Rosiglitazone treatment and cardiovascular disease in the Veterans Affairs Diabetes Trial.

AIMS: To evaluate the relationship between patterns of rosiglitazone use and cardiovascular (CV) outcomes in the Veterans Affairs Diabetes Trial (VADT). METHODS: Time-dependent survival analyses, case-control and 1 : 1 propensity matching approaches were used to examine the relationship between patterns of rosiglitazone use and CV outcomes in the VADT, a randomized controlled study that assessed the effect of intensive glycaemic control on CV outcomes in 1791 patients with type 2 diabetes (T2D) whose mean age was 60.4 ± 9 years. Participants were recruited between 1 December 2000 and 31 May 2003, and were followed for 5-7.5 years (median 5.6) with a final visit by 31 May 2008. Rosiglitazone (4 mg and 8 mg daily) was initiated per protocol in both the intensive-therapy and standard-therapy groups. Main outcomes included a composite CV outcome, CV death and myocardial infarction (MI). RESULTS: Both daily doses of rosiglitazone were associated with lower risk for the primary composite CV outcome [4 mg: hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.49-0.81 and 8 mg: HR 0.60, 95% CI 0.49-0.75] after adjusting for demographic and clinical covariates. A reduction in CV death was also observed (HR 0.25, p < 0.001, for both 4 and 8 mg/day rosiglitazone); however, the effect on MI was less evident for 8 mg/day and not significant for 4 mg/day. CONCLUSIONS: In older patients with T2D the use of rosiglitazone was associated with decreased risk of the primary CV composite outcome and CV death. Rosiglitazone use did not lead to a higher risk of MI.

Intensive glucose control and macrovascular outcomes in type 2 diabetes.

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.

Glycaemic separation and risk factor control in the Veterans Affairs Diabetes Trial: an interim report.

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/m(2) 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 <6% in INT. Lifestyle, blood pressure and lipids are treated uniformly in both arms. RESULTS: A1C improved in both arms. INT kept median A1C <7% all years, A1C separation is 1.5-1.7%. From year 1 to 4, mean blood pressure is <129/74 mmHg, similar throughout. Median LDL-C was <97 mg/dl by year 1 and triglycerides 150 or less by 2 years. Triglycerides were lower in INT (12-16 mg/dl; p < 0.01). By 4 years, 88% are on lipid-lowering agents and 93% are on antiplatelet/anticoagulant agents. BMI is higher in INT every year (0.9-1.6 kg/m(2); p < 0.01). CONCLUSION: VADT is maintaining the expected A1C in both STD and INT, and LDL-C, triglycerides and blood pressure are at target. The trial is continuing to June 2008. It will be the first long-term completed type 2 diabetes study of the role of glycaemia on CV disease with modern treatments.

Effect of intensive glycemic control on microalbuminuria in type 2 diabetes. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes Feasibility Trial Investigators.

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.

Two years of intensive glycemic control and left ventricular function in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM).

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.

Beneficial and detrimental effects of intensive glycaemic control, with emphasis on type 2 diabetes mellitus.

Diabetes mellitus is a major health problem in the world. Several clinical trials have shown that some of the major complications of diabetes mellitus can be partially prevented or delayed by intensive glycaemic control. However, there are benefits and risks in aiming for near normal blood glucose levels. Intensive glycaemic control delays the onset and progression of retinopathy, nephropathy and neuropathy. Epidemiological and observational studies have shown that cardiovascular events may be correlated with the severity and duration of diabetes mellitus, but major randomised trials have only shown weak and nonsignificant benefits of intensive glycaemic management in decreasing event rates. A modest improvement in lipid profile results from blood glucose control although, in the majority of cases, not enough to reach current targets. Detrimental effects of intensive glycaemic control include bodyweight gain and hypoglycaemia. Controversial issues in the management of patients with diabetes mellitus include the unproven increase in cardiovascular morbidity from sulphonylureas and hyperinsulinaemia, and the still unknown long term effects of newer oral antihyperglycaemic agents alone or in combination with traditional therapies (such as sulphonylureas and metformin). It is important to individualise management in setting glycaemic goals. Control of cardiovascular risk factors through blood pressure and lipid control and treatment with aspirin (acetylsalicylic acid) and ACE inhibitors have consistently shown benefits in the prevention of both macro- and microvascular complications in patients with diabetes mellitus; these measures deserve priority.

