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The goal of the VA Diabetes Trial (VADT) was to determine the effect of intensive glucose control on macrovascular events in subjects with difficult-to-control diabetes. No significant benefit was found. This report examines predictors of the effect of intensive therapy on the primary outcome in this population.This trial included 1791 subjects. Baseline cardiovascular risk factors were collected by interview and the VA record. The analyses were done by intention to treat.Univariate analysis at baseline of predictors of a primary cardiovascular (CV) event included a prior CV event, age, insulin use at baseline, and duration of diagnosed diabetes (all P.0001). Multivariable modeling revealed a U-shaped relationship between duration of diabetes and treatment. Modeled estimates for the hazard ratios (HRs) for treatment show that subjects with a short duration (3 years or less) of diagnosed diabetes have a nonsignificant increase in risk (HR1.0) after which the HR is below 1.0. From 7 to 15 years' duration at entry, subjects have HRs favoring intensive treatment. Thereafter the HR approaches 1.0 and over-21-years' duration approaches 2.0. Duration over 21 years resulted in a HR of 1.977 (CI 1.77-3.320, P.01). Baseline c-peptide levels progressively declined up to 15 years and were stable subsequently.In difficult-to-control older subjects with type 2 DM, duration of diabetes altered the response to intensive glucose control. Intensive therapy may reduce CV events in subjects with a duration of 15 years or less and may increase risks in those with longer duration.

OBJECTIVE The Veterans Affairs Diabetes Trial (VADT) was a randomized, prospective, controlled trial of 1,791 patients with type 2 diabetes to determine whether intensive glycemic control would reduce cardiovascular events compared with standard control. The effect of intensive glycemic control and selected baseline variables on renal outcomes is reported. RESEARCH DESIGN AND METHODS Baseline mean age was 60.4 years, mean duration of diabetes was 11.5 years, HbA1c was 9.4%, and blood pressure was 132/76 mmHg. The renal exclusion was serum creatinine >1.6 mg/dL. Renal outcomes were sustained worsening of the urine albumin-to-creatinine ratio (ACR) and sustained worsening by one or more stages in the estimated glomerular filtration rate (eGFR). RESULTS Intensive glycemic control did not independently reduce ACR progression but was associated with a significant attenuation in the progression of ACR in those who had baseline photocoagulation, cataract surgery, or both. The beneficial effect of intensive glycemic control increased with increasing BMI and with decreasing diastolic blood pressure (DBP). Intensive glycemic control was associated with less worsening of eGFR with increasing baseline ACR and insulin use. Baseline systolic blood pressure, triglycerides, and photocoagulation were associated with worsening of eGFR. CONCLUSIONS Intensive glycemic control had no significant effect on the progression of renal disease in the whole cohort but was associated with some protection against increasing ACR in those with more advanced microvascular disease, lower baseline DBP, or higher baseline BMI and on worsening of eGFR in those with high baseline ACR.

OBJECTIVE Blood pressure ranges associated with cardiovascular disease (CVD) events in advanced type 2 diabetes are not clear. Our objective was to determine whether baseline and follow-up (On-Study) systolic blood pressure (SBP), diastolic blood pressure (DBP), and SBP combined with DBP predict CVD events in the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS Participants in the VADT (n = 1,791) with hypertension received stepped treatment to maintain blood pressure below the target of 130/80 mmHg in standard and intensive glycemic treatment groups. Blood pressure levels of all subjects at baseline and On-Study were analyzed to detect associations with CVD risk. The primary outcome was the time from randomization to the first occurrence of myocardial infarction, stroke, congestive heart failure, surgery for vascular disease, inoperable coronary disease, amputation for ischemic gangrene, or CVD death. RESULTS Separated SBP ≥140 mmHg had significant risk at baseline (hazards ratio [HR] 1.508, P < 0.001) and On-Study (HR 1.469, P = 0.002). DBP CONCLUSIONS Increased risk of CVD events with SBP ≥140 mmHg emphasizes the urgency for treatment of systolic hypertension. Increased risk with DBP

OBJECTIVE To determine the predictors of progression of calcified atherosclerosis and the effect of intensive glycemic control on this process in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS As part of the Risk Factors, Atherosclerosis, and Clinical Events in Diabetes (RACED) substudy of the Veterans Affairs Diabetes Trial (VADT), 197 and 189 individuals with type 2 diabetes received baseline and follow-up computed tomographic scans for measurement of coronary and abdominal artery calcium, respectively. Standard and novel risk factors were assessed at baseline, and progression of calcified atherosclerosis was determined by several methods. Progression was defined both as a categorical (square root increase of volumetric scores ≥2.5 mm3) and continuous variable. In addition, annualized percent change of volume scores was determined. RESULTS After an average follow-up of 4.6 years, >75% of individuals demonstrated coronary (CAC) and abdominal artery calcification (AAC) progression. Progression increased with higher baseline calcium categories but was not influenced by standard risk factors. However, the albumin-to-creatinine ratio (ACR) (P = 0.02) and lipoprotein-associated phospholipase A2 (Lp-PLA2) (P = 0.01) predicted progression of CAC, and these results were not altered by adjustment for age and other traditional risk factors. Treatment assignment (intensive versus standard) within the VADT did not influence CAC or AAC progression, irrespective of baseline calcium category. CONCLUSIONS In patients with long-standing type 2 diabetes, baseline CAC, Lp-PLA2, and ACR predicted progression of CAC. Intensive glycemic control during the VADT did not reduce progression of calcified atherosclerosis.

The treatment of type 2 diabetes is shifting from secondary specialist centres to the primary care setting. However, for this shift to be sustainable and successful, primary care physicians (PCPs) must effectively provide aspects of diabetes care traditionally supplied by specialists. In particular, the early and appropriate use of insulin in type 2 diabetes will increasingly become the responsibility of PCPs. This review examines how patients with type 2 diabetes are currently managed across several European countries, and explores the evidence around insulin use in type 2 diabetes and the implications for primary care.

Objective The Veterans Affairs Diabetes Trial (VADT) is a 20-medical center, prospective, randomized study of 1792 Type 2 diabetic individuals primarily aimed at determining whether intensive glycemic control prevents macrovascular events. We report a comparison of fundus photographs and ophthalmologic examination at baseline, permitting an evaluation of multiple settings similar to common clinical practice. Research Design and Methods A 340-patient subset had both local dilated fundus examinations and centrally read seven-field stereo fundus photographs completed within 60 days of each other (median 28 days). Local examiners were unaware of the stereo photographs. Results Overall, agreement within one step was 76% and exact agreement between ophthalmoscopy and central gradings of fundus photographs on a five-step retinopathy severity scale was 43% (weighted kappa 0.42, CI 0.35–0.48). In about 90% of disagreements the severity level was higher by photographic grading. The sensitivity for ophthalmoscopy compared to grading of fundus photographs for the detection of any retinopathy was 51% and specificity was 91%. For proliferative diabetic retinopathy (PDR), sensitivity was 61% and specificity 98%. Only one eye was high-risk PDR, and it was detected by both methods. For clinically significant macular edema, these measures were 24% and 98%, respectively. The disagreements were of possible clinical importance in three cases ( Conclusion Most disagreements occurred in eyes rated near the milder end of a category and/or resulted from small differences between the ophthalmoscopic and photographic definitions used in classifying severity. There were reasonably few disagreements of possible clinical significance.

Objective: The Veterans Affairs Diabetes Trial (VADT) will assess the effect of intensive (INT) vs improved standard (STD) glycaemic control on major cardiovascular (CV) events, treating other risk factors equally in both arms. Four-year results of main metabolic parameters are presented. Research design and methods: VADT is a 7.5 years prospective randomized study of 1791 patients, 20 centres, of men and women of age 60.5 ± 8.7 years, diagnosed for 11.5 ± 7.5 years. Their body mass index (BMI) at baseline was 31 ± 4 kg/m2 and mean A1C 9.4 ± 1.5% after maximum dose of oral agents or insulin treatment. Step treatment consists of glimepiride or metformin, rosiglitazone, insulin and other agents; A1C goals are 8–9% in STD and

The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain.We randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene.The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group.Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications with the exception of progression of albuminuria (P = 0.01) [added]. (ClinicalTrials.gov number, NCT00032487.)

