Robert E. Ratner

Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial

BACKGROUND New treatments for type 2 diabetes mellitus are needed to retain insulin-glucose coupling and lower the risk of weight gain and hypoglycaemia. We aimed to investigate the safety and efficacy of liraglutide as monotherapy for this disorder. METHODS In a double-blind, double-dummy, active-control, parallel-group study, 746 patients with early type 2 diabetes were randomly assigned to once daily liraglutide (1.2 mg [n=251] or 1.8 mg [n=247]) or glimepiride 8 mg (n=248) for 52 weeks. The primary outcome was change in proportion of glycosylated haemoglobin (HbA(1c)). Analysis was done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NTC00294723. FINDINGS At 52 weeks, HbA(1c) decreased by 0.51% (SD 1.20%) with glimepiride, compared with 0.84% (1.23%) with liraglutide 1.2 mg (difference -0.33%; 95% CI -0.53 to -0.13, p=0.0014) and 1.14% (1.24%) with liraglutide 1.8 mg (-0.62; -0.83 to -0.42, p<0.0001). Five patients in the liraglutide 1.2 mg, and one in 1.8 mg groups discontinued treatment because of vomiting, whereas none in the glimepiride group did so. INTERPRETATION Liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and leads to greater reductions in HbA(1c), weight, hypoglycaemia, and blood pressure than does glimepiride.

The Effect of Metformin and Intensive Lifestyle Intervention on the Metabolic Syndrome: The Diabetes Prevention Program Randomized Trial

