Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas.

Type 2 diabetes (T2DM) is a progressive disease, and pharmacotherapy with a single agent does not generally provide durable glycaemic control over the long term. Sulphonylurea (SU) drugs have a history stretching back over 60 years, and have traditionally been the mainstay choice as second-line agents to be added to metformin once glycaemic control with metformin monotherapy deteriorates; however, they are associated with undesirable side effects, including increased hypoglycaemia risk and weight gain. Dipeptidyl peptidase (DPP)-4 inhibitors are, by comparison, more recent, with the first compound being launched in 2006, but the class now globally encompasses at least 11 different compounds. DPP-4 inhibitors improve glycaemic control with similar efficacy to SUs, but do not usually provoke hypoglycaemia or weight gain, are relatively free from adverse side effects, and have recently been shown not to increase cardiovascular risk in large prospective safety trials. Because of these factors, DPP-4 inhibitors have become an established therapy for T2DM and are increasingly being positioned earlier in treatment algorithms. The present article reviews these two classes of oral antidiabetic drugs (DPP-4 inhibitors and SUs), highlighting differences and similarities between members of the same class, as well as discussing the potential advantages and disadvantages of the two drug classes. While both classes have their merits, the choice of which to use depends on the characteristics of each individual patient; however, for the majority of patients, DPP-4 inhibitors are now the preferred choice.

Treatment of Patients with Obese Type 2 Diabetes with Tantalus-DIAMOND® Gastric Electrical Stimulation: Normal Triglycerides Predict Durable Effects for at Least 3 Years.

The objectives of the present work are to evaluate long-term benefit of nonexcitatory gastric electrical stimulation (GES) by the DIAMOND(®) device on glycemic control and body weight in patients with type 2 diabetes inadequately controlled with oral agents and to determine the magnitude of the modulating effects of fasting plasma triglyceride (FTG) levels on these effects of GES. Sixty one patients with type 2 diabetes [HbA1c > 7.0% (53 mmol/mol) to < 10.5% (91 mmol/mol)] were implanted with the DIAMOND(®) GES device and treated with meal-mediated antral electrical stimulation for up to 36 months. The effects of baseline HbA1c and FTG on glycemic control, body weight, and systolic blood pressure were measured. GES reduced mean HbA1c by 0.9% and body weight by 5.7%. The effects were greater in patients with normal fasting plasma triglycerides (NTG) as compared to those with hypertriglyceridemia. The mean decrease in HbA1c in patients with NTG averaged 1.1% and was durable over 3 years of follow-up. ANCOVA indicated that improvement in HbA1c was a function of both baseline FTG group (p = 0.02) and HbA1c (p = 0.001) and their interaction (p = 0.01). Marked weight loss (≥ 10%) was observed in a significant proportion of NTG patients by 12 months of treatment and persisted through the 3 years. GES improves glycemic control and reduces body weight by a triglyceride-dependent mechanism in patients with type 2 diabetes inadequately controlled on oral agents. It is postulated that this is through a gut-brain interaction that modulates effects on the liver and pancreatic islets.

Fasting plasma triglycerides predict the glycaemic response to treatment of type 2 diabetes by gastric electrical stimulation. A novel lipotoxicity paradigm.

BACKGROUND: Non-stimulatory, meal-mediated electrical stimulation of the stomach (TANTALUS-DIAMOND) improves glycaemic control and causes modest weight loss in patients with Type 2 diabetes who are inadequately controlled on oral anti-diabetic medications. The magnitude of the glycaemic response in clinical studies has been variable. A preliminary analysis of data from patients who had completed 6 months of treatment indicated that the glycaemic response to the electrical stimulation was inversely related to the baseline fasting plasma triglyceride level. METHOD: An analysis of 40 patients who had had detailed longitudinal studies for 12 months. RESULTS: Twenty-two patients with fasting plasma triglycerides ≤ 1.7 mmol/l had mean decreases in HbA1c after 3, 6 and 12 months of gastric contraction modulation treatment of -15 ± 2.1 mmol/mol (-1.39 ± 0.20%), -16 ± 2.2 mmol/mol (-1.48 ± 0.20%) and -14 ± 3.0 mmol/mol (-1.31 ± 0.26%), respectively. In contrast, 18 patients with fasting plasma triglyceride > 1.7 mmol/l had mean decreases in HbA1c of -7 ± 1.7 mmol/mol (-0.66 ± 0.16%), -5 ± 1.6 mmol/mol (-0.44 ± 0.18%) and -5 ± 1.7 mmol/mol (-0.42 ± 0.16%), respectively. Pearson's correlation coefficient between fasting plasma triglyceride and decreases in HbA1c at 12 months of treatment was 0.34 (P < 0.05). Homeostasis model assessment of insulin resistance was unchanged during 12 months of treatment in patients with high baseline fasting triglycerides, while it progressively improved in patients with low fasting plasma triglycerides. Patients with low fasting plasma triglycerides had a tendency to lose more weight than those with high fasting plasma triglycerides, but this did not achieve statistical significance. CONCLUSIONS: The data presented suggest the existence of a triglyceride lipotoxic mechanism that interferes with gastric/neural mediated pathways that can regulate glycaemic control in patients with type 2 diabetes. The data suggest the existence of a triglyceride lipotoxic pathway that interferes with gastric/neural mediated pathways that can regulate glycaemic control.

