Secondary Sulfonylurea Failure Research Articles

Association among insulin receptor substrate1 genetic polymorphism, sulfonylurea therapeutic efficacy, and insulin resistance in patients with type 2 diabetes mellitus

Background Insulin receptor substrate-1 gene (IRS-1) is an endogenous substrate of the insulin receptor present in insulin-sensitive tissues, allowing insulin signaling to take place. The IRS-1, rs1801278 gene with Gly972Arg substitution polymorphism is one of the most commonly studied variants in relation with type 2 diabetes mellitus (T2DM). Objective The objective of this study was to detect the genetic association of the IRS-1, rs1801278 gene polymorphism with secondary sulfonylurea (SU) failure and insulin resistance (IR) in T2DM in Egyptian patients. Patients and methods A total of 81 T2DM Egyptian patients (49 nonresponders and 32 responders to SU) were recruited. Genotyping of IRS-1, rs1801278 single nucleotide polymorphism was done using a TaqMan allelic discrimination assay with allele-specific designed fluorescent probes. Results Taking GG genotype and G allele as references, the genotypic and allelic frequency distribution of the IRS-1 Gly972Arg rs1801278 single nucleotide polymorphism showed a significant difference with GA + AA genotypes and A allele, being of higher frequency in the nonresponders group when compared with the responder group (odds ratio: 8.79; 95% confidence interval: 1.11–69.37) and in IR patients when compared with non-IR ones (odds ratio: 4.27; 95% confidence interval: 1.2–14.4). The association of the SU response with the presence or absence of IR showed a statistically significant difference, with more IR patients in the nonresponder group. Conclusion IRS-1 rs1801278 gene with Gly972Arg substitution polymorphism may be a significant genetic associate for SU efficacy and IR in Egyptian patients with T2DM.

Clinical and Genetic Predictors of Secondary Sulfonylurea Failure in Type 2 Diabetes Patients: the Suclingen Study

Background: Due to several limitations in the study designs of sulfonylurea pharmacogenomics studies, we investigated the clinical and genetic predictors of secondary sulfonylurea failure in Type 2 diabetes patients. Materials & methods: Patients receiving the maximum sulfonylurea and metformin doses for >1year were enrolled. Secondary sulfonylurea failure was defined as HbA1c >7.0% (>53mmol/mol) after a 12-month follow-up. Results: By multivariate analysis, increased insulin resistance (HOMA2-IR), baseline HbA1c >7.0%, residing in eastern Peninsular Malaysia, and the CC genotype of rs757110 ABCC8 gene polymorphism were independent predictors of secondary sulfonylurea failure (p<0.05) while sulfonylurea-induced hypoglycemia was protective against such failure (p<0.05). Conclusion: Sulfonylurea does not benefit patients with an increased risk of secondary sulfonylurea failure.

Factors of primary and secondary sulfonylurea failure in type 2 diabetic subjects.

The aim of the present study was to investigate the value of clinical characteristics in predicting sulfonylurea (SU) treatment responses. All 747 subjects in the present study were from the Xiaoke Pill Clinical Trial evaluating the safety and efficacy of SU. Subjects had the same initial dose of glibenclamide and drug doses were adjusted every 4 weeks during the 48-week follow-up period. Primary SU failure was defined as a <10% reduction in fasting plasma glucose (FPG) at the end of Week 4 from randomization, whereas secondary SU failure was defined as a consecutive confirmed level of FPG >7 mmol/L. Kaplan-Meier survival analysis revealed that lower baseline basal disposition index (DI b ) and higher FPG predict secondary SU failure. Inversely, higher baseline DI b and lower FPG predict primary SU failure. Primary SU failure can predict secondary SU failure. The combination of lower baseline DI b with primary SU failure is a better predictor of secondary SU failure than lower baseline DI b or primary SU failure alone. Patients with good glycemic control and higher β-cell reserve at entry are more likely to experience primary SU failure but are less likely to experience secondary SU failure. By combining baseline DI b with initial response at the first month of treatment, we can get quick information about the long-term efficacy of SU treatment.

