet alone, 11(25%) with diet and glibenclamide, 5(11.36%) with diet and gliclazide, and 3(6.81%) with diet and chlorpropamide, more than at least 3 months known duration of diagnosed type 2 diabetes, body mass index (BMI) 23.69 +/- 0.49 kg/m2, were insufficiently controlled on diet alone, or diet plus sulfonylureas, were studied. The dosage of acarbose was started with 50 mg t.i.d with each meal, if necessary, was titrated upward on subsequent visits to 100 mg t.i.d with each meal, based on tolerability and efficacy. Fasting blood glucose, lipid and lipoprotein profiles were determined at the baseline and at the end of the study. Acarbose treatment was associated with significant reduction in fasting blood glucose from (mean +/- SE) 173.89 +/- 3.89 mg/dl at day 0 to 161.29 +/- 3.41 mg/dl at day 90 (P < 0.01). The serum total triglyceride level was (mean +/- SE) 188.85 +/- 5.91 mg/dl at entry, and was also significantly decreased to 158.57 +/- 4.48 mg/dl at day 90, this reduction was found statistically significant (P < 0.01). Whereas very-low density lipoprotein cholesterol reduced significantly from 33.08 +/- 1.09 mg/dl at day 0 to 31.02 +/- 0.95 mg/dl at day 90 (P < 0.01). Acarbose had no significant effect on serum total cholesterol, low-density lipoprotein cholesterol, and High-density lipoprotein cholesterol concentrations. Almost, all adverse experiences, as reported by patients on acarbose, were related to the digestive system and included diarrhea, flatulence, bloating and nausea. Most symptoms were of mild to moderate intensity and tended to improve with time. Overall, acarbose was well tolerated and the adverse experience profile was clinically acceptable. In type 2 diabetic patients, acarbose as monotherapy for 12 weeks resulted in beneficial effects on glycemic control, fasting blood glucose, mean serum total triglyceride and very-low density lipoprotein cholesterol decreased significantly. Perhaps attainment of normoglycemia on a long-term basis would result in more normal lipid and lipoprotein levels. Furthermore use of acarbose can be considered as a useful alternative in such type 2 patients, if they are difficult to control with diet alone or diet plus sulfonylureas (JPMA 50:152, 2000).

[Bedtime administration of metformin may reduce insulin requirements].

The administration of metformin, as glucophage retard, at bedtime instead of supper time may improve diabetes control by reducing morning hyperglycemia. This modification of glucophage treatment was tried in 3 groups of diabetic patients: I. those with secondary failure of routine treatment with sulfonylurea (SU) and glucophage; II. those with combined SU and bedtime insulin; III. Type 1 patients with early morning hypoglycemia. The first 3 months of observation in 258 patients showed that 136 (52.7%) reacted very well to the change. In Group I the addition of insulin to SU could be postponed. In Group II, night insulin could be reduced or eliminated. In Group III, evening or night insulin could be reduced by up to 70%. There was no early morning hypoglycemia nor morning hyperglycemia. The success rate in the 2 Type 2 groups was better (72% and 60%) than in the Type 1 group (34%). 30 patients (11.6%) had to stop the treatment because of side effects of the glucophage (mainly diarrhea or nausea). So far, we have found no clinical signs that might indicate which patients might benefit from this modification of treatment. A fasting blood sugar done within 2-3 days after the change in treatment may immediately indicate whether the new treatment is effective.

The effect of metformin on glycemic control, serum lipids and lipoproteins in diet alone and sulfonylurea-treated type 2 diabetic patients with sub-optimal metabolic control.