Oral therapies for diabetic hyperglycemia.

Many classes of oral antihyperglycemic agents are available for the treatment of type 2 diabetic patients. These classes improve glucose metabolism by different mechanisms, and their effects are additive. Therapy with lifestyle modification and a single oral antihyperglycemic agent infrequently achieves target glycemic goals, and, if it does, the effect is usually not sustained. A more rational approach would seem to be therapy with combinations of drugs with different mechanisms of action. Initial therapy might be with submaximal concentrations of two drugs. As the diabetic abnormalities progress, maximal concentrations of the drugs and addition of other classes of oral agents or insulin may be needed to maintain the target glycemic goal. In choosing combinations of oral antihyperglycemic agents, their effects on the components treatment of type 2 diabetic patients. These classes improve glucose considered, as must the specific effects of the agents on glucose metabolism.

Effect of the postprandial state on nontraditional risk factors.

Hyperglycemia is the cause of chronic microvascular complications in diabetes. Increased macrovascular disease occurring in diabetes is multifactorial, with hyperglycemia being only 1 of the factors responsible. A major deficiency in our understanding of the role of hyperglycemia in the pathogenesis of chronic diabetic complications is the contribution made by exaggerated postprandial glycemic excursions, in contrast to that made by chronic fasting hyperglycemia. Hyperglycemia is thought to cause chronic diabetic complications through > or = 1 of the following biochemical mechanisms: (1) an exaggerated polyol pathway, (2) protein glycation and the formation of advanced glycation end products, (3) excessive activation of protein kinase C (PKC) isoenzymes in vascular and mesangial cells, and (4) greater oxidative stress. The focus of this article is how postprandial hyperglycemia and glucose excursions might specifically activate > or = 1 of these mechanisms and how they might contribute to the development of the chronic complications of diabetes by causing endothelial dysfunction, a procoagulant state, carbonyl stress, and/or vascular and oxidative effects secondary to PKC activation.

Insulin resistance: definition and consequences.

Insulin resistance is defined clinically as the inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and utilization in an individual as much as it does in a normal population. Insulin action is the consequence of insulin binding to its plasma membrane receptor and is transmitted through the cell by a series of protein-protein interactions. Two major cascades of protein-protein interactions mediate intracellular insulin action: one pathway is involved in regulating intermediary metabolism and the other plays a role in controlling growth processes and mitoses. The regulation of these two distinct pathways can be dissociated. Indeed, some data suggest that the pathway regulating intermediary metabolism is diminished in type 2 diabetes while that regulating growth processes and mitoses is normal.--Several mechanisms have been proposed as possible causes underlying the development of insulin resistance and the insulin resistance syndrome. These include: (1) genetic abnormalities of one or more proteins of the insulin action cascade (2) fetal malnutrition (3) increases in visceral adiposity. Insulin resistance occurs as part of a cluster of cardiovascular-metabolic abnormalities commonly referred to as "The Insulin Resistance Syndrome" or "The Metabolic Syndrome". This cluster of abnormalities may lead to the development of type 2 diabetes, accelerated atherosclerosis, hypertension or polycystic ovarian syndrome depending on the genetic background of the individual developing the insulin resistance.--In this context, we need to consider whether insulin resistance should be defined as a disease entity which needs to be diagnosed and treated with specific drugs to improve insulin action.

Rosiglitazone monotherapy is effective in patients with type 2 diabetes.

