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Accelerated atherosclerosis and the increased risk of thrombotic vascular events in diabetes may result from dyslipidemia, endothelial dysfunction, platelet hyperreactivity, an impaired fibrinolytic balance, and abnormal blood flow. There is also a correlation between hyperglycemia and cardiovascular (CV) events. The importance of platelets in the atherothrombotic process has led to investigation of using antiplatelet agents to reduce CV risk. A meta-analysis conducted by the Antiplatelet Trialists’ Collaboration demonstrated that aspirin reduced the risk of ischemic vascular events as a secondary prevention strategy in numerous high-risk groups, including patients with diabetes. Based on results from placebo-controlled randomized trials, the American Diabetes Association recommends low-dose enteric-coated aspirin as a primary prevention strategy for people with diabetes at high risk for CV events. Clopidogrel is recommended if aspirin allergy is present. There is occasionally a need for an alternative to aspirin or for additive antiplatelet therapy. Aspirin in low doses inhibits thromboxane production by platelets but has little to no effect on other sites of platelet reactivity. Agents such as ticlopidine and clopidogrel inhibit ADP-induced platelet activation, whereas the platelet glycoprotein (Gp) IIb/IIIa complex receptor antagonists block activity at the fibrinogen binding site on the platelet. These agents appear to be useful in acute coronary syndromes (ACSs) in diabetic and nondiabetic patients. A combination of clopidogrel plus aspirin was more effective than placebo plus standard therapy (including aspirin) in reducing a composite CV outcome in patients with unstable angina and non-ST segment elevation myocardial infarction. In a meta-analysis of six trials in diabetic patients with ACSs, intravenous GpIIb-IIIa inhibitors reduced 30-day mortality when compared with control subjects. Results from controlled prospective clinical trials justify the use of enteric-coated low-dose aspirin (81–325 mg) as a primary or secondary prevention strategy in adult diabetic individuals (aged >30 years) at high risk for CV events. Recent studies support the use of clopidogrel in addition to standard therapy, as well as the use of GpIIb-IIIa inhibitors in ACS patients.

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.

The rationale for intensive insulin therapy and results from major clinical trials in diabetes are reviewed. The Diabetes Control and Complications Trial (DCCT) has shown that intensive insulin therapy will prevent or delay the onset of retinopathy, nephropathy, and neuropathy in type I diabetes. The University Group Diabetes Program (UGDP) and the U.K. Prospective Diabetes Study (UKPDS) have addressed the issue of insulin versus oral agent or diet therapy in people with recently diagnosed type II diabetes. The UGDP showed that effective glycemie control could be achieved with intensive insulin therapy, but no effect on vascular end points was seen. Early data from the UKPDS also suggest that intensive insulin therapy may be more effective in lowering HbA1c toward normal than oral agents or diet. A pressing clinical problem is the question of the use of intensive insulin therapy in type II diabetic individuals who remain hyperglycemie despite pharmacological therapy. A Veterans Affairs Cooperative Study explored the feasibility of using intensive insulin therapy in 153 male type II diabetic patients with these characteristics. A 2% lowering of HbA1c was seen, with no increase in weight gain or in hypoglycemia. However, 40 of 153 patients (26.1%) had cardiovascular events during the 27-month trial; no difference in cardiovascular event rates was seen between the two treatment groups. A long-term multicenter collaborative trial is needed to assess the benefltcrisk ratio of intensive insulin therapy for type II diabetic patients in whom pharmacological therapy failed to provide glycemie management.

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 compare platelet plasminogen activator inhibitor 1 (PAI-1) concentration in type 11 diabetic patients and healthy control subjects. RESEARCH DESIGN AND METHODS We studied a group of 12 diabetic patients whose disease was controlled by diet or sulfonylurea therapy and a group of 17 nondiabetic control subjects. All subjects were free of clinically advanced vascular disease. PAI-1 antigen concentrations were measured in 5 × 108 isolated platelets, which were lysed by 1% Triton X-100. RESULTS Mean platelet PAI-1 was significantly higher in diabetic patients (264 ± 83 ng/5 × 108 platelets) compared with control subjects (202 ±71 ng/5 × 108platelets) (P < 0.05). A significant independent positive correlation was found between platelet PAI-1 concentrations and fasting plasma specific insulin levels in the diabetic patients (r = 0.63, P = 0.03). CONCLUSIONS These findings suggest that 1) a higher platelet PAI-1 concentration may contribute to enhanced thrombosis in type II diabetes and 2) megakaryo-cyte PAI-1 synthesis may be under the control of insulin.