The problem Macrovascular disease (MVD), especially coronary heart disease, is the most common cause of mortality in Type 2 diabetes. We assessed the association between demographic and clinical variables (particularly HbA1c) and prevalent MVD at time of enrollment into the VA Diabetes Trial (VADT), a 7-year randomized trial to determine whether intensive glycemic control will reduce risk of MVD events in older participants with established Type 2 diabetes. Research design and methods We compared the demographic, treatment, and clinical characteristics of participants with and without known MVD, then assessed the interaction of multiple variables with HbA1c. Logistic regression models evaluated the association between HbA1c quartiles and prevalence of MVD, adjusting for potentially confounding variables. Results Several variables were associated with prevalent MVD (age, duration of diabetes, insulin use but not daily dosage, smoking history, hypertension, BMI, Caucasian race, non-Hispanic ethnicity, lower HDL cholesterol, higher triglycerides, lower LDL cholesterol, and statin use). In univariate analysis, there was no association of HbA1c with MVD (mean: 9.4±1.46% in those with MVD, 9.5±1.58% in those without). Multivariate analyses found little confounding of the lack of association of HbA1c with MVD. Only adjustment for age produced a slight increase in the odds ratio, but only for the highest quartile of HbA1c. Conclusions In this cross-sectional analysis, MVD was associated with a number of clinical and demographic variables but not with HbA1c. Determining whether intensive lowering of HbA1c will reduce the prospective rate of MVD events in this population of older participants with established Type 2 diabetes is the primary objective of our trial.

OBJECTIVE—The Veterans Affairs Diabetes Trial (VADT) cohort is enriched with ∼20% Hispanics and 20% African Americans, affording a unique opportunity to study ethnic differences in retinopathy. RESEARCH DESIGN AND METHODS—Cross-sectional analyses on the baseline seven-field stereo fundus photos of 1,283 patients are reported here. Diabetic retinopathy scores are grouped into four classes of increasing severity: none (10–14), minimal nonproliferative diabetic retinopathy (NPDR) (15–39), moderate to severe NPDR (40–59), and proliferative diabetic retinopathy (60+). These four groups have also been dichotomized to none or minimal (10–39) and moderate to severe diabetic retinopathy (40+). RESULTS—The prevalence of diabetic retinopathy scores >40 was higher for Hispanics (36%) and African Americans (29%) than for non-Hispanic whites (22%). The difference between Hispanics and non-Hispanic whites was significant (P < 0.05). Similarly, the prevalence of diabetic retinopathy scores >40 was significantly higher in African Americans than in non-Hispanic whites (P < 0.05). These differences could not be accounted for by an imbalance in traditional risk factors such as age, duration of diagnosed diabetes, HbA1c (A1C), and blood pressure. Diabetic retinopathy severity scores were also significantly associated with increasing years of disease duration, A1C, systolic and diastolic blood pressure, the degree of microalbuminuria, fibrinogen, and the percentage of patients with amputations. There was no relationship between retinopathy severity and the percentage of people who had strokes or cardiac revascularization procedures. There was an inverse relationship between retinopathy severity and total cholesterol, triglycerides, and plasminogen activator inhibitor-1 as well as with smoking history. Diabetic retinopathy scores were not associated with age. CONCLUSIONS—In addition to many well-known associations with retinopathy, a higher frequency of severe diabetic retinopathy was found in the Hispanic and African-American patients at entry into the VADT that is not accounted for by traditional risk factors for diabetic retinopathy, and these substantial ethnic differences remain to be explained.

Introduction Long-term glycemic control trials in type 2 diabetes show as the main clinical benefit a difference in retinal photocoagulation (3/1000 in the UK Prospective Diabetes Study [UKPDS]), but no effect on visual acuity or renal failure. No intensive glycemic control trial has yet affected cardiovascular (CV) events, the main cause of morbidity and mortality. By contrast, modest blood pressure reduction has protective effects on visual acuity, renal function, CV events, and mortality. Optimal glycemic control goals are not established in elderly, obese persons with advanced complications, the most common patients in the Veterans Affairs (VA) system. The earlier feasibility trial in such patients (VA-CSDM) suggested potentially worse CV outcomes with lower attained hemoglobin A1c (HbA1c) levels. Objectives The primary objective of the Veterans Affairs Diabetes Trial (VADT) is the assessment of the effect of intensive glycemic treatment on CV events. Other objectives are effects on microangiopathy, quality of life, and cost effectiveness. Research Design and Methods The VADT, started in December 2000, is enrolling 1700 men and women previously uncontrolled on insulin or maximum doses of oral agents at 20 VA medical centers. Accrual is 2 years and follow-up is 5–7 years, with visits every 1.5 months. The study has a power of 86% to detect a 21% relative reduction in major CV events (CV death, myocardial infarction [MI], cerebrovascular accident [CVA], congestive heart failure [CHF], revascularization and amputation for ischemia). Subjects are randomized to an intensive arm aiming at normal HbA1c levels or to a standard arm with usual, improved glycemic control. An HbA1c separation of >1.5% is to be maintained (expected 2%). Both arms receive step therapy: glimepiride or metformin plus rosiglitazone and addition of insulin or other oral agents to achieve goals. Strict control of blood pressure and dyslipidemia, daily aspirin, diet, and education are identical in both arms. Plasma fibrinogen, plasminogen-activating inhibitor I (PAI-I), lipids, renal function parameters, and ECG are measured throughout. Stereo retinal photographs are obtained at entry and 5 years, eye examinations yearly, and intervention as needed to prevent visual deterioration. Recruitment is proceeding on schedule: the current mean HbA1c at entry is 9.4±1.6% and mean duration of diagnosed diabetes 11±8 years.

In Brief Glycemic control is a well-established treatment objective in diabetes care. However, the effectiveness and specific goals of glycemic control are not yet known for older type 2 diabetic patients with advanced complications and suboptimal response to current treatments. Therefore, current glycemic guidelines for such patients are variable. This article presents the rationale for ongoing long-term clinical trials to answer these questions and reviews the demonstrated effectiveness of hypertension and dyslipidemia control in reducing both microvascular and macrovascular complications.

The Veterans Affairs Cooperative Studies Program (VACSP) has just initiated a trial of the effect of intensive glucose control on cardiovascular complications in patients with type 2 diabetes. The name of the trial is “VACSP #465, Glycemic Control and Complications in Diabetes Mellitus type 2” (V.A. Diabetes Trial [VADT]). The trial is expected to generate discussion in the diabetes community because the central role of glucose control in preventing or delaying long-term complications is generally accepted. The data on macrovascular disease are not yet conclusive. The VADT is directed at type 2 diabetic patients with established uncontrolled diabetes. This is the population most frequently encountered by the practicing physician. Cardiovascular (CV) complications are the major causes of morbidity and mortality in patients with type 2 diabetes (1). Efforts to reduce glucose levels in these patients must be balanced between risks and benefits. Consideration of intensive therapy must include effects of glucose control on microvascular complications, macrovascular complications, complications of therapy, and socioeconomic issues, including patient quality of life, compliance with therapy, and distribution of available funds for care of patients with diabetes. ### Microvascular disease Both the Diabetes Control and Complications Trial (DCCT) (type 1 diabetes) and the UK Prospective Diabetes Study (UKPDS) (new-onset type 2 diabetes) showed a significant beneficial effect of glucose control on microvascular complications (2,3), as did the smaller Kumamoto study (4). Basic biochemical and animal studies provide a solid foundation for these findings, as do epidemiological studies. From a clinical standpoint, this issue is more complicated. Risk-to-benefit ratios must be considered. This has not been adequately addressed in older established patients with type 2 diabetes. In the UKPDS the main effect of glucose control after 10.5 years was a 3/1,000 reduction in photocoagulation for retinal disease (from 1.1% in the standard arm to 0.8% in the …

Although the association between inflammation and hepatic fat is fairly established, it remains unclear whether this association is independent of general measures of obesity and standard cardiovascular risk factors. Therefore, the aim of this study was to investigate the contribution of hepatic steatosis as an independent predictor of chronic inflammation in 281 subjects with type 2 diabetes mellitus. Reduced hepatic steatosis significantly ( P r = −0.16) and adiponectin ( r = 0.23). The association of hepatic steatosis with both C-reactive protein and adiponectin remained significant after adjustment for age, ethnicity, body mass index (or waist circumference), triglycerides, high-density lipoprotein, and total cholesterol. These data support the concept that accumulation of hepatic fat is related to enhanced inflammation in type 2 diabetes mellitus independent of general measures of obesity and standard cardiovascular risk factors.