To see if Metformin Monotherapy affects glycemic control, serum lipid or lipoprotein levels in the treatment of type 2 diabetes who were poorly controlled with diet alone or despite maximal doses of (sulfonylurea) oral glucose lowering agents. A prospective, clinical intervention trial conducted between 1996-1997. Two out patient diabetic clinics of Karachi. A 12-week prospective clinical intervention trial. A total of 30 type 2 diabetic subjects were enrolled, of Whom 21 (12 men and 9 women) completed the study period. Their ages ranged between 35 and 70 years, (mean +/- SD 53.3 +/- 9.31) years, with a mean duration since diagnosis of diabetes was 4.5 +/- 2.3 years, body mass index (mean +/- SD) 26.8 +/- 3.53 kg/m2. They were previously treated with diet alone or had already been taking maximum doses of sulfonylurea monotherapy with suboptimal glycemic control, i.e., raised fasting blood glucose concentrations of 6-15 mmol/L or (108-270 mg/dL) on two occasions, with significant hyperglycemic symptoms. The patients were treated with metformin monotherapy with a follow up of 12 weeks. The initial dosage was 500 mg twice daily, and the dosage was increased to two or three tablets depending on the patient's metabolic changes. By comparing before and after 12 weeks therapy with metformin we assessed the importance of baseline parameters (glycemic control, serum lipid and lipoprotein concentrations, and measures of change in body weight and body mass index). Metformin therapy significantly decreased fasting blood glucose levels in all patients [(mean +/- SD) 227.2 +/- 37.5 to 168.6 +/- 20.5 mg/dl, p < 0.001)]. Serum total cholesterol decreased marginally [(mean +/- SD) 200.3 +/- 18.7 to 181.4 +/- 19.4 mg/dl, p < 0.01)]. Serum total triglycerides concentration also decreased [(mean +/- SD) 195.9 +/- 31.9 to 174.2 +/- 26.6 mg/dl, P < 0.01)]. Low-density lipoproteins declined [(mean +/- SD) 123.5 +/- 16.9 to 105.5 +/- 19.1 mg/dl, P < 0.01)], and very-low density lipoprotein cholesterol also decreased [(mean +/- SD) 39.2 +/- 6.4 to 34.8 +/- to 5.3 mg/dl, P < 0.01)]. Whereas, high-density lipoprotein cholesterol tended to increase [(mean +/- SD) 37.7 +/- 5.1 to 39.5 +/- 4.9 mg/dl, P < 0.01)], while no significant changes occurred in body weight and body mass index. Metformin treatment was effective, safe, and generally well tolerated.

Treatment strategies for secondary sulfonylurea failure. Should we start insulin or add metformin? Is there a place for intermittent insulin therapy?

Which therapy should be used in non-insulin dependent diabetes mellitus (NIDDM) with secondary sulfonylurea failure? Should we start insulin therapy, try a period of intensified insulin therapy and then switch back to sulfonylurea or should we add metformin therapy? To address this question, we have compared these three treatment strategies in 36 NIDDM patients who failed on treatment with sulfonylureas during a 6 month period. Insulin (short and intermediate-acting insulin before breakfast and dinner) and the combination of 21 mg of glibenclamide and 1.5 g of metformin resulted in an equivalent 30% improvement in glycemic control without significant effects on lipids. Intensified insulin therapy (6 weeks of intermediate and short-acting insulin 3 times daily), on the other hand, initially lowered blood glucose to the same degree as during the other two treatment regimes, but after switching back to sulfonylurea therapy (21 mg of glibenclamide/day) blood glucose concentrations returned to pretreatment values. Insulin therapy resulted in a 5 kg increase in body weight, 63% of which was accounted for by an increase in fat mass. Although body weight was unchanged during glibenclamide/sulfonylurea therapy, lean body mass and energy expenditure decreased significantly (p less than 0.05). Body weight and energy metabolism remained unchanged during intermittent insulin therapy. Despite similar blood glucose lowering properties, insulin and the combination of sulfonylurea and metformin have different effects on energy metabolism and body composition. Since these effects were not observed during treatment with sulfonylurea alone, they must be ascribed to metformin.

Gynecology_Novak

Initiate an ADA reducing diet (50% CHO, 30% fat, 20% protein, high fiber) with three meals a day. Maintain ideal body weight or to reduce weight by 5% to 15% in 3 months if obese. Modify risk factors (smoking, exercise, fat intake). Check fasting blood glucose by finger stick daily for 2 months. If FBS declines, no other therapy is needed. If FBG does not decline or increases, use of an oral hypoglycemic agent may be considered. ADA, American Diabetic Association; CHO, carbohydrate; FBS, fasting blood glucose. Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2000;23:S4–S42. medicines (i.e., metformin, a biguanide), insulin therapy should be initiated and referral should be considered because of the increased rate of complications.

Mealtime 50/50 basal + prandial insulin analogue mixture with a basal insulin analogue, both plus metformin, in the achievement of target HbA1c and pre- and postprandial blood glucose levels in patients with type 2 diabetes: a multinational, 24-week, randomized, open-label, parallel-group comparison.