Kir6.2 E23K polymorphism is related to secondary failure of sulfonylureas in non‐obese patients with type 2 diabetes

The Kir6.2 E23K polymorphism was studied with a special reference to secondary sulfonylurea (SU) failure in non-obese patients with type2 diabetes. We recruited 278 non-obese (body mass index ≤30.0kg/m(2)) Japanese patients with type2 diabetes who had a history of SU treatment (for 11.2±6.3years) and compared the frequency of the secondary SU failure among the genotypes of the polymorphism. Genotyping of the Kir6.2 E23K was carried out by polymerase chain reaction-restriction fragment length polymorphism. The genotype frequencies of the polymorphism were similar to those previously reported in Japanese patients with type2 diabetes. The frequency with which patients deteriorated into secondary SU failure was significantly higher in those with the KK genotype than those with EE or EK genotypes. Among 214 patients who eventually received insulin therapy because of secondary SU failure, the period of SU treatment in those with the KK genotype was significantly shorter than those with the EE or EK genotype, although the period from diagnosis to the start of SU treatment was not significantly different. These data suggest that the Kir6.2 E23K polymorphism is related to the acceleration of secondary SU failure in non-obese Japanese patients with type2 diabetes.

Increment of C-peptide after glucagon injection determines the progressive nature of Japanese type 2 diabetes: A long-term follow-up study

Type 2 diabetes (T2D) is characterized by a steady worsening of β-cell dysfunction as the disease progresses. The objective of this study was to estimate the decline of insulin secretion in Japanese type 2 diabetic patients (T2D-patients) by glucagon injection over an observation period of more than 10 years. Thirty-three T2D-patients were followed for 10.4 ± 1.4 years. Fasting C-peptide immunoreactivity (FCPR), the 6 min value of CPR after glucagon injection (6MCPR), and the increment of CPR (ΔCPR) were measured at baseline and follow-up. FCPR, 6MCPR, ΔCPR were significantly lower at follow-up than at baseline (p<0.05, p<0.005, and p<0.0005, respectively). The annual change of ΔCPR was significantly (p<0.05) greater than the annual change of FCPR (-0.062 ± 0.076 ng/mL/year and -0.025 ± 0.067 ng/mL/year, respectively). In contrast, CPR-index (an index of β-cell function) and SUIT-index (secretory units of islets in transplantation) calculated based on fasting blood samples were unaltered. The annual changes of FCPR, 6MCPR, and ΔCPR were negatively correlated with the FCPR, 6MCPR, and ΔCPR values at baseline, respectively. Duration of diabetes, BMI, diabetic retinopathy, and secondary sulfonylurea failure at baseline were not correlated with the annual changes of FCPR, 6MCPR, and ΔCPR. In conclusion, our longitudinal observations suggest that β-cell function progressively declines in Japanese T2D-patients. The annual declines of ΔCPR were more prominent than the annual declines of FCPR. ΔCPR after glucagon injection may be more useful for estimating individual longitudinal insulin secretion than fasting blood samples.

Predictive characteristics of patients achieving glycaemic control with insulin after sulfonylurea failure

We investigated the clinical and metabolic parameters in type 2 diabetic patients who were inadequately controlled on sulfonylurea (SU) before initiating insulin therapy to characterise patients who are likely to achieve target glycaemic control with insulin analogues. A total of 120 Korean patients aged ≥ 40 years with insulin-naïve, poorly controlled, SU-treated type 2 diabetes were randomised on the basis of SU dose, and obesity with 1 : 1 ratio of insulin detemir (long-acting analogue; LAA) and 70% insulin aspart protamine and 30% insulin aspart (biphasic insulin analogue; BIA). Patients who failed to reach ≤ 20% glycated albumin (GA) at 3 weeks were switched to therapy with a twice-daily BIA for 16 weeks. Mean HbA(1c) , GA, fasting and stimulated plasma glucose levels were significantly reduced after 16 weeks compared with the baseline in all groups, and 40% of patients reached the target HbA(1c) ( ≤ 7%). Compared with responders, non-responders had significantly longer duration of diabetes and higher dose of glimepiride. However, there was no significant difference in insulin secretory profiles between responders and non-responders. Clinical factors such as diabetes duration, SU dose and BMI were independently associated with inadequate response to insulin analogues in patients with secondary failure. In type 2 diabetics with secondary SU failure, clinical parameters such as duration of diabetes (< 10 years), SU dose ( ≤ 4 mg) and BMI should be taken into consideration as important factors than laboratory indices related to β-cell function when predicting the response to insulin analogues.