This study evaluated the efficacy and safety of rosiglitazone monotherapy in patients with type 2 diabetes. After a 4-week placebo run-in period, 493 patients with type 2 diabetes were randomized to receive rosiglitazone [2 or 4 mg twice daily (bd)] or placebo for 26 weeks. The primary end point was change in hemoglobin A(1c); other variables assessed included fasting plasma glucose, fructosamine, endogenous insulin secretion, urinary albumin excretion, serum lipids, and adverse events. Rosiglitazone (2 and 4 mg bd) decreased mean hemoglobin A(1c) relative to placebo by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations relative to placebo by 3.22 and 4.22 mmol/L, respectively. Fasting plasma insulin and insulin precursor molecules decreased significantly. Homeostasis model assessment estimates indicate that rosiglitazone (2 and 4 mg bd) reduced insulin resistance by 16.0% and 24.6%, respectively, and improved ss-cell function over baseline by 49.5% and 60.0%, respectively. Urinary albumin excretion decreased significantly in the rosiglitazone (4 mg bd) group. There was no increase in adverse events with rosiglitazone. In the short-term, rosiglitazone is an insulin sensitizer that is effective and safe as monotherapy in patients with type 2 diabetes who are inadequately controlled by lifestyle interventions.

Insulin resistance and its treatment by thiazolidinediones.

Insulin resistance is a change in physiologic regulation such that a fixed dose of insulin causes less of an effect on glucose metabolism than occurs in normal individuals. The normal compensatory response to insulin resistance is an increase in insulin secretion that results in hyperinsulinemia. If the hyperinsulinemia is sufficient to overcome the insulin resistance, glucose regulation remains normal; if not, type 2 diabetes ensues. Associated with insulin resistance, however, is a cluster of other metabolic abnormalities involving body fat distribution, lipid metabolism, thrombosis and fibrinolysis, blood pressure regulation, and endothelial cell function. This cluster of abnormalities is referred to as the insulin resistance syndrome or the metabolic syndrome. It is causally related not only to the development of type 2 diabetes but also to cardiovascular disease. A major unresolved issue is whether there is a single underlying cause of this syndrome and, if so, what might it be? Several promising hypotheses have been proposed. There are some data to support the hypothesis that fetal malnutrition imprints on metabolic regulatory processes that, in later adult life, predispose to the development of the insulin resistance syndrome. Visceral obesity also has been a candidate for the cause of the syndrome. Whatever mechanism is ultimately found to be responsible, it will undoubtedly have both genetic and environmental components. Among the biochemical mediators that are likely to be responsible for the interference with insulin's effects on intermediary metabolism are free fatty acids and other products from adipose tissue. Recent data suggest that the substances stimulate serine phosphorylation of molecules involved in the initial steps of insulin action, thereby blocking the ability of these molecules to be tyrosine phosphorylated and initiate the subsequent steps of the insulin action cascade. The thiazolidinediones are a new class of agents that have been developed to treat type 2 diabetic patients. These drugs act as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Following their binding to the receptor, the heterodimer molecule that contains the binding site is activated. The activated complex binds to the response elements of specific genes that regulate molecules that effect insulin action and lipid metabolism. These genes are either activated or inhibited. Specifically, the thiazolidinediones improve insulin action and decrease insulin resistance. The exact mechanism by which these agents decrease insulin resistance is not clear but they do decrease the elevated free fatty acid levels present in insulin-resistant patients and they appear to change the body distribution of adipose tissue. Treatment of insulin-resistant type 2 diabetic patients with thiazolidinediones not only improves glycemic control and decreases insulin resistance, it also improves many of the abnormalities that are part of the insulin resistance syndrome.

Near-normoglycaemic remission in African-Americans with Type 2 diabetes mellitus is associated with recovery of beta cell function.