OBJECTIVE: Microalbuminuria can reflect the progress of microvascular complications and may be predictive of macrovascular disease in type 2 diabetes. The effect of intensive glycemic control on microalbuminuria in patients in the U.S. who have had type 2 diabetes for several years has not previously been evaluated. RESEARCH DESIGN AND METHODS: We randomly assigned 153 male patients to either intensive treatment (INT) (goal HbA(1c) 7.1%) or to standard treatment (ST) (goal HbA(1c) 9.1%; P = 0.001), and data were obtained during a 2-year period. Mean duration of known diabetes was 8 years, mean age of the patients was 60 years, and patients were well matched at baseline. We obtained 3-h urine samples for each patient at baseline and annually and defined microalbuminuria as an albumin:creatinine ratio of 0.03-0.30. All patients were treated with insulin and received instructions regarding diet and exercise. Hypertension and dyslipidemia were treated with similar goals in each group. RESULTS: A total of 38% of patients had microalbuminuria at entry and were evenly assigned to both treatment groups. INT retarded the progression of microalbuminuria during the 2-year period: the changes in albumin:creatinine ratio from baseline to 2 years of INT versus ST were 0.045 vs. 0.141, respectively (P = 0.046). Retardation of progressive urinary albumin excretion was most pronounced in those patients who entered the study with microalbuminuria and were randomized to INT. Patients entering with microalbuminuria had a deterioration in creatinine clearance at 2 years regardless of the intensity of glycemic control. In the group entering without microalbuminuria, the subgroup receiving ST had a lower percentage of patients with a macrovascular event (17%) than the subgroup receiving INT (36%) (P = 0.03). Use of ACE inhibitors or calcium-channel blockers was similarly distributed among the groups. CONCLUSIONS: Intensive glycemic control retards microalbuminuria in patients who have had type 2 diabetes for several years but may not lessen the progressive deterioration of glomerular function. Increases in macrovascular event rates in the subgroup entering without albuminuria who received INT remain unexplained but could reflect early worsening, as observed with microvascular disease in the Diabetes Control and Complications Trial.

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM) was a multicenter randomized prospective study of 153 male type 2 diabetic patients to assess the ability to sustain clinically significant glycemic separation between intensive and standard treatment arms. A trend toward an excess of combined cardiovascular events in the intensive treatment arm of this trial was reported earlier. The present analysis was done to evaluate the effect of 2 years of intensive glycemic control on the left ventricular (LV) function. RESEARCH DESIGN AND METHODS: The patients were randomized to intensive step treatment with insulin alone or with sulfonylurea (intensive treatment arm [INT], n = 75) or to standard once-daily insulin injection (standard treatment arm [STD], n = 78) treatment. A total of 136 patients (standard treatment arm [STD], n = 70; INT, n = 66) had radionuclide ventriculography at entry and at 24 months for the assessment of LV function. RESULTS: There was no difference in the mean LV ejection fraction (at entry: STD 57.1+/-9.51%; INT 58.1+/-8.7%; at 24 months: STD 57.3+/-10.8%, INT 59.5+/-10.7%), peak filling rate (at entry: STD 2.6+/-0.7 end diastolic volume per second, INT 2.4+/-0.8 end diastolic volume per second; at 24 months: STD 2.7+/-1.0 end diastolic volume per second, INT 2.5+/-0.7 end diastolic volume per second), or time to peak filling rate (at entry: STD 195.3+/-69.5 ms, INT 185.6 +/-62.4 ms; at 24 months: STD 182.6+/-64.8 ms, INT 179.2+/-61.2 ms) between the 2 treatment arms. A subgroup analysis of 104 patients (STD, n = 53; INT, n = 51) that omitted individuals with intervening cardiac events/revascularization or a change in cardioactive medications also showed no difference in the LV function at entry and at 24 months between the 2 groups. Abnormal LV ejection fraction at baseline predicted cardiac events (interval between cardiac beats [RR] = 2.5). CONCLUSIONS: Two years of intensive glycemic control does not affect the LV systolic or diastolic function in patients with type 2 diabetes.

Hermes Florez1†, Jennifer Marks1,2 & Carlos Abraira1,3 †Author for correspondence 1Miami VA Healthcare System GRECC (11GRC), 1201 NW 16th Street, Miami, FL 33125, USA and, University of Miami Miller School of Medicine, Miami, FL, USA Tel.: +1 305 575 3388; Fax: +1 305 575 3365; E-mail: hflorez@ med.miami.edu 2Tel.: +1 305 243 6433; Fax: +1 305 243 3313; E-mail: jmarks@ med.miami.edu 3Tel.: +1 305 575 3585; Fax: +1 305 575 3315; E-mail: cabraira@ med.miami.edu ‘There is clear evidence that use of aspirin, a statin, and the targeted lowering of blood pressure are each associated with substantial reductions in cardiovascular risk in patients with diabetes.’

The American Diabetes Association has established lipid goals for patients with diabetes. Although diabetic populations historically have poor low-density lipoprotein (LDL) cholesterol goal adherence, little is known about adherence to triglyceride and high-density lipoprotein (HDL) cholesterol goals. To determine the degree of lipid goal attainment among patients with diabetes, and to characterize the patterns of lipid medication use, we evaluated the baseline data from 1,742 enrollees of the national Veterans Affairs Diabetes Trial. Using current American Diabetes Association lipid guidelines, we calculated the proportion of participants achieving a LDL cholesterol level100 mg/dl, triglyceride level150 mg/dl, and HDL cholesterol level40 mg/dl in men (50 mg/dl in women). We also performed a descriptive analysis of the use of lipid medications in this population. The baseline LDL cholesterol level was 111 +/- 63 mg/dl, triglyceride level was 213 +/- 277 mg/dl, and HDL cholesterol was 36 +/- 10 mg/dl. At enrollment, 44% of veterans met the LDL cholesterol goal, 58% met the triglyceride goal, and 16% met the HDL cholesterol goal, but only 6% met all 3 goals. Of the 1,742 enrollees, 2/3 were receiving lipid therapy, with statins (58%) the most commonly used drug. Combination lipid therapy was used by 11% of enrollees. Although the enrollees of the Veterans Affairs Diabetes Trial demonstrated better adherence to the American Diabetes Association's LDL cholesterol goal than other diabetic populations recently studied, more aggressive and directed lipid medication use is needed to treat the overall lipid profile better.