Efficacy, safety and cost-effectiveness of insulin sensitizers as add-on therapy in metabolic syndrome in patients with secondary sulfonylurea failure: A comparative study

Objectives:Prevalence of metabolic syndrome (MS) is ~25% and it is currently becoming prevalent in children also. India is estimated to have the maximum number of patients of MS in the world. As insulin resistance is an integral part of MS and the rate of secondary sulfonylurea failure (SSUF) is also high, the present study was planned to evaluate the effects of insulin sensitizers as add-on therapy in MS with SSUF.Materials and Methods:An open-label, prospective, randomized study was conducted on 200 patients of MS with SSUF, included according to ATP III criteria, after dividing them into two groups. Group I patients were given pioglitazone 30 mg/day while group II patients were given metformin 1,000 mg/day as add-on therapy to the sulfonylurea already prescribed.Results:Fall in fasting blood glucose, glycosylated hemoglobin and serum triglycerides was higher with metformin, but rise in high-density lipoprotein–cholesterol was higher with pioglitazone. Only metformin caused a significant reduction in body mass index. Significant reduction in waist circumference, systolic blood pressure and diastolic blood pressure was not seen with any therapy. Incremental cost-effective ratio was almost six-times higher with pioglitazone.Conclusion:Among insulin sensitizers, metformin has more favorable, persistent and multifacet effects in MS with SSUF. Studies of longer duration are required for calculating reduction in the mortality and morbidity.

Endoplasmic reticulum stress in diabetes: New insights of clinical relevance

The endoplasmic reticulum (ER) is a cellular compartment responsible for multiple important cellular functions including the biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. A myriad of pathological and physiological factors perturb ER function and cause dysregulation of ER homeostasis, leading to ER stress. Accumulating evidence suggests that ER stress plays a role in the pathogenesis of diabetes, contributing to pancreatic β-cell loss and insulin resistance. ER stress may also link obesity, inflammation and insulin resistance in type 2 diabetes. In this review, we address the transition from physiology to pathology, namely how and why the physiological UPR evolves to a proapoptotic ER stress response in diabetes and its complications. Special attention was given to elucidate how ER stress could explain some of the 'clinical paradoxes' such as secondary sulfonylurea failure, initial worsening of retinopathy during tight glycemic control, insulin resistance induced by protease inhibitors and other clinically relevant observations.

The effects of metformin plus sulfonylurea therapy on clinical features of the metabolic syndrome

Insulin resistance is a well-known leading factor in the development of metabolic syndrome. The aim of this study was to evaluate metabolic effects of metformin added to sulfonylurea in unsuccessfully treated type 2 diabetic patients with metabolic syndrome. A group of thirty subjects, with type 2 diabetes, secondary sulfonylurea failure and metabolic syndrome were administered the combined therapy of sulfonylurea plus metformin for six months. Metformin 2000 mg/d was added to previously used sulfonylurea agent in maximum daily dose. Antihypertensive and hypolipemic therapy was not changed. The following parameters were assessed at the beginning and after six months of therapy: glycemic control, body mass index, waist circumference, blood pressure, triglycerides, total cholesterol and its fractions, homeostatic models for evaluation of insulin resistance and secretion (HOMA R, HOMA B) and C- peptide. Glycemic control was significantly improved after six months of the combined therapy: (fasting 789 vs. 10.61 mmol/l. p < 0.01; postprandial 11.12 vs. 12.61 mmol/l. p < 0.01, p < 0.01; glycosylated hemoglobin 6.81 is. 8.83%. p < 0.01) the body mass index and waist circumference were significantly lower (26.7 vs. 27.8 kg/m2, p < 0.01 and 99.7 vs. 101.4 cm for men, p < 0.01, 87.2 vs. 88.5 for women, p < 0.01). Fasting plasma triglycerides decreased from 3.37 to 2.45 mmol/l (p < 0.01) and HOMA R from 7.04 to 5.23 (p < 0.001). No treatment effects were observed on blood pressure, cholesterol, and residual insulin secretion. Administration of metformin in type 2 diabetes with metabolic syndrome decreased cardiovascular risk factors by reducing glycemia, triglycerides, BMI, central obesity and insulin resistance.