The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM).

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.

Effect of intensive glycemic control on fibrinogen, lipids, and lipoproteins: Veterans Affairs Cooperative Study in Type II Diabetes Mellitus.

BACKGROUND: 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. OBJECTIVE: To assess the effect of intensive therapy on serum fibrinogen and lipid levels, compared with standard treatment. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Ethnic differences in the glycemic response to exogenous insulin treatment in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM).

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 < or = 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.

Response to intensive therapy steps and to glipizide dose in combination with insulin in type 2 diabetes. VA feasibility study on glycemic control and complications (VA CSDM).

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 four-step 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 day-time 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 day-time 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.

Acetyl-L-carnitine effects on nerve conduction and glycemic regulation in experimental diabetes.

UNLABELLED: 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 glucose > 200 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, p<0.0005). 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 (p < 0.0005), 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 (p < 0.02) in normal rats as compared with their saline-treated counterparts. ALC treatment lowered baseline free fatty acids in normal (p < 0.04) and diabetic (p < 0.03) animals, and the 60 minute levels in the normal group only (p < 0.003). CONCLUSION: 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.

Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes.

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 (HbA1c) was sustained for a mean follow-up of 27 months (P < .001). Predefined cardiovascular events were assessed by a committee unaware of treatment assignment. 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 < .001). There were 61 new cardiovascular events in 24 patients (32%) in the intensive treatment arm and in 16 patients (20%) in the standard treatment arm (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 HbA1c 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.

Evaluations of retinopathy in the VA Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VA CSDM). A feasibility study.

OBJECTIVE: The main goal of the study of 153 male veterans was to determine whether a statistically and clinically significant difference in HbA1c could be achieved between a standard therapy and an intensively treated group of patients with type II diabetes. A second major goal was to assess the feasibility of collecting reliable high-quality endpoint data, including microvascular and macrovascular events. Retinopathy was defined as a key microvascular endpoint. RESEARCH DESIGN AND METHODS: This was a randomized prospective trial of 153 men between the ages of 40 and 69 years, with type II diabetes for 15 years or less. Of the patients, 78 were assigned to the standard therapy arm and 75 to the intensive therapy arm. The goal of standard therapy was good general medical care and well-being and avoiding excessive hyperglycemia, glycosuria, ketonuria, or hypoglycemia. This was generally accomplished with one shot of insulin per day. The goal of intensive therapy was to obtain an HbA1c within two standard deviations of the mean of nondiabetic subjects (4.0-6.1%). This was obtained by a four-step management technique, with patients moving to the next step only if operational goals were not met. The steps were as follows: step 1: evening intermediate or long-acting insulin only; step 2: evening insulin with daytime glipizide; step 3: insulin, twice a day, no glipizide; and step 4: more than two injections of insulin, no glipizide. Retinopathy was assessed at baseline, 12, and 24 months by seven-field stereo fundus photography done at each of the five participating VA medical centers and read at the Central Reading Center at the Department of Ophthalmology, University of Wisconsin Medical School, Madison. Visual acuity was determined by ophthalmologists at each of the participating hospitals. RESULTS: After the 6th month of the 24-month study, an average HbA1c of approximately 7.1% in the intensively treated group was sustained for the full study and was significantly lower than that seen in the standard group (9.2%, P < 0.001). Compliance in obtaining fundus photographs was excellent. Near normalization of glycemia did not cause transient worsening of retinal morphology nor did it prevent the onset or delay the progression of retinopathy. There was no effect on visual acuity. CONCLUSIONS: 1) A glycemic control intervention study in people with type II diabetes is feasible and safe; 2) intensive control did not cause transient deterioration of retinopathy; and 3) although no improvement was seen in retinopathy, the follow-up was 24 months, an interval shorter than the 3 years or more of intensive therapy before improvement is seen in type 1 diabetic studies. This does not rule out the possibility that longer periods of intensive therapy would have improved retinopathy. A full-scale intervention trial in type II diabetes is needed to resolve this issue.

Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). Results of the feasibility trial. Veterans Affairs Cooperative Study in Type II Diabetes.

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.

Comparison of morning or bedtime insulin with and without glyburide in secondary sulfonylurea failure.

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.