Acetyl-L-Carnitine (ALC), an activator of carnitine, can accelerate nerve regeneration after experimental surgical injury in rats. In this study, we examined the ability of ALC to improve nerve conduction velocity and its effect on intravenous glucose tolerance test in streptozotocin-induced diabetic rats. Diabetic (blood glucose200 mg%) and normal animals were treated intraperitoneally for four weeks with ALC, 50 mg/Kg/d and 150 mg/Kg/d. Nerve conduction velocity was measured by direct exposure of sural nerve. Two-hour IVGTT was studied by measuring plasma glucose, insulin and free fatty acids after intravenous injection of glucose, 1.75 gm/Kg/body weight in animals treated either with ALC 150 md/Kg/d or saline alone. Six weeks of STZ-induced diabetes resulted in impairment of nerve conduction velocity in animals injected with saline (16.05 +/- 1.09 m/s), as compared to saline-treated normals who did not receive streptozotocin (31.0 +/- 0.84 m/s, p0.0005). Diabetic animals treated with ALC, 150 mg/Kg/d, preserved near normal nerve conduction (27.10 +/- 1.42 m/s), compared with the saline-treated diabetic animals (p0.0005), but diabetic animals treated with ALC, 50 mg/Kg/d, had a non-significant increase in nerve conduction (23.68 +/- 1.6). ALC treatment had no effect on fasting or post-intravenous plasma glucose in normal or diabetic rats, although it moderately reduced baseline and 40 minute insulin levels (p0.02) in normal rats as compared with their saline-treated counterparts. ALC treatment lowered baseline free fatty acids in normal (p0.04) and diabetic (p0.03) animals, and the 60 minute levels in the normal group only (p0.003).ALC at a dose of 150 mg/Kg/d given for one month, produced near normalization of nerve conduction velocity in streptozotocin-induced diabetes with no adverse effects on glucose, insulin or free fatty acid levels.

OBJECTIVE It is not clear whether intensive pharmacological therapy can be effectively sustained in non-insulin-dependent diabetes mellitus (NIDDM). The relative risks and benefits of intensive insulin therapy in NIDDM are not well defined. Accordingly, we designed a feasibility study that compared standard therapy and intensive therapy in a group of NIDDM men who required insulin due to sustained hyperglycemia. RESEARCH DESIGN AND METHODS A prospective trial was conducted in five medical centers in 153 men of 60 ± 6 years of age who had a known diagnosis of diabetes for 7.8 ± 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: 1) an evening insulin injection, 2) the same injection adding daytime glipizide, 3) two injections of insulin alone, and 4) multiple daily injections. Patient accrual and adherence, glycohemoglobin (HbA1c), side effects, and measurements of endpoints for a prospective long-term trial were assessed. RESULTS Accrual goals were met, mean follow-up time was 27 months (range 18–35 months), and patients kept 98.6% of scheduled visits. After 6 months, the mean HbA1c in the intensive therapy group was at or below 7.3% and remained 2% lower than the standard group for the duration of the trial. Most of the decrease in the mean HbA1c in the intensive group was obtained by a single injection of evening intermediate insulin, alone or with daytime glipizide. By the end of the trial, 64% of the patients had advanced to two or more injections of insulin a day, aiming for normal HbA1c. However, only a small additional fall in HbA1c was attained. Severe hypoglycemia was rare (two events per 100 patients per year) and not significantly different between the groups, nor were changes in weight, blood pressure, or plasma lipids. There were 61 new cardiovascular events in 40 patients and 10 deaths (6 due to cardiovascular causes). CONCLUSIONS Intense stepped insulin therapy in NIDDM patients who have failed glycemic control on pharmacological therapy is effective in maintaining near-normal glycemic control for > 2 years without excessive severe hypoglycemia, weight gain, hypertension, or dyslipidemia. Cardiovascular event rates are high at this stage of NIDDM. A long-term prospective trial is needed to assess the risk-benefit ratio of intensified treatment of hyperglycemia in NIDDM patients requiring insulin.

OBJECTIVE To determine, after 1 yr of follow-up in type II diabetes patients, whether a statistically and clinically significant difference can be achieved in HbA1c between a standard therapy group and an intensively treated group, while maintaining HbA1c levels in both groups within ranges acceptable in regular community practice. Secondary objectives include assessment of patient adherence to protocol, side effects, and accuracy of data collection. RESEARCH DESIGN AND METHODS This is a prospective, randomized, controlled VA CS conducted with 151 patients at five VAMCs. Patients are males, age 40–69 yr, treated at entry with a maximum dose of sulfonylurea or with insulin, exhibiting an HbA1c level > 3 SDs above the normal mean (5.05 + 3 × 0.50 = > 6.55%). Standard control is achieved with insulin and intensive control with a step-up regimen including insulin alone or insulin/glipizide combinations. Education and management of cardiovascular risk factors are handled similarly in both groups. Primary macrovascular end points are nonfatal myocardial infarction, congestive heart failure, stroke, amputation, and cardiovascular death. Primary microvascular end points are appearance and progression of retinopathy, documented by centrally read seven-field-stereo fundus photographs. Other measured indicators include resting and ambulatory ECGs, ventricular function (MUGA scan), serum lipid and apolipoprotein levels, plasma fibrinogen, nonsymptomatic peripheral vasculopathy, neuroautonomic status by heart-beat variation on Valsalva maneuver, and microalbuminuria. CONCLUSIONS This study may be the basis for a long-term trial, involving 1400 patients, to assess the long-term effects of metabolic control on macro- and microvascular end points.

OBJECTIVE This study investigated the hypothesis that baseline calcified coronary atherosclerosis may determine cardiovascular disease events in response to intensive glycemic control within the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS At baseline, 301 type 2 diabetic participants in the VADT, a randomized trial comparing the effects of intensive versus standard glucose lowering on cardiovascular events, had baseline coronary atherosclerosis assessed by coronary artery calcium (CAC) measured by computed tomography. Participants were followed over the 7.5-year study for development of cardiovascular end points. RESULTS During a median follow-up duration of 5.2 years, 89 cardiovascular events occurred. Although intensive glucose-lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole, there was evidence that the response was modified by baseline CAC, as indicated by significant P values for treatment by log(CAC + 1) interaction terms in unadjusted and multivariable-adjusted models (0.01 and 0.03, respectively). Multivariable-adjusted hazard ratios (HRs) for the effect of treatment indicated a progressive diminution of benefit with increasing CAC. Subgroup analyses were also conducted for clinically relevant CAC categories: those above and below an Agatston score of 100. Among those randomized to intensive treatment, for the subgroup with CAC >100, 11 of 62 individuals had events, while only 1 of 52 individuals with CAC ≤100 had an event. The multivariable HR for intensive treatment for those with CAC >100 was 0.74 (95% CI 0.46–1.20; P = 0.21), while for the subgroup with CAC ≤100, the corresponding HR was 0.08 (0.008–0.77; P = 0.03), with event rates of 39 and 4 per 1,000 person-years, respectively. CONCLUSIONS These data indicate that intensive glucose lowering reduces cardiovascular events in those with less extensive calcified coronary atherosclerosis.

AIMS/HYPOTHESIS: Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. METHODS: A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. RESULTS: A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84-0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76-0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90-1.20) and 1.10 for cardiovascular death (95% CI 0.84-1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91-3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89-1.13, vs HR 0.84, 95% CI 0.74-0.94, respectively; interaction p = 0.04). CONCLUSIONS/INTERPRETATION: Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.