Clinical Medicine: Endocrinology and Diabetes: Gender-associated Differences in Weight Gain, Insulin Requirement and Metabolic control in Newly Insulin-treated Type 2 Diabetic Patients with Secondary Sulfonylurea Failure–-a One-year Observation

Objective The aim of the present study was to determine differences between male and female type 2 diabetic patients concerning body weight, metabolic control, insulin requirement and prevalence of vascular diseases during the first year insulin therapy. Patients and Methods We investigated 102 newly insulin-treated type 2 diabetic patients (60 female) with secondary sulfonylurea failure. Observation period was the first year insulin therapy. We compared BMI, HbA1c, lipids and insulin requirement at the begin and after one year, C-peptide and prevalence of vascular diseases at the start of insulin therapy. Results At the start of insulin substitution, omen had a higher BMI (27 + 3 versus 25 + 3; p &lt; 0.05). Women also required a higher insulin dose than did men (28 + 6 versus 24 + 6 IU/day) Mean HbA1c and cholesterol levels were similar in both groups whereas triglycerides were higher in women (244 + 88 versus 203 + 76 mg/dl; p &lt; 0.05). Both groups achieved a similar gain in body weight after one year (+2.5% versus +2.6%; NS). HbA1c decreased from 9.2 + 1.1 to 7.4% + 0.9% (–19%) in women and from 9.4 + 1.1 to 7.5% + 1.0% (–20%) in men. The prevalence of vascular diseases was not significantly different in both groups. Conclusions At the start of insulin therapy female type 2 diabetic patients showed a significant higher BMI and a higher insulin requirement than male patients. The metabolic control was similar in men and women, only the triglycerides were higher in the female patients. Weight gain and increase of needed insulin as well as prevalence of macroangiopathy were the same in both groups.

Effect of intensive insulin therapy on systemic nitric oxide levels and adenosine deaminase activity in secondary sulfonylurea failure

Effect of intensive insulin therapy on systemic nitric oxide levels and adenosine deaminase activity in secondary sulfonylurea failure

Endoplasmic reticulum stress in beta cells: Latent mechanism of secondary sulfonylurea failure in type 2 diabetes?

Sulfonylureas, by stimulating beta cell to secrete insulin, are still largely used for treatment of type 2 diabetic patients. More recently concern has been raised with respect to possible adverse effects associated with the use of these agents, like favoring beta cell apoptosis and beta cell exhaustion, which is believed as the reason for high rate secondary sulfonylurea failure. Endoplasmic reticulum (ER) stress often occurred when load of client protein exceed the folding capacity in secretory cell. Here, we hypothesize that overstimulation by chronic use of sulfonylureas could probably leads to ER stress and finally apoptosis in beta cell, which might be the latent mechanism for secondary sulfonylurea failure.