Objective— Patients with NIDDM have a two- to fourfold increased risk of macrovascular disease. The constellation of elevated TGs and decreased HDL cholesterol are recognized as risk factors and constitute the major dyslipidemia in NIDDM. We therefore sought to determine if gemfibrozil (600 mg b.i.d.) was effective in correcting the dyslipidemia of NIDDM. Research Design and Methods– After 8 wk of placebo stabilization, 442 patients from 46 study centers were randomized to double-blind treatment, in a designated 2:1 ratio, 295 received gemfibrozil and 147 received placebo for 20 wk. The primary end point was plasma TG; secondary end points were TC, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and HbA1c. No baseline differences were noted between groups in sex, age, weight, type of diabetic therapy, fasting plasma levels of TGs, HbA1c, or C-peptide. About two-thirds received oral hypoglycemic drugs, one-third insulin Results– TG fell 26.4% in the gemfibrozil group and rose 7.4% in the placebo group (P < 0.023), by an intent-to-treat analysis. When patients who were noncompliant or with inadequate data were excluded, similar results were found—a 30.4% fall with gemfibrozil and a 4.8% increase with placebo (P < 0.0001). TG levels fell within 4 wk and remained low for 20 wk (P < 0.001). Mean HDL cholesterol rose by 4 wk and increased further at 12 wk (8–12%), P < 0.0001. TC fell. We observed a significant rise in LDL cholesterol in both gemfibrozil- and placebo-treated groups, with no significant differences between these groups. Changes in HbA1c were similar in gemfibrozil and placebo groups. No differences were observed in responses in groups treated with insulin and or oral hypoglycemic drugs. Overall AEs that were clinically important occurred in 6.1% in the gemfibrozil group vs. 2.0% in the placebo group (NS). Conclusions– We conclude that gemfibrozil is an effective and safe agent in combating the dyslipidemia of NIDDM, irrespective of type of diabetic therapy.

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.

Various parameters of coagulation and fibrinolysis were measured in 13 men (aged 54 +/- 3 yr) with non-insulin-dependent diabetes mellitus (NIDDM) before and after 12-14 wk of exercise training. Subjects exercised for 30 min 3 times/wk at 70% of maximum O2 consumption (VO2max). Training increased VO2max by 12.5% but did not alter body weight, relative body fat, blood pressure, cholesterol, triglycerides, or high-density lipoprotein cholesterol. Slight downward trends were apparent for fasting glucose and insulin, but glycosylated hemoglobin was unchanged. There were no changes in coagulation parameters of plasminogen, hematocrit, or alpha 2-antiplasmin. Plasma fibrinogen (303 +/- 24.2 vs. 256 +/- 12.3 mg/dl) and fibronectin (380 +/- 41.9 vs. 301 +/- 22.2 micrograms/ml) were significantly reduced (P less than 0.02) by exercise conditioning. Three assays of fibrinolytic activity (tissue plasminogen activator, euglobulin lysis time, and an isotopic measure of fibrinolysis) confirmed that neither basal fibrinolysis nor the fibrinolytic responses to venous occlusion and maximal exercise were significantly altered. Exercise conditioning may have antithrombotic effects in NIDDM by reducing plasma fibrinogen and fibronectin. Although the significance of the fall in fibronectin awaits further studies, the reduction in plasma fibrinogen gives a rationale for the use of exercise training in men with NIDDM.