In people without diabetes, approximately 50% of daily insulin secretion is basal and the remainder is postprandial. Hence, it would be expected that insulin replacement therapy in a 50/50 ratio with each meal would mimic physiologic insulin secretion better than treatment with once-daily basal insulin in patients with diabetes mellitus. Using lispro mix (LM) 50/50 before meals may be a logical approach to achieving glycemic targets (glycosylated hemoglobin [HbA(lc)] and pre- and postprandial blood glucose [BG] concentrations) in these patients. The aim of this study was to test the hypothesis that treatment with a premixed insulin analogue containing 50/50 basal + prandial insulins administered before each meal would achieve lower overall and mealtime glycemic control than once-daily basal insulin analogue, both plus metformin (Met), in patients with type 2 diabetes mellitus. This 24-week, randomized, open-label, parallel-group trial was conducted at 38 sites across Australia, Greece, India, The Netherlands, Poland, Puerto Rico, and the United States. Male and female patients aged 35 to 75 years with type 2 diabetes mellitus and an HbA(1c) level of 6.5% to 11.0%, who were receiving metformin and/or a sulfonylurea with a stable dose of 0 to 2 daily insulin injections over the previous 3 months were eligible. Patients were randomly assigned to receive LM50/50 (50% insulin lispro protamine suspension [ILPS] and 50% lispro) TID plus metformin (to a maximally tolerated daily dosage of 500-1000 mg BID) (LM50/50 + Met) or insulin glargine QD at bedtime plus metformin (500-1000 mg BID) (G + Met) for 24 weeks. With LM50/50 + Met, the insulin dose was titrated to target a fasting BG (FBG) level of <6.7 mmol/L (<120 mg/dL) and a 2-hour post-prandial BG (PPBG) level of <8.0 mmol/L (<144 mg/dL); those who did not reach the FBG target would be switched from presupper LM50/50 to LM75/25 (75% ILPS, 25% lispro). A total of 315 patients were randomized and received treatment (158 women, 157 men; mean age, 57.7 years; mean body mass index, 32.1 kg/m2; LM50/50 + Met, 157 patients; G + Met, 158 patients). At 24 weeks, the mean (SD)HbA(1c) level was significantly lower in the LM50/50 + Met group than in the G + Met group (7.1% [0.9%] vs 7.5% [1.0%]; P<0.001), and the proportion who reached an HbA(1c) target of < or = 7.0% was greater (88 [56.1%] vs 63 [39.9%]; P = 0.005). The G + Met group had a lower mean (SD)FBG value (6.5 [1.6] vs 8.1 [1.8] mmol/L; P<0.001). The LM50/50 + Met group had lower mean preprandial BG levels prelunch (7.4 [1.9] vs 7.9 [2.1] mmol/L; P=0.03) and presupper (8.3 [2.0] vs 8.9 [2.8] mmol/L; P=0.04). The LM50/50 + Met group also had lower mean 2-hour PPBG values postbreakfast (8.7 [2.2] vs 9.2 [2.5] mmol/L; P=0.03), postlunch (8.4 [1.9] vs 9.8 [2.6], mmol/L; p<0.001), and postsupper (8.7 [2.2] vs 10.7 [3.2], mmol/L; P<0.001). The mean (SD) total insulin doses at study end point were 0.7 (0.3) U/kg in the LM50/50 + Met group and 0.6 (0.3) U/kg in the G + Met group (P<0.001). The mean (SD)M-value (an expression of mean glycemia and the effect of glucose swings) was statistically similar between the 2 groups at baseline but significantly lower in the LM50/50 + Met group at end point (17.3 [13.8] vs 25.1 [24.8] mmol/L; P<0.001). During the entire treatment period, mean (SD) overall and nocturnal hypoglycemia rates (episodes per patient for 30 days) were statistically similar between the 2 groups (overall, 0.8 [1.4] vs 0.5 [1.0]; nocturnal, 0.2 [0.7] vs 0.3 [0.6]). At end point, the mean (SD) nocturnal hypoglycemia rates were similar between the 2 groups (0.2 [0.9] vs 0.2 [0.6]), but the overall and non-nocturnal hypoglycemia rates were higher with LM50/50 + Met (overall, 0.7 [1.7] vs 0.3 [0.8]; P=0.02; non-nocturnal, 0.5 [1.2] vs 0.1 [0.4]; P=0.002). In these patients with type 2 diabetes, mealtime LM50/50 + Met was associated with lower overall (HbA(1c)) and preprandial BG and PPBG levels (except for FBG), with similar nocturnal hypoglycemia and less glycemic variability, compared with G + Met.