Contemporary Analysis of Secondary Failure of Successful Sulfonylurea Therapy

To revise older estimates of secondary failure that may no longer describe the contemporary pattern of sulfonylurea (SU) monotherapy and to identify predictors of such failure. We identified 4,091 patients who achieved hemoglobin A1c (A1C) <8% within 1 year after initiation of SU therapy as their first-ever antihyperglycemic drug after January 1, 1996. The study subjects underwent follow-up until they added or switched antihyperglycemic medication, had A1C > or =8%, or terminated health plan membership or until December 31, 2004. We defined secondary failure by using two separate but overlapping approaches: (1) the addition of or switch to another antihyperglycemic drug after 6 months of SU therapy or (2) the first A1C measurement > or =8.0%. The level of A1C achieved within 1 year after initiation of SU treatment was the most powerful predictor of secondary SU failure. About 50% of patients whose best A1C was 7.0% to 7.9% added or switched antihyperglycemic drugs within 40 months, whereas it took nearly 60 months for those in the 6.0% to 6.9% A1C category and 74 months in the A1C <6.0% category to reach a 50% failure rate. Similarly, more than half of those patients whose best A1C was 7.0% to 7.9% had an A1C value > or =8% within 24 months, whereas it took nearly 60 months for study subjects in the 6.0% to 6.9% A1C category and 86 months for those in the <6.0% category to have SU failure. Younger age and weight gain were also predictive of failure. Secondary failure of SU therapy is inversely associated with the level of A1C achieved within the first year of SU monotherapy. Clinicians should quickly consider therapeutic adjustments to lower the A1C level rapidly if initial success is not achieved.

The E23K Variant of KCNJ11 Encoding the Pancreatic β-Cell Adenosine 5′-Triphosphate-Sensitive Potassium Channel Subunit Kir6.2 Is Associated with an Increased Risk of Secondary Failure to Sulfonylurea in Patients with Type 2 Diabetes

Several studies suggest that genetic factors may play a role in the different responses to antidiabetic therapy; however, conclusive evidence is still lacking. The objective of the study was to investigate whether diabetic patients carrying the E23K variant in KCNJ11 are at increased risk for secondary sulfonylurea failure. Secondary sulfonylurea failure was defined as fasting plasma glucose greater than 300 mg/dl despite sulfonylurea-metformin combined therapy and appropriate diet, in the absence of other conditions causing hyperglycemia. The study was conducted in an ambulatory care facility. A total of 525 Caucasian type 2 diabetic patients were enrolled in the study. Sulfonylurea treatment was followed by sulfonylurea-metformin combined therapy and then insulin treatment. Secondary failure was the main outcome measure. Of the diabetic patients enrolled in the study, 38.5% were E23E homozygous, 51.4% were E23K heterozygous, and 10.1% were K23K homozygous. The frequency of carriers of the K allele was 58 and 66.8% among patients treated with oral therapy or secondary sulfonylurea failure, respectively (odds ratio, 1.45; 95% confidence interval, 1.01-2.09; P = 0.04). Adjustment for age, gender, fasting glycemia, glycosylated hemoglobin, age at diagnosis, and duration of diabetes in a logistic regression analysis did not change this association (odds ratio, 1.69; 95% confidence interval, 1.02-2.78; P = 0.04). Islets isolated from carriers of the K allele showed no differences in glucose-stimulated insulin secretion and a tendency toward reduced response upon glibenclamide stimulation (P = 0.09). After 24-h exposure to high (16.7 mmol/liter) glucose concentration, impairment of glibenclamide-induced insulin release was significantly (P = 0.01) worse with the E23K variant. These data suggest that the E23K variant in KCNJ11 may influence the variability in the response of patients to sulfonylureas, thus representing an example of pharmacogenetics in type 2 diabetes.