AIMS: To prospectively determine the frequency of remission and possible mechanism of beta cell recovery in non-Whites with Type 2 diabetes mellitus in the setting of intensive glycaemic regulation using pharmacological agents. METHODS: Twenty-six consecutive, newly diagnosed African-American, Type 2 diabetic patients presenting primarily for severe hyperglycaemia (31.0+/-12.8 mmol/l) were followed for at least 1 year. Initial hospitalization included treatment with insulin, fluids and electrolytes. Outpatient intensive glycaemic regulation included insulin or glibenclamide, diabetes education and diet that altered nutrient content. Plasma glucose and C-peptide responses to an oral glucose tolerance test and HbA1c were measured at < 14, 15-56 and 57-112 days after presentation. Remission was defined as a HbA1c < or = 6.3% and fasting plasma glucose < 6.9 mmol/l, 3 months after discontinuing all pharmacological agents. RESULTS: Eleven of 26 patients (42.3%) developed remission after a mean of 83 days of pharmacological treatment and remained in remission during follow-up for 248-479 days; one relapsed after 294 days. Fifteen patients who did not develop a remission and were followed for 168-468 days, required continuing pharmacological therapy to be well-controlled. (mean HbA1c = 7.1%). There was no significant difference in age, sex, plasma glucose at presentation, initial glycaemic regulation, final body mass index, magnitude of weight change or pharmacological agents used for treatment between the two groups. Plasma C-peptide response to oral glucose was initially (< 14 days) suppressed in all subjects and subsequently increased. The increase was significantly greater in those who underwent a remission than those who did not. Neither significant weight loss nor severe hypoglycaemia was observed in either group during intensive treatment. CONCLUSIONS: Forty-two per cent of newly diagnosed, unselected African-Americans with Type 2 diabetes, treated intensively using pharmacological agents, education and diet developed near-normoglycaemic remission. Remission was associated with a greater recovery of glucose-stimulated insulin secretion suggesting that therapies directed at promoting beta cell recovery and preservation are potentially useful approaches to the treatment of Type 2 diabetes mellitus.

Diagnosis, classification, and pathogenesis of diabetes mellitus.

Diabetes mellitus is a metabolic disorder that is characterized by inappropriate hyperglycemia and is associated with both acute and chronic complications. Currently, diabetes mellitus is diagnosed by blood or plasma glucose levels. A random plasma glucose level > or = 200 mg/dL in an individual with classic symptoms is sufficient to make the diagnosis. Otherwise, a fasting plasma glucose level > or = 126 mg/dL or a 2-hour plasma glucose level > or = 200 mg/dL after an oral glucose challenge of 75 g on 2 occasions is sufficient evidence upon which to diagnose diabetes mellitus. The major types of diabetes mellitus are type 1 diabetes (insulin deficient) and type 2 diabetes (combination of insulin resistance and insulin deficiency). In both types, there is a genetic predisposition as well as environmental factors that contribute to the expression of the genetic predisposition. In type 1 diabetes, the primary abnormality is extensive deficiency of beta cell function. In type 2 diabetes, insulin resistance occurs, and the marked compensatory increases in insulin secretion necessary to maintain normal glucose tolerance cannot be achieved or maintained. As beta cell function continues to decrease, the individual progresses from normal glucose tolerance to impaired glucose tolerance to diabetes with primarily postprandial hyperglycemia to diabetes with fasting hyperglycemia. Drugs can cause diabetes by interfering with beta cell insulin secretion, by increasing insulin resistance, or by a combination of both. Atypical antipsychotic drugs have been reported to cause diabetic ketoacidosis, obesity and insulin resistance, type 2 diabetes, and hypertriglyceridemia. A monitoring system should be in place in patients started on treatment with these agents to detect metabolic abnormalities as they are evolving so that adequate and timely treatment can be initiated.

Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus.

AIM: To determine the efficacy and tolerability of sibutramine hydrochloride in obese patients whose type 2 diabetes was poorly controlled on diet alone or with an oral antidiabetic agent. METHODS: This study was a 24-week, double-blind, multicentre trial following a 5-week placebo run-in period. One hundred and seventy-five obese (body mass index (b.m.i.) > or =27 kg/m2) patients with poorly controlled type 2 diabetes mellitus were randomized either to sibutramine (n = 89; mean age 53.5 years; mean weight 99.3 kg) or placebo (n = 86; mean age 55 years; mean weight 98.2 kg) at 16 participating centres. To achieve moderate calorie restriction (deficit > or = 250-500 kcal/day), individual dietary counselling was accompanied by either placebo or sibutramine (initial dosage of 5 mg/day titrated up by 5 mg biweekly through week 6, and maintained at 20 mg through week 24). The main outcome measures included changes in weight, b.m.i., waist and hip circumference, glycaemic control, lipid profile, and quality of life, and evaluation of reported adverse events. RESULTS: Sixty-seven per cent of sibutramine patients and 71% of placebo patients completed the study. At week 24 when comparing those who completed the course, sibutramine compared with placebo patients showed significantly greater (p < 0.001) absolute (-4.3 vs. -0.4 kg) and percentage (-4.5% vs. -0.5%) weight loss. Weight loss > or =5% or 10% was achieved by 33% and 8% of sibutramine patients, respectively, but no placebo patients (p < 0.03 or better). Improvement in glycaemic control was correlated with weight loss (p < 0.001). In 5% and 10% weight-loss responders, mean treatment differences were -0.53% and -1.65% (p < or = 0.05), respectively, for HbA1c, and -1.4 mmol/l (p < or =0.05) and -3.8 (p < or =0.05) mmol/l for fasting plasma glucose. Sibutramine patients also showed improvements in fasting insulin, triglycerides, HDL cholesterol, and quality-of-life assessments. Overall, sibutramine was well tolerated compared with the placebo. Sibutramine treatment was associated with small mean increases in blood pressure (BP) and pulse, although an increase in BP was not seen in sibutramine-treated patients who lost > or = 5% of their weight. CONCLUSIONS: Sibutramine produced statistically and clinically significant weight loss when used in combination with recommendations for moderate caloric restriction. This weight loss was associated with improvements in metabolic control and quality of life, and sibutramine was generally well tolerated in obese patients with type 2 diabetes.