Efficacy of 24-week monotherapy with acarbose, metformin, or placebo in dietary-treated NIDDM patients: the Essen-II Study.

To compare the therapeutic potential of acarbose, metformin, or placebo as first line treatment in patients with non-insulin-dependent diabetes mellitus (NIDDM). Ninety-six patients with NIDDM (35-70 years of age, body mass index (BMI) < or = 35 kg/m2, insufficiently treated with diet alone, glycated hemoglobin (HbA1c; 7% to 11%) were randomized into 3 groups and treated for 24 weeks with acarbose, 3 x 100 mg/day, or metformin, 2 x 850 mg/day, or placebo. Efficacy, based on HbA1c (primary efficacy criterion), fasting blood glucose (BG) and insulin, 1 hour postprandial BG and insulin (after standard meal test), postprandial insulin increase, plasma lipid profile, and tolerability, based on subjective symptoms and laboratory values were determined every 6 weeks. Analysis of covariance was performed for endvalues with adjustment on baseline values. Ninety-four patients were valid for efficacy evaluation. Both active drugs showed the same improvement of efficacy criteria compared with placebo. Baseline adjusted means at endpoint were as follows: BG, fasting and 1 hour postprandial, 9.2 mM and 10.9 mM with placebo, 7.6 mM and 8.7 mM with acarbose, and 7.8 mM and 9.0 mM with metformin; HbA1c was 9.8% with placebo, 8.5% with acarbose, and 8.7% with metformin. Comparisons: acarbose versus placebo and metformin versus placebo were statistically significant, but not acarbose versus metformin. No effect on fasting insulin could be observed. Relative postprandial insulin increase was 1.90 with placebo, 1.09 with acarbose, and 1.03 with metformin. Comparisons: acarbose versus placebo and metformin versus placebo were statistically significant, but not acarbose versus metformin. With respect to lipid profile, acarbose was superior to metformin. Low-density lipoprotein (LDL)/high-density lipoprotein (HDL) cholesterol ratio increased by 14.4% with placebo, was unchanged with metformin, but decreased by 26.7% with acarbose. Comparisons: acarbose versus placebo and acarbose versus metformin were statistically significant, but not metformin versus placebo. Slight body weight changes were observed with acarbose (-0.8 kg) and metformin (-0.5 kg), but not with placebo. Acarbose led to mild or moderate intestinal symptoms in 50% of the patients within the first 4 weeks, but in only 13.8% of the patients within the last 4 weeks. Acarbose and metformin are effective drugs for the first line monotherapy of patients with NIDDM. With respect to plasma lipid profile, especially HDL cholesterol, LDL cholesterol and LDL/HDL cholesterol ratio acarbose may be superior to metformin.

[Non-insulin therapy in diabetes mellitus].

Changes to nutritional habits, including the reduction of weight, are basic therapy principles for the treatment of diabetes mellitus. With overweight patients a reduction of energy intake is important. Patients with diabetes mellitus should eat plenty of carbohydrates, the intake of fat should be limited to a maximum of 35%. Patients treated with insulin must be made to calculate carbohydrate exchange units. Unless there are contraindications, diabetic patients should be encouraged to engage in physical exercise. Educating the patients is of major importance in the treatment of diabetics; this must be undertaken by trained personnel. All diabetic patients treated with oral antidiabetic drugs or insulin should be encouraged to measure their blood glucose levels themselves, in cases of insulin therapy this is an absolutely necessity. If with the aid of basic therapy measures, which include the control of fasting blood glucose, postprandial blood glucose and HbA1c levels, the aims of the therapy are not reached, this is an indication for the use of oral antidiabetic drugs. The drug should be chosen with the dominant pathophysiological disturbance in mind. In the case of increased fasting blood glucose values (hepatic insulin resistance leading to increased glucose production by the liver), after contraindications have been excluded, the use of metformin is recommended. If there are significantly increased postprandial blood glucose values (due to an early-insulin-secretion deficiency or severe insulin resistance), the use of alpha-glucosidase-inhibitors, metformin, sulphonylureas or glinides is indicated. With obese patients alphaglucosidaseinhibitors and metformin are the drugs of choice, with patients with BMI < 25 kg/m2 these are sulfonylureas or glinides. In cases of severe insulin resistance the use of glitazones in conjunction with metformin or sulphonylureas may be indicated.