Weight Gain and Metabolic Control in Newly Insulin-treated Patients With Type 2 Diabetes With Different Insulin Regimens

ABSTRACT OBJECTIVE Weight gain with insulin therapy is a well-known side effect of the pharmacologic management of type 2 diabetes, but appears to occur less frequently when an insulin analogue is used.The aim of the study was to determine differences in weight gain and insulin requirement in patients on different insulin therapy regimens. METHODS We retrospectively evaluated 154 patients with type 2 diabetes newly treated with insulin due to failure of secondary sulfonylurea treatment. The indication was secondary sulfonylurea failure with A1C > 7.5% (2 measurements). All patients had participated in a 5-day diabetes education program and were permitted to select their own insulin regimen from the following choices: 1) conventional insulin therapy (an insulin mix containing 25 or 30% regular insulin or insulin lispro and 70 or 75% NPH insulin injected twice daily); 2) the combination of insulin (insulin mix or NPH insulin, injected once daily) and sulfonylurea (glimepiride or gliclazide); or 3) prandial insulin therapy consisting of regular or lispro insulin as short-acting insulin 3 times daily and bedtime NPH insulin. The following parameters were compared at the start of insulin therapy and after 12 months: weight, body mass index (BMI), glycosylated hemoglobin (A1C), cholesterol, triglycerides (TG), insulin requirement and the influence of metformin on the insulin requirement. In addition, we measured basal C-peptide at the start of insulin therapy and evaluated the incidence of hypoglycemia during the observation period. RESULTS Weight gain was similar in the 3 groups: 2.6%, 2.7% and 2.5%, respectively; mean weight gain was 2.1 kg (2.6%). A1C decreased by − 2.2% (23%), -1.8% (19%) and − 1.8% (18%), respectively. The group who received the insulin and sulfonylurea combination required a much lower initial insulin dose than the other groups. The increase in the required insulin dose over 12 months was similar in the 3 groups: 8% in patients receiving insulin and sulfonylurea, 10% in those receiving the conventional insulin regimen and 8% in the group receiving prandial insulin substitution. Mean total cholesterol levels did not decrease significantly from baseline in the 3 groups (decrease: -4%, -3% and − 5%, respectively), and there were no significant difference between the groups. TG levels decreased to a similar extent: 20, 18 and 17%, respectively.The patients in each group who also took metformin experienced a 22% lower increase in their mean insulin requirement than did those who used insulin without metformin. CONCLUSION Weight gain in insulin-treated patients with type 2 diabetes was similar with different insulin regimens; the mean increase at 1 year was 2.6%. The 3 patient groups experienced similar metabolic control and similar increases in insulin requirements. The additional intake of metformin was associated with a 22% lower increase in the required insulin dose.

Secondary sulfonylurea failure: Comparison of period until insulin treatment between diabetic patients treated with gliclazide and glibenclamide

We retrospectively evaluated a possible difference in periods until start of insulin treatment between type 2 diabetic patients treated with gliclazide (GCZ) and glibenclamide (GBC), because GCZ might be protective for beta cells than GBC. Subjects were Japanese patients. GCZ group consisted of patients treated with GCZ alone or with GCZ and GBC in the separate treatment periods in combination with or without other oral hypoglycemic agents (OHAs), while GBC group consisted of patients with GBC alone or in combination with other OHAs except GCZ. The periods until the treatment of insulin commenced were calculated using the Kaplan-Meier method. Proportional hazards models were used to adjust the differing variables between GCZ and GBC groups. The periods until the start of insulin treatment from diabetes onset, diabetes treatment, or GCZ or GBC treatment were significantly longer in the GCZ group than those in GBC group ( P < 0.001 in each group). Independent variables affecting the period were average HbA1c levels during GCZ or GBC treatment (hazard ratio = 2.5 per %), other OHAs combined (hazard ratio = 1.9 on combination), and difference between GCZ and GBC groups (hazard ratio = 0.5 on GCZ). These results imply that GCZ may be more protective against secondary beta cell failure than GBC.

The Arg972 variant in insulin receptor substrate-1 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes.