Improved glucose disposal after repeated intravenous (IV) glucose loads, known as the Staub effect, is absent in both type I and type II diabetes. Acute decrements of insulin secretion (AID) are observed following the early phase of insulin release on IV glucose stimulation in non-insulin-dependent diabetes mellitus (NIDDM). The AID cannot be corrected by acute infusions of glyburide or glipizide, or phentolamine, or by glycemic control after 2 weeks of intensive insulin treatments. Fifteen male subjects had 3 hourly successive IV glucose tolerance tests before and after 6 months of glipizide, at a final maintenance dose of 30 ± 3 mg/d. Before treatment, AID, defined as the difference of the lowest of post IV glucose 7- or 10-minute samples from the preceding baseline insulin levels, was detected in the three loads: −6.4 ± 1.9 μU/mL in the first, and then more consistently in the second and third loads, −11 ± 2 μU/mL, and −17 ± 9 μU/mL, respectively. There was a stepwise increase in insulin sums after each load. After glipizide therapy, the AIDs following all three IV glucose loads were no longer demonstrable; both insulin values, as well as insulin sums, were significantly elevated after all three glucose loads. While in the untreated state, the Staub effect was absent: serum glucose disappearances (K), corrected for glycosuria, were K1 = 0.52 ± 0.02, K2 = 0.50 ± 0.04, and K3 = 0.52 ± 0.03. After glipizide, fasting glucose decreased from 215 ± 12 mg/dL to 132 ± 9 mg/dL, glucose values during the triple IV tolerance tests were significantly lower, and the glycohemoglobin decreased from 9.9% ± 0.5% to 8.2% ± 0.03%. Furthermore, glucose disappearance rates were improved: K1 = 0.62 ± 0.02, K2 = 0.68 ± 0.02, and K3 = 0.77 ± 0.04, also defining a positive Staub effect. There was a positive correlation between the glucose disappearance rates and the treatment-induced improvement of early insulin release in the second and third glucose loads (the difference from baseline of the higher of either the 3-minute or the 5-minute post IV samples). There was also a positive correlation between improvement in glucose disappearance rates in the third load with the total insulin sums. Mean AID in untreated overt NIDDM is potentiated by IV glucose priming, even while insulin levels increase. After treatment with glipizide, the AID is either reverted or insignificant, and the Staub effect is restored, along with post IV glucose improvement in insulin levels. Chronic sulfonylurea administration appears at present to be the only known conventional treatment restoring post IV glucose Staub effect and ameliorating the AID of NIDDM.

To determine risk factors in clinically significant macular edema (CSME) and if increased CSME in minorities is due to ethnicity or other factors in the Veterans Affairs Diabetes Trial (VADT).CSME prevalence based on 7-field stereo fundus photographs in 1268 patients with type 2 diabetes was related to ethnicity, demographics and biochemistries by univariate and multivariate analyses.Hispanics (H) made up 17.5% and African Americans (AA) 17.7% of the cohort. CSME prevalence was 10%. In univariate analysis, CSME was more prevalent in H, 18%, and AA, 15.6% than in non-Hispanic Whites (NHW), 6.3%, p0.01. Univariate regression of CSME associated with younger age, younger onset of diabetes; longer duration; retinopathy severity; and high HbA1c, BP, urine albumin/creatinine, and amputation, all p0.01. In multivariate regression, CSME was associated with ethnicity/race (Hispanic White vs. non-Hispanic White, OR, (95% CI), 2.30, (1.35-3.92), p0.01; African American vs. non-Hispanic White, 2.30, (1.33-4.00), p0.01), diastolic BP (1.13 per 5 mm Hg, (1.02-1.23), p=0.03), amputation (3.0, (1.11-8.13), p=0.04), and retinopathy severity ( approximately 30, ( approximately 17 to approximately 59), p0.01).The prevalence of CSME in the VADT is associated with ethnicity as well as diastolic BP, amputation, and retinopathy severity.

OBJECTIVE—Increasing evidence suggests that macrovascular disease and retinopathy may be more closely linked than previously believed. We determined the relationship between retinopathy and coronary atherosclerosis as measured by computed tomography–detectable coronary artery calcium (CAC). RESEARCH DESIGN AND METHODS—The cross-sectional association between CAC and retinopathy was assessed on a Veteran Affairs Diabetes Trial subsample of 204 subjects with a mean duration of type 2 diabetes of 12.3 ± 8.3 years. RESULTS—Retinopathy was correlated with CAC (r = 0.19, P = 0.006). Median CAC increased across retinopathy categories: 197 in those with no retinopathy, 229 in those with microaneurysms only, 364 in those with mild nonproliferative diabetic retinopathy (NPDR), 300 in those with moderate to severe NPDR, and 981 in those with proliferative diabetic retinopathy (PDR). Stepwise multivariable linear regression analysis was performed to find a parsimonious subset of relevant risk factors to include along with PDR in predicting CAC. After adjustment for either this subset of standard factors (P = 0.047) or a more extensive panel of risk factors (P = 0.035), PDR was significantly associated with CAC. Moreover, using logistic regression, individuals with PDR were approximately sixfold more likely to have CAC >400 than those with no PDR, even after adjustment for other CVD risk factors. CONCLUSIONS—These data indicate an important relationship between retinopathy and extent of CAC and suggest the potential to identify and treat shared risk factors for these common micro- and macrovascular complications.

Objective To present a status report on the Veterans Affairs Diabetes Trial (VADT), a multisite long-term study examining the effect of glucose control on cardiovascular (CV) complications in older patients with established, poorly controlled type 2 diabetes. Methods We review the rationale, objectives, and design of the VADT and summarize the baseline data and the results achieved thus far. Results The main objective of this 20-site, 1,792-patient study is to ascertain whether intensive glucose control can reduce major CV events in patients with difficult-to-control type 2 diabetes. The study design consists of a standard treatment arm and an intensive treatment arm, with a goal of 1.5% difference in hemoglobin A1c values between the two groups. The trial is now in its fifth year, with completion expected in December 2007. The planned glucose separation has been achieved and maintained to this point. Blood pressure and hemoglobin A1c levels have been reduced from baseline values, and established CV risk factors are within recommended ranges. Conclusion The current results of the VADT show that excellent control of glucose and CV risk factors can be achieved and maintained in the population studied. The results of these interventions on CV outcomes will ultimately have important implications for the clinical care of older patients with advanced type 2 diabetes. (Endocr Pract. 2006;12[Suppl 1]:85-88)

Objective The Veterans Affairs Cooperative Study in Diabetes Mellitus Type 2 Feasibility Trial (VA CSDM) studied standard and intensive glycemic treatment groups, achieving and maintaining for 27 months a difference in HbA1c of 2.1% (9.2% vs. 7.1%, respectively). A substudy planned in advance examined health status as assessed by a health status questionnaire obtained at baseline and 24 months. Design and methods A randomized, prospective trial was carried out at five VA Medical Centers from 1990 to 1993. The sample involved 153 male veterans 40–69 years of age and with diabetes duration of 8±4 years, who were suboptimally controlled with standard glucose lowering treatment. The participants were randomized to intensive and standard treatment groups. In addition to a variety of indicators of glycemic control and complications, health-related qualify of life data were assessed using a 20-question version of the Medical Outcome Study instrument. Scores were evaluated at baseline and 24 months for changes between the treatment groups. Results The two groups were similar at baseline with respect to age, duration of diabetes, complications, comorbidities, and reported physical activity. The intensive treatment group had more frequent, mandatory self-glucose monitoring (vs. occasional measurement in the standard) and received two or more daily insulin injections (only one in the standard). This group had three times the number of clinic visits and 10-fold higher reported incidence of mild/moderate hypoglycemia. There were no significant changes in the health status over time in either the standard or intensive treatment groups, nor was there a difference between the two groups. Conclusions Intensive glucose control in advanced Type 2 diabetes mellitus (DM) has no effect on health status over 2 years. The successful lowering of glycemia does not improve health-related quality of life nor do the increased demands of an intensive therapy regimen worsen it.