Context Intensive diet and exercise or metformin can prevent the development of diabetes in individuals with impaired fasting glucose, but the effects of these interventions on development of the metabolic syndrome are unknown. Contribution This secondary analysis of Diabetes Prevention Program data showed that lifestyle intervention and metformin each reduced the development of the metabolic syndrome among the 45% of participants who did not have it at baseline. The impact of lifestyle intervention was much more marked than that of metformin. Implications Interventions that prevent diabetes will also reduce the development of the metabolic syndrome. The Editors Considerable attention has recently been paid to the metabolic syndrome, a constellation of risk factors associated with insulin resistance and increased cardiovascular and diabetes risk. The third report of the National Cholesterol Education Programs Adult Treatment Panel now calls for the identification and treatment of this high-risk state and provides a simple set of criteria for diagnosis (1). The World Health Organization (WHO) and the American College of Endocrinology have also provided definitions (2). Although recent studies have provided estimates of the prevalence of the metabolic syndrome in the United States (3, 4), its interrelationship with impaired glucose tolerance is unclear. In particular, it is largely unknown what proportion of participants with impaired glucose tolerance have the metabolic syndrome and whether this varies by ethnicity, age, and sex. Clearly, because an elevated blood glucose level is a common criterion for all definitions, a close association is to be expected. This association may be even stronger in the subgroup of persons with both impaired glucose tolerance and impaired fasting glucose (that is, a fasting plasma glucose level 6.1 to 6.9 mmol/L [110 to 125 mg/dL]). The extent to which we may be able to reduce cardiovascular risk in patients with impaired glucose tolerance by preventing the metabolic syndrome through lifestyle or medication interventions is also unknown. The Diabetes Prevention Program (5, 6) provides a unique opportunity to begin to address these issues. It involves a large sample of more than 3000 participants with impaired glucose tolerance who were carefully followed and randomly allocated to treatment with an intensive lifestyle intervention, metformin, or placebo. In this report, we address 2 questions: the prevalence of the metabolic syndrome at baseline in the trial population (and how this varies by age and sex) and whether the 2 interventions reduced the incidence of new cases of the metabolic syndrome or increased resolution of existing cases compared with placebo. Methods Participants and Procedures Full details of the protocol have been published elsewhere (5, 6). The current report includes 3234 participants seen at baseline. This number includes participants from the 3 treatment arms investigated (that is, standard lifestyle or placebo, intensive lifestyle, and metformin), but not participants from the troglitazone arm, which was discontinued. Individuals were recruited between June 1996 and May 1999 from a variety of sources, including community screenings and household mailings, on the basis of perceived risk for diabetes. Written informed consent was obtained from all participants before screening, consistent with the Declaration of Helsinki and the guidelines of each centers institutional review board. The initial screening step consisted of a fasting glucose measurement. If the participant was eligible, this was followed by a 75-g oral glucose tolerance test. Inclusion criteria were as follows: a fasting plasma glucose level of 5.3 to 7.0 mmol/L (95 to 125 mg/dL) (7.0 mmol/L [125 mg/dL] for Native Americans); a 2-hour plasma glucose level of 7.8 to 11.1 mmol/L (140 to 199 mg/dL) following the glucose load; age of at least 25 years; and body mass index of at least 24 kg/m2 (22 kg/m2 for Asian Americans because of differences in body size in this group). Main exclusion criteria were recent myocardial infarction, symptoms of coronary heart disease, major illness, previous diagnosis of diabetes, use of medications known to impair glucose tolerance, or triglyceride level of at least 6.8 mmol/L (600 mg/dL), as previously detailed (5). Standardized interviewer-administered questionnaires were used to obtain self-reported data on personal medical history, medications, and diet. Self-reported race or ethnicity was classified according to the question used in the 1990 U.S. Census questionnaire (7). Overall, adiposity was assessed by body mass index. Waist circumference was assessed in the standing position midway between the highest point of the iliac crest and the lowest point of the costal margin in the mid-axillary line. All anthropometric measures reflected the average of 2 measurements. Blood pressure was measured twice at 30-second intervals by using a standard mercury manometer. The participant was seated in a chair for 5 minutes before the first measurement was taken, and the mean of the 2 readings was used in the analyses. The metabolic syndrome was defined according to criteria from the National Cholesterol Education Programs Adult Treatment Panel III (1), namely 3 or more of the following conditions: waist circumference greater than 102 cm in men and greater than 88 cm in women; serum triglyceride level of at least 1.7 mmol/L (150 mg/dL); high-density lipoprotein (HDL) cholesterol level less than 1.03 mmol/L (<40 mg/dL) in men and less than 1.3 mmol/L (<50 mg/dL) in women; blood pressure of 130/85 mm Hg or greater; and fasting plasma glucose level of 6.2 mmol/L (110 mg/dL). Participants who were being treated with blood pressurelowering or triglyceride-lowering medications (niacin or fibric acid derivatives) were classified as positive for the respective criterion. We chose the Adult Treatment Panel III (1) criteria because they are commonly used in the United States and are simpler to apply in clinical practice than, for example, the WHO criteria (2). Participants were randomly assigned to receive 1 of 3 interventions: standard lifestyle recommendations plus metformin, 850 mg twice per day; standard lifestyle recommendations plus placebo; or an intensive program of lifestyle intervention. The randomization was done centrally by computer; assignments to the lifestyle group were blinded until randomization, while assignments to the medication groups were blinded until the end of the study. The goals of the lifestyle program were to achieve and maintain a weight reduction of at least 7% of clinical body weight through a healthy low-calorie, low-fat diet and to engage in physical activity of moderate intensity, such as brisk walking, for at least 150 minutes per week. Participants were seen quarterly, when blood pressure was assessed. Fasting glucose levels were determined at the 6-month visits, and fasting lipid levels and waist circumference were measured annually. Further details have been published elsewhere (5, 6). Figure 1 shows the number of participants observed at each annual examination by treatment group. Figure 1. Randomly assigned participants by treatment group and annual visit. Laboratory Methods All of the analytic measurements were performed at the central biochemistry laboratory (Northwest Lipid Research Laboratories, University of Washington, Seattle, Washington). Fasting plasma glucose level was measured on a chemistry autoanalyzer by the glucokinase method. Insulin measurements were performed by using a polyethylene glycolaccelerated double antibody radioimmunoassay method developed in the Diabetes Endocrinology Research Center Immunoassay Core Laboratory (University of Washington, Seattle, Washington). This method is based on the use of an antihuman insulin guinea pig antibody and measures total immunoreactive insulin. The homeostasis model assessment for insulin resistance was calculated as follows (8): Measurements of total plasma cholesterol and triglycerides were performed enzymatically on a chemistry autoanalyzer by using methods standardized to the Centers for Disease Control and Prevention reference methods (9). We obtained HDL fractions for cholesterol analysis by treating whole plasma with dextran sulfate magnesium chloride to precipitate all of the apolipoprotein Bcontaining lipoproteins (10). We calculated low-density lipoprotein cholesterol by using the Friedewald equation (11). In participants with triglyceride levels higher than 4.5 mmol/L (>400 mg/dL), the lipoprotein fractions were separated by using preparative ultracentrifugation of plasma by beta quantification (12). Statistical Analyses Participants were followed for an average of 3.2 years (range, 0.04 to 5.0 years) from the start of the study in June 1996 through 31 July 2001, a period 4 months longer than that reported previously (5). This period was chosen to maximize the available data that were collected during the masked phase of the Diabetes Prevention Program, since unmasking occurred in early August 2001. Random treatment assignments were stratified according to clinical center and were generated by the coordinating center through computer linkup to the field center at time of randomization. Therefore, assignment was unknown until randomization. Assignments to metformin and placebo were double-blinded. The study design and analysis followed the intention-to-treat principle. Nominal (unadjusted) P values and confidence intervals are reported. Logistic regression was used to compare the prevalence of the metabolic syndrome and its components at baseline among the demographic variables. The time to the outcome was assessed by using life-table methods (13). Modified product-limit curves for the cumulative incidence of the metabolic syndrome and for its resolution were compared by using the log-rank test. The estimated cumulative incidence, or resolution, at 3 years and the ris