Monitoring of metabolic control in patients with non-insulin-dependent diabetes mellitus on oral hypoglycaemic agents: value of evening blood glucose determination.

Monitoring of metabolic control in patients with non-insulin-dependent (Type 2) diabetes (NIDDM) is usually based upon blood glucose assay in the morning (after an overnight fast) and in the postprandial state (breakfast or lunch). However, this schedule does not seek low blood glucose values, especially in the evening. We have conducted a prospective study of laboratory blood glucose profiles (8 am, 9.30 am after a 35 g carbohydrate breakfast and in the evening between 5 and 7 pm). We have included 58 consecutive NIDDM patients regularly followed in our clinic (39 men, age 60 +/- 11.5 years, diabetes duration 8.6 +/- 6.5 years, BMI 25.5 +/- 3 kg m-2), treated with the sulphonylurea gliclazide, alone (40-320 mg 24 h-1, mean 170 +/- 110 mg) (group 1, n = 32) or in combination with metformin (1000-3000 mg 24 h-1, 2400 +/- 620 mg) (group 2, n = 26). All patients were stable, with no change in dosage for at least 3 months. Mean glycaemic control was good (group 1 HbA1c: 6.5 +/- 1.1%, group 2: 6.9 +/- 0.7%). Evening blood glucose values were the lowest of the day in 26 patients of group 1 (81.3%) and in 22 of group 2 (84.6%). Mean evening blood glucose levels were lower (p = 0.001) than 8 am values (group 1: 5.8 +/- 1.4 vs 6.1 +/- 1.6 mmol l-1, group 2: 6.5 +/- 1.8 vs 6.9 +/- 1.9) and than 9.30 am values (group 1: 7.6 +/- 1.5, group 2: 12.3 +/- 2.8). No blood glucose values in the hypoglycaemic range were observed. HbA1c was strongly correlated (p = 0.002 to 0.0001) in the whole group with 8 am (r = 0.39), 9.30 am (r = 0.56), and evening blood glucose values (r = 0.42). These results indicate that, in patients treated with the sulphonylurea gliclazide, alone or in combination with metformin, the lowest blood glucose values occur in the evening more frequently (4/5) than in the morning. Therefore, evening blood glucose determination should be performed systematically in the course of the metabolic evaluation of NIDDM patients on oral hypoglycaemic agents.

Antidiabetic agents.

Although either insulin or oral hypoglycemics may be used in conjunction with diet and exercise in the management of type II diabetes, drug therapy for type I diabetes involves only insulin. C-peptide levels can be tested to assess whether the patient has remaining pancreatic endocrine function. Patients being started on insulin for the first time should receive a single injection of an intermediate-acting insulin of "human" origin at a dose of approximately 0.5 U/kg. Thereafter, fasting, mid-morning, mid-afternoon, bedtime, and possibly early morning blood sugars should be examined periodically to determine if the insulin dose needs to be increased, decreased, split, or if the patient needs to be on a two-insulin regimen. Intensive insulin therapy has become commonplace to control plasma glucose levels in the majority of patients receiving insulin therapy. Proper patient education regarding the insulin regimen, injection techniques, blood glucose monitoring, as well as diet, exercise, and foot care are essential if the patient's diabetes is to be controlled adequately. Guidelines for "adequate" glycemic control are outlined in Table 6. Recent evidence suggests that tight control of plasma glucose levels may decrease the macrovascular complications of diabetes. Although there is also evidence to suggest that the onset of microvascular complications might be delayed with strict glycemic control, the data are conflicting. The benefits of strict control must be weighted against the problems of hypoglycemia experienced by many patients who attempt tight control of their blood glucose levels. Biguanide compounds are available in Europe, but the sulfonylureas comprise the only class of oral agents in the United States commercially available for the treatment of type II diabetes. The two generations of these drugs reflect their potency and possible side-effect profiles. Of the first-generation agents, tolbutamide and chlorpropamide are the most widely prescribed. Tolbutamide is the weakest of the sulfonylureas, possibly making it a good drug for initiating oral therapy in the elderly. Chlorpropamide is becoming a less popular agent because of its long duration of action and its increased incidence of side effects. Of the second-generation agents, glyburide offers a better dosing schedule (once daily compared with twice daily for glipizide); however, glyburide may produce a greater incidence of hypoglycemia, particularly in the elderly or in patients with significant renal impairment. There are few good studies comparing these two drugs so that recommending one over the other is difficult. Drug interactions are numerous with the first-generation drugs, but less so with the newer second-generation agents.(ABSTRACT TRUNCATED AT 400 WORDS)

Troglitazone add-on therapy to a combination of sulfonylureas plus metformin achieved and sustained effective diabetes control.