The aim of this study was to investigate whether diabetic patients carrying the Arg(972) insulin receptor substrate-1 (IRS-1) variant are at increased risk for secondary failure to sulfonylurea. A total of 477 unrelated Caucasian type 2 diabetic patients were recruited according to the following criteria: onset of diabetes after age 35 years, absence of ketonuria at diagnosis, and anti-GAD(-) antibody. Type 2 diabetes was diagnosed according to the American Diabetes Association criteria. Patients with secondary sulfonylurea failure were defined as those requiring insulin due to uncontrolled hyperglycemia (fasting plasma glucose >300 mg/dl) despite sulfonylurea-metformin combined therapy, appropriate diet, and absence of any conditions causing hyperglycemia. Of the total patients, 53 (11.1%) were heterozygous for the Arg(972) IRS-1 variant, 1 (0.2%) was homozygous, and the remainder (88.7%) were homozygous for the wild-type allele. The genotype frequency of the Arg(972) IRS-1 variant was 8.7% among diabetic patients well controlled with oral therapy and 16.7% among patients with secondary failure to sulfonylurea (odds ratio 2.1 [95% CI 1.18-3.70], P = 0.01). Adjustment for age, sex, BMI, metabolic control, age at diagnosis, duration of diabetes, and Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma2 gene in a logistic regression analysis with secondary failure to sulfonylurea as a dependent variable did not change this association (2.0 [1.38-3.86], P = 0.038). These data demonstrate that the Arg(972) IRS-1 variant is associated with increased risk for secondary failure to sulfonylurea, thus representing a potential example of pharmacogenetics in type 2 diabetes.

Targeting postprandial blood glucose concentrations reduced haemoglobin A1c concentrations in type 2 diabetes mellitus

(2000) Diabetes Care 23, 1236. Bastyr EJ 3d, Stuart CA, Brodows RG, et al, . for the IOEZ Study Group. . Therapy focused on lowering postprandial glucose, not fasting glucose,...

Glimepiride: role of a new sulfonylurea in the treatment of type 2 diabetes mellitus.

To review the clinical pharmacology data regarding the sulfonylurea glimepiride, and to summarize the clinical trials of glimepiride efficacy and safety alone and in combination with insulin for the treatment of type 2 diabetes mellitus. A MEDLINE database search (English language, January 1985-April 1997) was performed to identify relevant published articles, including reviews and abstracts; the manufacturer (Hoechst Marion Roussel, Kansas City, MO) provided unpublished data. Pharmacology information was taken from representative original research articles. Eight clinical studies were selected for analysis on the basis of large enrollment, appropriate study design, and publication of results. All clinical trials, published and unpublished, were reviewed. Glimepiride is a sulfonylurea that is pharmacologically distinct from other sulfonylureas because of differences in receptor-binding properties and potentially selective effects on ATP-sensitive K+ channels. The pharmacokinetic and pharmacodynamic profile of glimepiride makes it suitable for once-daily dosing. The safety and efficacy of glimepiride have been confirmed in studies involving more than 5000 patients with type 2 diabetes. In one study, once-daily doses of 1-8 mg reduced fasting plasma glucose from baseline by 43-74 mg/dL more than did placebo (p < 0.001), and hemoglobin (Hb) A1C values decreased by 1.2-1.9% more than with placebo (p < 0.001). Two-thirds of patients achieved tight control (i.e., HbA1C < or = 7.2%). Glimepiride was as effective as second-generation sulfonylureas. The most common adverse events were dizziness and headache, but no single adverse event occurred in more than 2% of patients. Glimepiride appears to be a useful option for patients with type 2 diabetes not controlled by diet and exercise and who want to achieve tight glucose control. Glimepiride can be used alone, in combination with other antihyperglycemic agents, or in patients with secondary sulfonylurea failure, as an adjunct to insulin therapy.

Effect of insulin therapy on body fat distribution in NIDDM patients with secondary sulfonylurea failure: a preliminary report.

To clarify the influence of insulin therapy on body weight and fat distribution, we compared these parameters in five non-insulin dependent diabetes mellitus (NIDDM) patients, with secondary sulfonylurea failure, before and after insulin therapy. Body weight increased significantly after instituting insulin treatment. However, the visceral to subcutaneous fat (V/S) ratio decreased significantly due to a marked increase in S-fat without a change in V-fat. Insulin therapy necessitated by sulfonylurea failure does not appear to accelerate the atherogenic process in NIDDM patients as there is no increase in visceral fat.