Type 2 diabetes: an overview.

Type 2 diabetes is a heterogeneous disorder. Clinical expression of the disorder requires both genetic and environmental factors. One theory concerning its etiology is that it is the result of the evolution of a thrifty genotype that had survival benefits in the past but is detrimental in the current environment. An opposing theory is that it represents an adult metabolic response to fetal malnutrition. Hyperglycemia in type 2 diabetes results from absolute or relative insulin deficiency. Most often relative insulin deficiency is attributable to an inability to adequately compensate for insulin resistance. Insulin resistance may be caused by a variety of genetic or metabolic factors. The most common etiological factor in insulin resistance is central obesity. Insulin resistance is associated with a cluster of metabolic abnormalities that include glucose intolerance, hypertension, a unique dyslipidemia, a procoagulant state, and an increase in macrovascular disease. Clinical intervention studies have demonstrated that reduction in the chronic microvascular and macrovascular complications of type 2 diabetes requires treatment of hyperglycemia to achieve hemoglobin A1c <7.0%, blood pressure

Effects of oral antihyperglycemic agents in modifying macrovascular risk factors in type 2 diabetes.

Management of patients with type 2 diabetes should focus on decreasing the excess macrovascular disease with which it is associated as well as preventing or minimizing microvascular disease. Near-normoglycemic control can reduce microvascular disease. Reducing macrovascular disease requires concomitant management of the cardiovascular risk factors (components of the insulin resistance syndrome) associated with type 2 diabetes. The first phase of such treatment is to identify the effects that the various drugs to treat the hyperglycemia are likely to have on these associated cardiovascular risk factors. Appropriate combinations of antihyperglycemic agents should be selected for specific patients to help achieve good glycemic control and produce beneficial, or at least nondetrimental, effects on cardiovascular risk.

Body composition, visceral fat, leptin, and insulin resistance in Asian Indian men.

There is a high prevalence of type 2 diabetes mellitus and coronary artery disease among urban and migrant Asian Indians despite the absence of traditional risk factors. Evidence exists that Asian Indians are more hyperinsulinemic than Caucasians and that hyperinsulinemia may be important in the development of these diseases. To test whether insulin action was related to total or regional adiposity and to explore the potential role of plasma leptin and lipids, we measured insulin-mediated glucose disposal by the euglycemic insulin clamp, adipose distribution and muscle volume using computed axial tomography, and fasting serum leptin and lipid levels in 20 healthy Asian Indian male volunteers (age, 36 +/- 10 yr). A mean body mass index of 24.5 +/- 2.5 kg/m2 was associated with an unusually high percentage of body fat (33 +/- 7%). The majority of the fat was sc, and 16% was visceral (intraabdominal) adipose tissue. The majority (66%) of these nonobese men were insulin resistant. The mean fasting serum leptin level was 7.6 +/- 3.3 ng/mL. Insulin action was inversely correlated with visceral adipose tissue, not total or abdominal sc adipose tissue. In contrast, leptin levels correlated with sc and total (not visceral) adipose tissue. Serum triglyceride and high density lipoprotein cholesterol levels were inversely correlated with each other and were directly related to insulin resistance and visceral (not subcutaneous) fat. Increased visceral fat in Asian Indians is associated with increased generalized obesity, which is not apparent from their nonobese body mass index. Increased visceral fat is related to dyslipidemia and increased frequency of insulin resistance and may account for the increased prevalence of diabetes mellitus and cardiovascular disease in Asian Indians.