Long-term glycemic control trials in type 2 diabetes show as the main clinical benefit a difference in retinal photocoagulation (3/1000 in the UK Prospective Diabetes Study [UKPDS]), but no effect on visual acuity or renal failure. No intensive glycemic control trial has yet affected cardiovascular (CV) events, the main cause of morbidity and mortality. By contrast, modest blood pressure reduction has protective effects on visual acuity, renal function, CV events, and mortality. Optimal glycemic control goals are not established in elderly, obese persons with advanced complications, the most common patients in the Veterans Affairs (VA) system. The earlier feasibility trial in such patients (VA-CSDM) suggested potentially worse CV outcomes with lower attained hemoglobin A1c (HbA1c) levels.The primary objective of the Veterans Affairs Diabetes Trial (VADT) is the assessment of the effect of intensive glycemic treatment on CV events. Other objectives are effects on microangiopathy, quality of life, and cost effectiveness.The VADT, started in December 2000, is enrolling 1700 men and women previously uncontrolled on insulin or maximum doses of oral agents at 20 VA medical centers. Accrual is 2 years and follow-up is 5-7 years, with visits every 1.5 months. The study has a power of 86% to detect a 21% relative reduction in major CV events (CV death, myocardial infarction [MI], cerebrovascular accident [CVA], congestive heart failure [CHF], revascularization and amputation for ischemia). Subjects are randomized to an intensive arm aiming at normal HbA1c levels or to a standard arm with usual, improved glycemic control. An HbA1c separation of1.5% is to be maintained (expected 2%). Both arms receive step therapy: glimepiride or metformin plus rosiglitazone and addition of insulin or other oral agents to achieve goals. Strict control of blood pressure and dyslipidemia, daily aspirin, diet, and education are identical in both arms. Plasma fibrinogen, plasminogen-activating inhibitor I (PAI-I), lipids, renal function parameters, and ECG are measured throughout. Stereo retinal photographs are obtained at entry and 5 years, eye examinations yearly, and intervention as needed to prevent visual deterioration. Recruitment is proceeding on schedule: the current mean HbA1c at entry is 9.4+/-1.6% and mean duration of diagnosed diabetes 11+/-8 years.

To determine whether a difference in HbA(1c) could be safely sustained between a standard therapy (STD) arm and an intensive therapy (INT) arm, while maintaining HbA(1c) levels in both arms within a range acceptable in community practice. The effects of intensive treatment on various parameters were studied in this feasibility trial. We report here the results of 24 months of INT on peripheral and autonomic neuropathy.A prospective trial was conducted in five medical centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: (1) an evening insulin injection, (2) the same injection adding daytime glipizide, (3) two injections of insulin alone, and (4) multiple daily injections. Peripheral neuropathy was diagnosed clinically by a history and physical examination, and by abnormal autonomic neuropathy Valsalva ratio (VR < 1.2) and RR variation (RRV < 10). An average HbA(1c) separation of 2.07% was achieved with INT, having HbA(1c) at or below 7.3% (p = 0. 001 versus STD). Baseline prevalence of peripheral neuropathy was 53% in STD, and 48% in INT. By 24 months, the prevalence increased to 69% in STD (p = 0.005 versus baseline), and to 64% in INT (p = 0. 008 versus baseline, but no different than STD). Though INT did not reverse all elements of peripheral neuropathy, there was a decreased prevalence of cranial neuropathy (p = 0.053 versus STD) and more frequent preservation of touch sensation in the upper extremities (p = 0.03 versus STD) in INT. At baseline, an abnormal Valsalva ratio and/or RR variation was seen in 38% of STD and 31% of INT. By 24 months in STD, the prevalence rose to 55% (p = 0.0067 versus baseline), and in INT, to 48% (p = 0.012 versus baseline and no different from STD). The prevalence of erectile dysfunction increased from 53% at baseline to 73% at 2 years, p = 0.002 in STD, and from 51% to 73% at 2 years (p = 0.003 versus baseline) and no different from STD. There was no change in the frequency of abnormal gastrointestinal or sweating symptoms. Our conclusion was that 2 years of meticulous glycemic control did not decrease overall prevalence of peripheral or autonomic neuropathy. In fact, the prevalence rose equivalently and significantly in both treatment arms. There was some benefit, however, in decreased frequency of cranial neuropathy and better preservation of touch sensation in INT.

To the Editor: The Supplementary Appendix in which we provided additional information related to our article (Jan. 8 issue)1 contains some errors. In both Appendix 1 and Appendix 2, the heading “6 Year Event Rate” should have read “6-Year Event-free Rate.” We thank the reader who detected this error. In addition, on further examination of the data on albuminuria from the Veterans Affairs Diabetes Trial, we found that the data set that we used to evaluate the progression of disease was constructed improperly. As a result, the rates of progression to microalbuminuria and macroalbuminuria were reported in Table 3 of . . .

The Veterans Affairs Cooperative Study in Type II Diabetes Mellitus prospectively studied insulin-treated patients with type 2 (non-insulin-dependent) diabetes mellitus, achieving 2.1% glycosylated hemoglobin separation between intensive- and standard-treatment arms (P.001) for 2 years.To assess the effect of intensive therapy on serum fibrinogen and lipid levels, compared with standard treatment.One hundred fifty-three male subjects with type 2 diabetes mellitus and who required insulin treatment were recruited from 5 Veterans Affairs medical centers. The subjects were divided into intensive- and standard-treatment arms for a randomized prospective study. Dyslipidemia was managed identically in both arms (diet, drugs). Fibrinogen levels and lipid fractions were measured in the full cohort. Lipid fractions are separately reported in patients not treated with hypolipidemic agents.There were no baseline differences between arms. Fibrinogen levels rose in the intensive-treatment arm at 1 year (from 3.34+/-0.12 to 3.75+/-0.15 g/L; P.001) but returned to baseline at 2 years (3.47+/-0.12 g/L). There was no change in the standard-treatment arm. Triglyceride levels decreased in the intensive-treatment arm from 2.25+/-0.27 to 1.54+/-0.14 mmol/L (199+/-24 to 136+/-12 mg/ dL) at 1 year (P = .004) and to 1.74+/-0.18 mmol/L (154+/-16 mg/dL) at 2 years (P = .03); there was no change in the standard-treatment arm. Cholesterol levels decreased in the intensive-treatment arm at 1 year from 5.4+/-0.21 to 4.99+/-0.13 mmol/L (207+/-8 to 193+/-5 mg/dL) (P = .02); there was no change in the standard-treatment arm. Levels of low- and high-density lipoprotein cholesterol decreased in the standard-treatment arm only by 2 years, from 3.44+/-0.13 to 3.16+/-0.10 mmol/L (133+/-5 to 122+/-4 mg/ dL) (P =.02) and from 1.10+/-0.03 to 1.00+/-0.03 mmol/L (42+/-1 to 38+/-1 mg/dL) (P.001) for low-density and high-density lipoprotein cholesterol, respectively. Levels of apolipoprotein B decreased in both treatment arms (P.001), and apolipoprotein A1 levels decreased in the standard-treatment arm (P.01). Lipoprotein (a) levels did not change in either treatment arm. Lipid results were essentially identical whether examined in the full cohort or excluding those patients receiving hypolipidemic agents.Intensive insulin therapy led to a potentially beneficial reduction in serum triglyceride levels and preservation of high-density lipoprotein cholesterol and apolipoprotein A1 levels. However, it caused transient elevation in plasma fibrinogen levels, a possible thrombogenic effect.

OBJECTIVE The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus was conducted in NIDDM patients to determine if a significant difference in HbA1c could be achieved between groups receiving standard and intensive treatment. We observed differences in the response to exogenous insulin between African-Americans and other intensively treated patients. Therefore, we assessed the variations of response and correlated factors that might explain such differences. RESEARCH DESIGN AND METHODS One hundred fifty-three men aged 40–69 years with NIDDM for ≤15 years were randomized to either the standard therapy (n = 78) or the intensive therapy (n = 75) arm. Of the 75 patients in the intensive therapy group, 57 completed the study on insulin therapy alone. Of these, 18 were African-Americans and 39 were non-African-Americans. We conducted an analysis of the data collected to determine differences in baseline characteristics, glycemic response, insulin requirement, body weight, exercise, and basal C-peptide level, factors that may explain a difference in response to insulin therapy. RESULTS Glycemic control improved in all patients with intensive insulin therapy. African-Americans achieved a greater improvement in HbA1c compared with non-African-Americans with a similar increment in insulin. This difference could not be explained by differences in body weight, activity, concomitant use of other medicines, or insulin-secretory capacity of the pancreas. CONCLUSIONS We conclude that ethnic differences may exist in the response to insulin therapy. A knowledge of such differences may aid in achieving good glycemic control, especially since minorities have a greater prevalence of and burden from the microvascular complications of diabetes.