Cardiac Outcomes After Screening for Asymptomatic Coronary Artery Disease in Patients With Type 2 Diabetes: The DIAD Study: A Randomized Controlled Trial

CONTEXT Coronary artery disease (CAD) is the major cause of mortality and morbidity in patients with type 2 diabetes. But the utility of screening patients with type 2 diabetes for asymptomatic CAD is controversial. OBJECTIVE To assess whether routine screening for CAD identifies patients with type 2 diabetes as being at high cardiac risk and whether it affects their cardiac outcomes. DESIGN, SETTING, AND PATIENTS The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study is a randomized controlled trial in which 1123 participants with type 2 diabetes and no symptoms of CAD were randomly assigned to be screened with adenosine-stress radionuclide myocardial perfusion imaging (MPI) or not to be screened. Participants were recruited from diabetes clinics and practices and prospectively followed up from August 2000 to September 2007. MAIN OUTCOME MEASURE Cardiac death or nonfatal myocardial infarction (MI). RESULTS The cumulative cardiac event rate was 2.9% over a mean (SD) follow-up of 4.8 (0.9) years for an average of 0.6% per year. Seven nonfatal MIs and 8 cardiac deaths (2.7%) occurred among the screened group and 10 nonfatal MIs and 7 cardiac deaths (3.0%) among the not-screened group (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.44-1.88; P = .73). Of those in the screened group, 409 participants with normal results and 50 with small MPI defects had lower event rates than the 33 with moderate or large MPI defects; 0.4% per year vs 2.4% per year (HR, 6.3; 95% CI, 1.9-20.1; P = .001). Nevertheless, the positive predictive value of having moderate or large MPI defects was only 12%. The overall rate of coronary revascularization was low in both groups: 31 (5.5%) in the screened group and 44 (7.8%) in the unscreened group (HR, 0.71; 95% CI, 0.45-1.1; P = .14). During the course of study there was a significant and equivalent increase in primary medical prevention in both groups. CONCLUSION In this contemporary study population of patients with diabetes, the cardiac event rates were low and were not significantly reduced by MPI screening for myocardial ischemia over 4.8 years. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00769275.

The Cost-Effectiveness of Lifestyle Modification or Metformin in Preventing Type 2 Diabetes in Adults with Impaired Glucose Tolerance

Context The Diabetes Prevention Program (DPP) showed that lifestyle changes or metformin effectively decreased the development of type 2 diabetes in adults with impaired glucose tolerance. The economics of these interventions is important to policymakers. Contribution This cost-effectiveness model estimates that the DPP life-style intervention would cost society about

Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance

8800 and metformin would cost about

Prevention of Diabetes in Women with a History of Gestational Diabetes: Effects of Metformin and Lifestyle Interventions