Human platelets are known to have Fc receptors that are able to recognize soluble immune complexes and to respond to that stimulation by aggregating and releasing soluble factors. In diabetes, enhanced platelet aggregation has been proposed as one of the factors contributing to the development of microangiopathy. Soluble immune complexes isolated from seven diabetic patients were found to enhance ADP-induced platelet aggregation and release of ATP. This enhancement was proven not to be an artifact due to the isolation protocol, by comparison of purified immune complexes with nonspecific protein purified from normal sera by identical or slightly modified isolation protocols. Soluble immune complexes appear to be the first well-characterized platelet aggregating factors from the sera of diabetic patients. The nature of the antigen involved in their formation does not appear relevant, since very similar results were obtained whether soluble immune complexes were purified from patients with insulin-anti-insulin complexes in their serum, or from those without such complexes but with positive results in nonspecific screening techniques.

Plasma lipid, lipoprotein, and apolipoprotein levels were measured in 55 insulin-dependent diabetics (20 males and 35 females) before and after 2–3 wk of intensive insulin therapy in a metabolic unit. At the time of discharge from the metabolic unit the levels of total, low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) cholesterol as well as triglycerides, VLDL triglycerides, and apolipoprotein B (Apo B) were significantly decreased. Conversely, the levels of high-density lipoprotein (HDL) cholesterol, and apolipoprotein A1 (Apo A1) were significantly increased. The data were further analyzed after subdividing the patients into two subgroups: (1) patients admitted in poor glycemic control (HbA1c > 11%) and (2) patients admitted in fair control (HbA1c < 11%). In the group admitted in poor control the changes in lipid and lipoprotein levels were similar to the ones found in the group of patients as a whole, while in patients admitted in fair control only the levels of total and VLDL triglycerides showed significant changes with control. Patients' sex appeared to influence the magnitude of changes observed in HDL cholesterol and Apo A1, levels. In males a significant increase in both HDL cholesterol and Apo A1 was achieved after glycemic control either in the whole group or in the subgroup admitted in poor control. In the subgroup admitted in fair control HDL cholesterol levels rose but no significant change was observed in the Apo A1 levels. In females no significant change was observed with improved control in HDL cholesterol and Apo A1, either in the whole group or in the group admitted in fair control. A small but significant increase was detected in the HDL cholesterol levels of the female patients admitted in poor control, but no change was observed in the Apo A1 levels. In conclusion, in insulin-dependent diabetics, normalization in plasma lipid, lipoprotein, and apolipoprotein levels was obtained after intensive insulin therapy.

Irreversible second-phase aggregation of platelets in diabetic patients is prevented in vitro by 5, 8, 11, 14-eicosatetraynoic acid (TYA), a competitive inhibitor of the labile aggregationstimulating substance (LASS) which is formed from arachidonic acid. Thus, inhibition of prostaglandin synthesis inhibits platelet aggregation in diabetic subjects. These findings indicate that platelets from diabetics are subject to control by intracellular mechanisms operative in the regulation of platelet function in normal individuals.

Three principal findings have resulted from this study: (1.) The plasma insulin response to glucose loading is lower in prediabetics than in normal individuals. This phenomenon, while apparent when the glucose and insulin curves are expressed as a function of time, can be better demonstrated and quantitated by expressing plasma insulin concentration as a function of glucose concentration during the early portion of the glucose tolerance curve. The findings in this report suggest the sensitivity of the pancreatic β cells of prediabetics to glucose stimulation is lower than that of normal persons. (2.) A low plasma insulin response to glucose loading is also seen in nonobese diabetic subjects. However, since these patients had elevated plasma glucose concentrations with insulin levels like those of the prediabetics, one must suspect that insulin in this group was less effective than in prediabetics in exerting its influence on blood glucose. Whether this is due to antagonists to insulin action or to physiologic defects in the immunoreactive insulin molecule has not been determined in this study. (3.) The same method of relating plasma insulin to glucose concentration was used in assessing the insulin secretion in an obese diabetic population. Diabetics with fasting glucose values in excess of 150 mg. per 100 ml. reveal a decreased insulin response to glucose stimulation. These findings suggest a decreased sensitivity of the β cells to glucose stimulation in this group.

Resection of 1,720 gm. of adipose tissue did not alter a chemical diabetic glucose tolerance and a late excessive plasma insulin rise in a patient with benign symmetric lipomatosis. This suggests that other factors than a feedback from adipose to the beta cell are responsible for the hyper-insulinemia of obesity.