OBJECTIVE The feasibility study for the VA Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes (VA CSDM) prospectively studied 153 insulin-requiring type 2 diabetes patients, randomized between an intensively treated arm and a standard treatment arm during a mean follow-up of 27 months. The glycemic response to each of the progressive, sequential phases of insulin treatment was assessed, along with the incidence of hypoglycemic reactions and the relative efficacy of different doses of glipizide in combination with fixed doses of insulin. RESEARCH DESIGN AND METHODS Five medical centers participated; half of the patients were assigned to the intensive treatment arm aiming for normal HbA1c levels. Age of patients was 60 ± 6 years, duration of diabetes 8 ± 3 years, and BMI 30.7 ± 4 kg/m2. A fourstep management technique was used, with patients moving to the next step if the operational goals were not met: Phase I, evening intermediate or long-acting insulin; phase II, added daytime glipizide; phase III, two injections of insulin alone; and phase IV multiple daily insulin injections. Home glucose monitoring measurements were done twice daily and at 3:00 A.M. once a week. Hypoglycemic reactions and home glucose monitoring results were recorded and counted in each of the treatment phases. RESULTS Baseline HbA1c was 9.3 ± 1.8%, and fasting plus serum glucose was 11.4 ± 3.3 mmol/1. Fasting serum glucose fell to near normal in phase I, and remained so in the other treatment phases. An HbA1c separation of 2.1% between the arms was maintained during the course of the study, while the intensive arm kept HbA1c levels below 7.3% (P = 0.001). Most of the decrease in HbA1c occurred with one injection of insulin alone (phase I, − 1.4%) or adding daytime glipizide (phase II, −1.9% compared with baseline). HbA1c did not decrease further after substituting two injections of insulin alone, with twice the insulin dose. Multiple daily injections resulted in an additional HbA1c fall (−2.4% compared with baseline). However, two-thirds of the patients were still on one or two injections a day at the end of the study Changes in home glucose monitoring levels paralleled those of the HbA1c, as did the increments in number of reported hypoglycemic reactions, virtually all either “mild” or “moderate” in character. For the combination of glipizide and insulin (phase II), the only significant effect was obtained with daily doses up to 10 mg a day; there were no significant additional benefits with up to fourfold higher daily doses, and HbA1c levels had an upward trend with doses >20 mg/day. CONCLUSIONS A simple regime of a single injection of insulin, alone or with glipizide, seemed sufficient to obtain clinically acceptable levels of HbA1c for most obese, insulin-requiring type 2 diabetes patients. Further decrease of HbA1c demanded multiple daily injections at the expense of doubling the insulin dose and the rate of hypoglycemic events. In combination therapy, doses of glipizide >20 mg/day offered no additional benefit.

OBJECTIVES— New treatment options are needed for glycemic control in NIDDM. We evaluated the effects of bedtime or morning insulin treatment, combined with daytime glyburide or given alone. RESEARCH DESIGN AND METHODS— Twenty-nine male patients with NIDDM, mean age 63 ± 1.7 yr, body weight 124 ± 2.98% of DBW, received a maximum glyburide dose (20 mg/day) for a minimum of 6 wk, to confirm sulfonylurea failure. Human lente insulin was added for 12 wk either AM (n = 14) or HS (n = 15) and adjusted to obtain fasting euglycemia (FPG; combination treatment phase). Glyburide was then stopped, and insulin was continued for 6 wk, aiming for normal FPG (insulin phase). RESULTS— After combination treatment phase, FPG decreased (P < 0.02) from 12.43 ± 0.68 to 5.73 ± 0.65 mM (AM) and from 12.68 ± 0.76 to 5.51 ± 0.48 mM (HS) (AM vs. HS, NS). Postbreakfast, presupper, and 0200 AM plasma glucose levels fell equally (P < 0.02) except for 1-h postprandial (AM 12.46 ± 0.51 mM, HS 10.88 ± 0.62 mM, AM vs. HS, P < 0.1). Mean HBA1c fell similarly in both AM and HS groups. At 2 wk of the insulin phase, FPG was higher in AM than HS, 9.8 ± 0.76 vs. 7.56 ± 0.7 mM (P < 0.1). At the end of insulin phase, plasma glucose levels were similar to the end of combination treatment phase, but the insulin dose had to be raised in AM by 39% (P < 0.02) and HS by 30% (P < 0.05). After the combination treatment phase, fasting C-peptide was significantly suppressed in HS group only, from 1.22 ± 0.12 to 0.82 ± 0.09 nM (P < 0.02). At the end of insulin phase, fasting C-peptide was further suppressed in both groups, but 2-h postprandial C-peptide levels decreased significantly in AM group only, from 1.85 ± 0.23 to 1.42 ± 0.13 nM (P < 0.02). Triglycerides and total and HDL cholesterol did not change significantly after either combination treatment phase or insulin phase. Mean weight gain was 6.5 lb during combination treatment phase (NS from baseline), without further change during insulin phase. Hypoglycemic reactions, all mild, were recorded at a rate of 1.35/patient in the AM group and 0.4/patient in the HS group (P < 0.025). CONCLUSIONS— Normal fasting glycemia and near-normal postprandial glucose profile could be obtained with combination therapy in NIDDM. Results were similar if insulin, alone or in combination with glyburide, was given before breakfast or at bedtime, but hypoglycemic reactions were more common with conventional morning insulin injections.

Background: The risks and benefits of intensive therapy in non—insulin-dependent diabetes mellitus (NIDDM) need to be defined. In preparation for a long-term trial, a feasibility study of 153 men in 5 medical centers compared standard vs intensive insulin therapy. Objective: To assess the rate of development of new cardiovascular events and their correlates. Methods: Patients with a mean ± SD age of 60 ± 6 years and diagnosis of NIDDM for 7.8±4.0 years were randomly assigned to a standard (1 insulin injection every morning) or to an intensive treatment arm (stepped plan from 1 evening injection of insulin, alone or with glipizide, to multiple daily injections) designed to attain near-normal glycemia levels. A 2.07% separation of glycosylated hemoglobin (HbA 1c ) was sustained for a mean follow-up of 27 months ( P Results: Mild and moderate hypoglycemic events were more frequent in the intensive than in the standard treatment arm (16.5 vs 1.5 per patient per year, respectively). Mean insulin dose was 23% lower in the standard treatment arm ( P P =.10). There was no difference in total and cardiovascular mortality (n=5 and n=3 in the intensive and standard treatment arms, respectively) or in new events in patients with cardiovascular history (n=10 in each arm). In Cox regression analysis, the only significant correlate for new cardiovascular events was previous cardiovascular disease ( P =.04). Entering in the analysis any baseline cardiovascular abnormality, the regression model indicated a lower HbA 1c level prior to the event as the only correlate for new cardiovascular events ( P =.05). Conclusion: A long-term prospective trial is needed to assess the risk-benefit ratio of intensive insulin therapy for NIDDM in patients who require it. Arch Intern Med. 1997;157:181-188

The facilitation of glucose disposal (Staub-Traugott effect) and potentiation of serum insulin (IRI) concentration normally occurring after closely spaced intravenous glucose loads, are known to disappear after prolonged starvation. To study the effects of minimal amounts of glucose during fasting upon the insulin response and disposal of repeated intravenous glucose tolerance tests, obese volunteers were fasted for a mean of 25 ± 2 days, while receiving either 8 or 16 gm of oral glucose every 6 hr, and compared to totally fasted subjects without glucose supplementation. Weight loss rate and the fall in basal IRI and glucose levels were similar to those of totally fasted subjects. However, the Staub-Traugott effect and insulin secretory dynamics after stimulation by repetitive intravenous glucose loading were preserved by this glucose modified fast, while baseline serum glucagon levels (IRG) were significantly lower, and the basal IRI/IRG ratios were thus unchanged from the fed state. IRG and free fatty acid suppression were similar in the fed and glucose modified fasted states. Lactic acid levels increased as expected after the repeated glucose injections in the fed state, but failed to do so after the prolonged modified fast until the second and third repetitive glucose loads, in which a significant rise coincided with accelerated glucose disposal. It is suggested that minimal amounts of carbohydrate during fasting preserve the insulin potentiating action of glucose, preferentially sparing a delayed releasable pool of insulin, while protecting the glucose utilization mechanisms, including increased glycolysis, responsible for the Staub-Traugott effect.