29900 per quality-adjusted life-year saved. While lifestyle intervention had a favorable cost-effectiveness profile at any adult age, metformin was not cost-effective after age 65 years. Implications The cost-effectiveness of lifestyle intervention to prevent type 2 diabetes in high-risk individuals is within the range that American society typically finds acceptable for health care interventions. The Editors During the past half century, the number of persons with diagnosed diabetes in the United States has increased 4- to 6-fold (1). Recent large clinical trials from Asia, Europe, and North America have demonstrated that behavioral and medication interventions can delay or prevent the development of type 2 diabetes in persons with impaired glucose tolerance, which is defined by a plasma glucose level between 7.77 mmol/L (140 mg/dL) and 11.04 mmol/L (199 mg/dL) 2 hours after a 75-g oral glucose load (2-6). The Diabetes Prevention Program (DPP) randomly assigned 3234 nondiabetic persons 25 years of age or older with impaired glucose tolerance and fasting glucose levels between 5.27 mmol/L (95 mg/dL) and 6.94 mmol/L (125 mg/dL) to placebo; a lifestyle-modification program with the goals of at least a 7% weight loss and 150 minutes of physical activity per week; or metformin, 850 mg twice daily (4). The mean age of participants was 51 years, and the mean body mass index was 34.0 kg/m2; 68% were women and 45% were members of minority groups (4). The average follow-up was 2.8 years. Compared with the placebo intervention, the lifestyle intervention reduced the incidence of type 2 diabetes by 58% and the metformin intervention reduced the incidence of type 2 diabetes by 31% (4). We have previously described the costs of the DPP interventions and their cost-effectiveness within the 3-year trial period (7, 8). In this analysis, we project the costs, health outcomes, and cost-effectiveness of the DPP lifestyle and metformin interventions over a lifetime relative to the placebo intervention. Methods Clinical Trial The lifestyle intervention involved a healthy, low-calorie, low-fat diet and moderate physical activity, such as brisk walking. The lifestyle intervention was implemented with a 16-lesson core curriculum covering diet, exercise, and behavior modification that was taught by case managers on a one-on-one basis, followed by individual sessions (usually monthly) and group sessions with case managers (9). At the end of the study, 38% of participants in the lifestyle intervention group had lost at least 7% of their initial body weight. The metformin and placebo interventions were initiated at a dosage of 850 mg once a day. At 1 month, the dosage of metformin or placebo was increased to 850 mg twice daily. Case managers reinforced adherence during individual quarterly sessions (10). At the end of the study, 72% of participants in the metformin intervention group and 77% of participants in the placebo intervention group took at least 80% of the prescribed dose. All participants received standard lifestyle recommendations through written information and an annual 20- to 30-minute individual session that emphasized the importance of a healthy lifestyle (10). Simulation Model We assessed the progression from impaired glucose tolerance to onset of diabetes to clinically diagnosed diabetes to diabetes with complications and death by using a lifetime simulation model originally developed by the Centers for Disease Control and Prevention and Research Triangle Institute International. The model has a Markov structure and includes annual transition probabilities between disease states (11). In addition to disease progression, the model tracks costs and quality-adjusted life-years (QALYs). The model has been described elsewhere (11). For our analyses, we modified the model to include data from the DPP on progression, costs, and quality of life associated with impaired glucose tolerance, data from the United Kingdom Prospective Diabetes Study (UKPDS) on diabetes progression and complications, and new data on cost and quality of life associated with diabetes. A technical report describing the model is available. Supplement. Technical Report Disease Progression, Complications, and Comorbid Conditions Impaired Glucose Tolerance to Onset of Type 2 Diabetes We analyzed data from the DPP to assess the annual hazard of diabetes onset in the lifestyle, metformin, and placebo intervention groups. For patients receiving the placebo intervention, the annual hazard of diabetes onset was 10.8 per 100 person-years. At 3 years of follow-up, the risk reductions for the lifestyle and metformin interventions were 55.8% and 29.9%, respectively. In the base-case analysis, we assumed that the lifestyle and metformin interventions would be applied until diabetes onset and that the health and quality-of-life benefits associated with the interventions persisted until diabetes onset. Complications and Comorbid Conditions Associated with Impaired Glucose Tolerance We analyzed data from the DPP and other published sources to assess the prevalence of complications and comorbid conditions in participants with impaired glucose tolerance. At baseline, 6.0% of DPP participants had microalbuminuria and 0.4% had nephropathy. The DPP did not measure peripheral neuropathy, but previous studies found that the prevalence of neuropathy in persons with impaired glucose tolerance was 74% of that in persons with newly diagnosed type 2 diabetes (12) and 12.3% of persons with newly diagnosed type 2 diabetes have neuropathy (13). Therefore, we assumed that at baseline, 8.5% of DPP participants had clinical neuropathy. At baseline, 28% of DPP participants had hypertension, 45% had dyslipidemia, 7% were smokers, 1.1% had a history of cerebrovascular disease, and 2.0% had a history of myocardial infarction. No other complications were present. We assumed that during impaired glucose tolerance, microvascular or neuropathic complications would not progress. We assumed that hypertension and dyslipidemia developed at the rates observed in the DPP. On the basis of 2 large studies (14, 15), we assumed that the incidences of coronary heart disease and cerebrovascular disease in patients with impaired glucose tolerance were 58% and 56%, respectively, of those observed in patients with type 2 diabetes. We further assumed that nondiabetes-related mortality for persons with impaired glucose tolerance was the same as for persons with diabetes (16). Onset of Type 2 Diabetes to Clinical Diagnosis of Type 2 Diabetes In the DPP, participants were tested for diabetes every 6 months; diabetes was diagnosed at onset. In routine clinical practice, type 2 diabetes is estimated to develop 8 to 12 years before its clinical diagnosis (17, 18). In our base-case analysis, we therefore assumed that a 10-year delay occurred between the onset and clinical diagnosis of diabetes. Participants in the DPP had a mean hemoglobin A1c level of 6.4% at the onset of diabetes. Participants in the UKPDS had a mean hemoglobin A1c of 7.1% after a dietary run-in period but before randomization (13). Both DPP placebo participants and UKPDS participants received standard lifestyle recommendations. Accordingly, we assumed that during the 10-year interval between onset and clinical diagnosis of diabetes, patients were treated for type 2 diabetes and that hemoglobin A1c level increased at 0.07% per year from 6.4% to 7.1%. Complications and Comorbid Conditions Associated with Undiagnosed Diabetes We further assumed that between onset and clinical diagnosis of diabetes, microvascular and neuropathic complications progressed slowly, such that by clinical diagnosis of type 2 diabetes, their prevalence reached the level observed in the UKPDS cohort at randomization (13, 19, 20). We assumed that blood pressure and lipid levels progressed as they did in DPP participants and that cardiovascular complications occurred as they would in type 2 diabetes according to risk factors and hemglobin A1c level (21, 22). Clinical Diagnosis of Type 2 Diabetes to Diabetes with Complications and Death We assumed that after clinical diagnosis, all persons with type 2 diabetes received intensive glycemic management as described in the UKPDS (13). We modeled changes in hemoglobin A1c and diabetes treatments to reflect those observed in the UKPDS intensive therapy group. We based risk for retinopathy progression on UKPDS 38 (23), risk for nephropathy progression on UKPDS 64 (20), and risk for neuropathy progression on UKPDS 33 (13). We based risk for cerebrovascular disease on UKPDS 60 (22) and risk for coronary heart disease on UKPDS 56 (21). Costs Costs of Impaired Glucose Tolerance To estimate the total direct medical costs of impaired glucose tolerance, we considered the costs of the DPP interventions (the cost of identifying participants, implementing and maintaining the interventions, and monitoring and treating the side effects of the interventions) and the costs of the medical care outside the DPP (7). In analyses from the perspective of society, we included both direct medical costs and direct nonmedical costs. We did not include indirect costs because they are captured in the assessment of QALYs (24). Table 1 shows the total direct medical costs by treatment group, sex, and year in the DPP (7). Costs were higher in the lifestyle and metformin interventions than in the placebo intervention and higher in women than in men. Costs decreased over time in all 3 intervention groups but after year 1 tended to decrease more in the lifestyle than t