To elucidate the effect of triple combination oral agent therapy on type 2 diabetes. We performed a prospective longitudinal study on 40 patients with type 2 diabetes who had failed to achieve a glycosylated hemoglobin (HbA1c) of < or = 8.0% despite optimal therapy with a combination of sulfonylureas plus metformin. Troglitazone was added and then titrated, with the intent to achieve at least a 1% reduction in HbA1c within 3 months. Responders were reassessed at 6 and 12 months. Nonresponders were reassessed at 6 months; in the absence of a significant HbA1c response, participation in the study was discontinued. Of the 40 study subjects, 25 were responders, 10 were nonresponders, and 5 were withdrawn from the study before completion of 3 months of therapy because of side effects. The 25 responders had a mean baseline HbA1c of 9.9%, which decreased significantly to 7.8% after 3 months of troglitazone therapy and to 7.4% at 6 months and at 12 months. In addition, the fasting blood glucose (FBG) in the responders decreased significantly from 168 mg/dL at baseline to 118 mg/dL at 6 months, which was sustained at 121 mg/dL at 12 months. In the responder group, a mean HbA1c < or = 8% was achieved in 68% at 6 months and sustained in 65% after 1 year. Furthermore, 40% of responders achieved a mean HbA1c < or = 7.0% at 6 months, and 39% sustained this degree of control at 12 months. The 10 nonresponders showed no significant change in HbA1c or FBG during the 6 months of troglitazone therapy. No difference existed in the mean baseline FBG, HbA1c, or C peptide level between the two groups. Responders, however, had a significantly lower mean body mass index (BMI) (31 kg/m2) than did nonresponders (37 kg/m2). Although responders were older than nonresponders (mean age, 65 years versus 55 years), no significant difference was noted in duration of diabetes (11.6 years versus 8.7 years). Multivariate analysis showed that male gender and BMI were the strongest predictors of a response to troglitazone add-on therapy to the prior combination of sulfonylureas plus metformin. This study showed that oral therapy with troglitazone added to sulfonylureas plus metformin achieved and sustained a significant improvement in control of diabetes in 71% of patients who had failed to achieve HbA1c < or = 8% with dual oral agent therapy. The positive response was evident within 3 months, reached maximum by 6 months, and was sustained to 12 months of therapy. Therefore, patients who fail to achieve HbA1c < or = 8% with sulfonylureas plus metformin should have at least 3 months of troglitazone add-on therapy before advancing to traditional insulin treatment.

Impact of health policy and practice on finding the best fit for patients with type 2 diabetes after metformin failure: Croatian pilot study.

We assessed the impact of clinical practice and health policy on the choice and efficacy of different second-line therapies for the treatment of type 2 diabetes (T2DM) after failure of metformin. This retrospective database analysis included 200 patients with a follow-up period of 6 months. The primary end-point was achievement of HbA1c <7% and fasting (FBG) and postprandial glucose levels (PPG) <7.2mmol/L and <10mmol/L, respectively after three and six months of different add-on treatments. Secondary end-points were weight change during treatment and incidence of hypoglycemia. All second-line therapeutic options, except human basal insulin (BHI) and thiazolidendions (TZD) significantly increased the proportion of patients reaching target HbA1c after 6 months (p<0.01). Only sulfonylurea (SU) and dipeptidyl peptidase-4 (DPP-4) inhibitors significantly reduced all monitored parameters of glucoregulation without changing body weight and BMI after 3 and 6 months as opposed to insulin agents. However, there were no statistically significant differences between the groups when adjusting for starting HbA1c, FBG and PPG (F=1.16, p=NS), although a statistically significant difference in HbA1c levels (F=3.35, p<0.01) persisted in DPP-4 inhibitor users. The incidence of hypoglycemia was significantly higher in patients treated with NPH insulin and premixed insulin than in patients treated with other agents. A more aggressive approach is needed with early treatment intensification using available agents.