Fifty-one adult male outpatients at or below ideal body weight (IBW) with no history of weighing more than 15% over IBW in the past 5 yr and no more than 25% in the past 15 yr were randomly assigned to a traditional calorically defined exchange-type diet (EXCH) or an unmeasured diet emphasizing avoidance of refined sugar and balance of food consumption throughout the day. All but 4 patients were insulin treated. With the exception of one patient in each group, all patients were classified as having type II diabetes. Subjects were followed in a single-blind design for 4 yr in the Diabetes Outpatient Clinic every 3 mo. The average mean fasting glycemia (FBS), coefficient of FBS variation, number of reported hypoglycemic reactions, mean fasting serum triglyceride and cholesterol levels, and mean total daily insulin dosage were similar in both groups. Each patient's mean daily caloric intake did vary over time, but there was no difference in mean caloric intake between diet groups. There was a significant correlation between a patient's mean FBS rating and his serum triglyceride level: patients with lower mean FBS had a significantly lower mean triglyceride level than patients with higher FBS. Overall body weights remained stable throughout the study. However, there was a significant difference in the number of patients in the EXCH group whose actual weight was 3% or more above IBW on 50% or more of their visits. The unmeasured diet group had a significantly greater number of patients whose actual weight was at IBW during the study. There was no relationship between FBS and changes from IBW. In the EXCH group only subjects who increased their weight over initial levels had lower FBS values than patients who reduced from initial weight. It is concluded that individuals without history of obesity before the diagnosis of diabetes mellitus can continue to regulate their weight without a precise caloric prescription. All of the parameters studied suggest that a calorically defined exchange diet might be as effective as an unmeasured diet in the conventional long-term treatment of the lean adult diabetic patient.

Overtly hypertriglyceridemic patients with non-insulin-dependent diabetes mellitus were given a control diet containing 120 g of sucrose and 50 percent carbohydrate, and later randomly assigned to receive isocaloric high- (220 g), intermediate- (120 g), or low(less than 3 g) sucrose/carbohydrate diets for four weeks. The low-sucrose diet group demonstrated a modest but significant decrease in mean fasting serum glucose level in the first week only, although this change was no different from the other two dietary groups and was not sustained. All groups had little change in late postprandial serum glucose levels from control values, and no significant alterations in 24-hour glycosuria. The high-sucrose diet group demonstrated a significant increase in fasting serum triglyceride levels by the second week of the study, whereas the intermediate-and low-sucrose diet groups showed a decrease in mean fasting triglyceride levels. In contrast, the low-sucrose diet group's late postprandial serum triglyceride levels increased by the fourth week, whereas levels fell in the high-sucrose diet group. Mean fasting serum cholesterol concentrations decreased from control values in the high-sucrose diet group. Thus, although very high sucrose and carbohydrate consumption is clearly deleterious to fasting tryglyceride levels in non-insulin-dependent diabetes mellitus with preexisting hypertriglyceridemia, it appears that low dietary sucrose and carbohydrate proportions do not further improve preprandial glycemia and glycosuria and may adversely affect late postprandial serum triglyceride concentration. This study suggests that isocaloric sucrose and carbohydrate restriction below usual daily levels (120 g per day) offers no consistent benefit in glycemia or lipid control in overt type II diabetes.

Although it is well recognized that mineralocorticoids enhance renal acid excretion, the effect of glucocorticoids on renal acidification is unclear. Oral administration of dexamethasone to six healthy volunteers for 1 week at a daily dose of 4.5 mg was associated with mild respiratory alkalosis and a small but statistically significant increase in baseline urine pH. However, neither the ability to lower urine pH nor to excrete titratable acid and ammonium after NH4Cl acid-loading was altered. Administration of a single intravenous dose of dexamethasone sodium phosphate (7.5 mg) was associated with a significant rise in urine pH and potassium excretion and decreased titratable acid, ammonium , and phosphorus excretion in the absence of changes in blood acid-base status, creatinine clearance, or urine flow.

The dialysis clearance of guanidinosuccinic acid (GSA) was measured in vitro and in vivo in patients undergoing maintenance hemodialysis. The in vitro (44 +/- 5 [SEM] ml/min) and in vivo (40 +/- 7 ml/min) clearances were similar to and lower than those of urea and creatinine. Plasma GSA concentrations predialysis (210 +/- 49 microgram/100 ml) were higher then those of controls ( less than 40 microgram/100 ml) and decreased substantially at the end of a single hemodialysis (percent decrease: 53 +/- 5). Marked increase of plasma GSA concentrations 12 h postdialysis were found in only two cases. An attempt was made to derive a single curve predicting plasma GSA decline during dialysis using the data obtained in these patients. The removal data suggest that the space of distribution of GSA approximates the extracellular fluid volume.

Earlier work shows that hyperlipemic type II diabetics tolerate wide ranges of sucrose and carbohydrate intake without effects on glycemic control, but a rise of fasting serum triglycerides sometimes occurs. To address further the issue of individual susceptibility to carbohydrate, the current study was designed to use each patient as his own control when given diets widely varying in sucrose content. After a stabilization period in the hospital on a normal sucrose content diet, each subject was given either a very low sucrose (less than 3 gm/day)-low carbohydrate (38 +/- 2%) diet or a high sucrose (220 gm)-high carbohydrate (63 +/- 3%) diet for 4 weeks. On a separate admission the opposite diet was assessed, again after an initial normal sucrose content diet. No consistent differences occurred in serum glucose levels or in 24-hr urinary glycosuria. High sucrose-carbohydrate intake raised fasting hypertriglyceridemia after 2 weeks but less thereafter. Severe sucrose-carbohydrate restriction did not significantly decrease fasting serum triglycerides; postprandial triglycerides changed in a trend opposite to fasting levels. No differences occurred in fasting serum insulin or serum cholesterol levels, but postprandial insulin levels were higher in high sucrose-carbohydrate diets. A diet with low sucrose and low total carbohydrate appears to offer no improvement in glycemic control over at least 70-fold higher dietary sucrose levels. However, high sucrose and carbohydrate diets increase fasting triglyceride levels in hypertriglyceridemic type II diabetics.

The mechanism of the Staub-Traugott effect or facilitated glucose disposal after successive glucose loads has remained elusive. In earlier publications, we have shown it can be independent of circulating hormone and free fatty acid levels. We have also proposed that it might partially depend on the rapid induction of glycolytic pathways, which are known to be depressed by prolonged fast. Mature rats were given 1.75 gm/kg glucose doses intravenously at 60-minute intervals. Respiratory CO2 was collected at 15-minute intervals over a 120-minute period following administration of the carrier glucose plus 6 microCi/100 gm rat weight of 14C-D-glucose, given either as the first, second, or third challenge. In rats fasted 14 hours there was potentiation of labeled CO2 recovered after each successive load. After three days of starvation, both relative 14C-glucose oxidation to 14CO2 as well as absolute 14CO2 increments after each load were lower. The changes in relative oxidation of an intravenous glucose load might partly account for the facilitated disposal of blood glucose seen in the second and third hours in overnight-fasted rats (Staub-Traugott effect). However, although rats fasted for three days had suppressed the Staub effect, the increments in oxidation were attenuated but still present, suggesting that alterations of other pathways must participate in the disappearance of this effect after fasting.