Randomized trial of an inhibitor of formation of advanced glycation end products in Diabetic nephropathy

BACKGROUND Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance. METHODS We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing. RESULTS Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima-media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007). CONCLUSIONS As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).

Unrecognized Diabetes Among Hospitalized Patients

CONTEXT A past history of gestational diabetes mellitus (GDM) confers a very high risk of postpartum development of diabetes, particularly type 2 diabetes. OBJECTIVE The Diabetes Prevention Program (DPP) sought to identify individuals with impaired glucose tolerance (IGT) and intervene in an effort to prevent or delay their progression to diabetes. This analysis examined the differences between women enrolled in DPP with and without a reported history of GDM. DESIGN The DPP was a randomized, controlled clinical trial. SETTING The study was a multicenter, National Institutes of Health-sponsored trial carried out at 27 centers including academic and Indian Health Services sites. PATIENTS A total of 2190 women were randomized into the DPP and provided information for past history of GDM. This analysis addressed the differences between those 350 women providing a past history of GDM and those 1416 women with a previous live birth but no history of GDM. INTERVENTIONS Subjects were randomized to either standard lifestyle and placebo or metformin therapy or to an intensive lifestyle intervention. MAIN OUTCOMES The primary outcome was the time to development of diabetes ascertained by semiannual fasting plasma glucose and annual oral glucose tolerance testing. Assessments of insulin secretion and insulin sensitivity were also performed. RESULTS Whereas entering the study with similar glucose levels, women with a history of GDM randomized to placebo had a crude incidence rate of diabetes 71% higher than that of women without such a history. Among women reporting a history of GDM, both intensive lifestyle and metformin therapy reduced the incidence of diabetes by approximately 50% compared with the placebo group, whereas this reduction was 49 and 14%, respectively in parous women without GDM. These data suggest that metformin may be more effective in women with a GDM history as compared with those without. CONCLUSIONS Progression to diabetes is more common in women with a history of GDM compared with those without GDM history despite equivalent degrees of IGT at baseline. Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM.

Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus

Background/Aims: Pimagedine inhibits the formation of advanced glycation end products and slows the progression of diabetic complications in experimental models. This study was undertaken to determine if pimagedine ameliorates nephropathy in type 1 (insulin-dependent) diabetes mellitus. Methods: This was a randomized, double-masked, placebo-controlled study performed in 690 patients with type 1 diabetes mellitus, nephropathy, and retinopathy. The patients received twice daily dosing with placebo, pimagedine 150 mg, or pimagedine 300 mg for 2–4 years. The primary end point was the time to doubling of serum creatinine; the secondary end points included evaluations of proteinuria, kidney function, and retinopathy. Results: Serum creatinine doubled in 26% (61/236) of the placebo-treated patients and in 20% (91/454) of those who received pimagedine (p = 0.099). The estimated glomerular filtration rate decreased more slowly in the pimagedine-treated patients with a 36-month decrease from baseline of 6.26 ml/min/1.73 m2 as compared with 9.80 ml/min/1.73 m2 in the placebo-treated patients (p = 0.05), and pimagedine reduced the 24-hour total urinary proteinuria. (The mean reduction from baseline at month 36 was 732 mg/24 h at the low dose and 329 mg/24 h at the high dose as compared with 35 mg/24 h in the placebo group; p ≤ 0.001.) Fewer pimagedine-treated patients with baseline and end point evaluations (31/324; 10%) as compared with those receiving placebo (16%; 28/179) experienced a three-step or greater progression of the retinopathy (Early Treatment of Diabetic Retinopathy Study) score (p = 0.030). Three patients receiving high-dose pimagedine but none receiving low-dose treatment developed glomerulonephritis. Conclusions: While this study did not demonstrate a statistically significant beneficial effect of pimagedine on the progression of overt nephropathy resulting from type 1 diabetes, it is noteworthy in providing the first clinical proof of the concept that inhibiting advanced glycation end product formation can result in a clinically important attenuation of the serious complications of type 1 diabetes mellitus.

Diabetic Kidney Disease: A Report From an ADA Consensus Conference

OBJECTIVE To evaluate the hospital care rendered to hyperglycemic individuals who did not have a diagnosis of diabetes before admission. RESEARCH DESIGN AND METHODS A total of 1,034 consecutively hospitalized adult patients at a 750-bed inner-city teaching hospital were evaluated. Patients with one or more plasma glucose values >200 mg/dl were identified by the laboratory data system on a daily basis. Patients without a diagnosis of diabetes at the time of admission were evaluated to determine if and how physicians addressed the hyperglycemia, whether a new diagnosis of diabetes was made during admission, and whether follow-up was planned to address the hyperglycemia. RESULTS After excluding patients who were admitted for a primary diagnosis of diabetes, 37.5% of all hyperglycemic medical patients and 33% of hyperglycemic surgical patients were without a diagnosis of diabetes at the time of admission. These patients had a mean peak glucose of 299 mg/dl, and 66% had two or more elevated values during their hospitalization. Fifty-four percent received insulin therapy, and 59% received bedside glucose monitoring, yet 66% of daily patient progress notes failed to comment on the presence of hyperglycemia or diabetes. Diabetes was documented in only three patients (7.3%) as a possible diagnosis in the daily progress notes. CONCLUSIONS Despite marked hyperglycemia, most medical records made no reference to the possibility of unrecognized diabetes. Given the average delay of a decade between the onset and diagnosis of type 2 diabetes, further evaluation of hyperglycemic hospitalized patients may present an important opportunity for earlier detection and the initiation of therapy.