Hyperfiltration in African-American patients with type 2 diabetes. Cross-sectional and longitudinal data.

OBJECTIVE: Hyperfiltration may play a role in the development of diabetic nephropathy. African-American patients with diabetes have more than a fourfold increase in end-stage renal disease. The purpose of this study is to evaluate the impact of hyperfiltration on renal function in African-American patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Renal function of 194 African-American patients with diagnosed type 2 diabetes from 1 month to 36 years was assessed by studies of isotopic glomerular filtration rate (GFR), serum creatinine, creatinine clearance, and 24-h urinary albumin excretion rates. Thirty-four patients with a duration of diagnosed type 2 diabetes from 1 month to 10 years were found to have hyperfiltration (GFR > or = 140 ml.min-1.1.73 m-2). Fifteen of these patients received longitudinal follow-up of renal function for as long as 15 years after the initial study. RESULTS: Hyperfiltration is present in 15 (36%) of 42 patients whose duration of diagnosed type 2 diabetes is < 1 year, and it persists for up to 10 years in 14-20% of patients with diagnosed type 2 diabetes. Patients with hyperfiltration are younger than their counterparts without hyperfiltration when matched for duration of diagnosed diabetes. When followed over time, those patients with hyperfiltration were not more likely to develop impaired renal function as measured by GFR or creatinine clearance. CONCLUSIONS: Hyperfiltration does not identify patients at risk for deterioration in renal function.

Advantages of alpha-glucosidase inhibition as monotherapy in elderly type 2 diabetic patients.

The objective of this study was to determine the safety, efficacy, and tolerability of the alpha-glucosidase inhibitor miglitol vs. the sulfonylurea glyburide in the treatment of elderly patients with type 2 diabetes mellitus, inadequately controlled by diet alone. This was a double-blind, randomized, placebo-controlled, 1-yr trial of miglitol 25 mg TID and 50 mg TID compared with placebo and a titrated dose of glyburide in a parallel group comparison study conducted in 30 out-patient sites across the United States. Four hundred eleven (411) diet-treated patients age 60 yr or greater were randomized to receive either placebo TID (n = 101), miglitol 25 mg TID (n = 104), miglitol 50 mg TID (n = 102), or a once-daily dose of glyburide titrated based on fasting plasma glucose (FPG) (n = 104), for a period of 56 weeks. Efficacy was assessed by glycated hemoglobin (HbA1c), fasting and post-meal glucose, insulin, and lipid levels, and by 24-h urinary excretion of glucose and albumin. Safety and tolerability were assessed by tabulation of adverse events, periodic laboratory determinations, and home blood glucose monitoring. HbA1c treatment effects (placebo-subtracted change in HbA1c from baseline) at the 1-yr endpoint were -0.49%, -0.40%, and -0.92% in the miglitol 25 mg TID, miglitol 50 mg TID, and glyburide groups, respectively (P < 0.05- 0.01 vs. placebo). Postprandial insulin levels were significantly greater than placebo and miglitol in the glyburide group (P < 0.01). Hypoglycemia, weight gain, and both routine and serious cardiovascular events were more frequent in the glyburide group (P < 0.05-0.01 vs. placebo or miglitol groups). Diarrhea (or soft stools) and flatulence were more common in both miglitol groups than in the other two groups in a dose-dependent manner, but resulted in relatively few study dropouts. Treatment with miglitol offers the elderly type 2 diabetic patient significant reductions in daylong glycemia as measured by HbA1c. The greater HbA1c reductions seen with once-a-day glyburide occurred at a cost of significant increases in weight, insulin levels, and the incidences of clinical and subclinical hypoglycemia, which did not occur in the miglitol groups. alpha-glucosidase inhibitors are a useful and relatively safe therapeutic option in the elderly patient with type 2 diabetes.

alpha-Glucosidase inhibitors.

Alpha-glucosidase inhibitors are antihyperglycemic agents that lower blood glucose by delaying the digestion and absorption of complex carbohydrates. They are competitive inhibitors of the enzymes in the brush border of enterocytes that cleave eligosaccharides to monosaccharides. Their major action is to reduce the rise of postprandial plasma glucose. In non-insulin-dependent diabetes mellitus patients, these inhibitors decrease postprandial plasma glucose by 40 to 50 mg/dL and hemoglobin A1C by 0.5% to 1.0%.