Treatment for the procoagulant state in type 2 diabetes.

A procoagulant state has been found to exist in diabetes mellitus. There may be activation of the intrinsic coagulation system, decreased fibrinolytic activity, or alterations in platelet function. Intensive glycemic control with insulin is effective in reducing the impact of this procoagulant state by favorably affecting all three components of the system. Decreased fibrinolytic activity, as influenced by plasma PAI-1 levels, may be favorably affected by weight loss, exercise, a low-GI diet, or by metformin, thiazolidinediones, gemfibrozil, and ACE inhibitor therapy. Insulin has variable effects on plasma PAI-1 activity. Estrogens will lower the elevated PAI-1 levels seen in the menopausal state. Collaborative trial evidence supports the use of low-dose aspirin as a primary or secondary prevention strategy in diabetic persons who are at high cardiovascular risk. A recent study suggests that this category includes virtually every type 2 diabetic individual in the United States. The American Diabetes Association recommends enteric-coated aspirin, 81 to 325 mg/day, as the first choice. In the case of aspirin allergy, clopidrogel is an alternate choice. Thus, recognition of and therapy for a procoagulant state in diabetes mellitus is likely to result in a decrease in the atherothrombotic events that characterize the later stages of this disease.

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.

Dental endosseous implant assessments in a type 2 diabetic population: a prospective study.

Diabetes mellitus, a prevalent disorder worldwide, is associated with systemic adverse sequelae, such as wound healing alterations, which may affect osseointegration of dental implants. This prospective multicenter study assessed the success of 2-stage endosseous root-form implants (3 different implant systems) placed in the mandibular symphysis of 89 male type 2 diabetic subjects. The implants were uncovered approximately 4 months after placement, restored with an implant-supported, Hader bar clip-retained overdenture, and maintained at scheduled follow-up data collection examinations for 60 months after loading. Sixteen (9.0%) of the 178 implants failed. Life table methods calculated implant survival at approximately 88%, from prosthesis placement through the 60-month follow-up, and at approximately 90% from implant placement through the observation period. No implants failed between surgical placement and uncovering, 5 failed at uncovering, 7 failed after uncovering before prosthesis placement, and 4 failed after prosthesis placement. Fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) values were determined before implant placement (baseline) and approximately 4 months later at surgical uncovering (follow-up). The 5-year implant outcomes (successes versus failures) were analyzed against the following predictor variables: (1) baseline and follow-up FPG values, (2) baseline and follow-up HbA1c values, (3) subject age, (4) duration of diabetes (years), (5) baseline diabetic therapy, (6) smoking history, and (7) implant length. Regression analysis found only duration of diabetes (P < .025) and implant length (P < .001) to be statistically significant predictors of implant failure. There was no statistically significant difference in failure rates between the 3 different implant systems used. This study supports the use of dental implants in type 2 diabetic patients.

Overview of the Diabetes Initiative of South Carolina.

Implementation is underway for many of these programs, and there are descriptions of activities elsewhere in this symposium. The Board recognizes that in dealing with the complications of a chronic disease like diabetes, many years of intense effort will be needed before significant results may be appreciated. Progress will be monitored regularly by the Surveillance Council and SCDCP/DHEC, and modifications of the plan will be made by the Board at intervals after review of the data. We are optimistic that over the next decade, this system will make a significant impact to reduce mortality, morbidity, and costs of diabetes, and the result will be an increased quality of life for people affected by diabetes in South Carolina.

Diabetes research in South Carolina: past, present, and future.

Medical investigators in South Carolina have been on the "cutting edge" of diabetes research for a number of decades. Despite this fact, our state ranks second in the nation in diabetes prevalence, and diabetes complications are more severe here than anywhere else. It is from the efforts of these investigators that our hope for a brighter future comes. Through a concerted effort toward prevention, improvements in care, and investigation of the pathophysiology of diabetes and its complications, researchers may reduce the substantial burden of diabetes in our state and throughout the world.

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.

Prevention of diabetes complications.

Basic and clinical research findings have led to an increased understanding about diabetes and its complications. Therapeutic approaches are now based not only on predicted effects from epidemiologic, correlative, or retrospective analyses, but often on prospective intervention trials comparing a new form of therapy to the standard methods. While this database may never be complete, partially due to the complexity and variability of the diabetic state, we now have excellent data that allow the development of aggressive new guidelines for care. Much of the material presented here reflects the views of the American Diabetes Association, as included in a recent publication (1). These guidelines are under review by a number of other organizations and will be subject to modification for special situations. Thus, the terminology "guidelines," rather than "standards of care," is chosen to indicate the flexibility necessary in developing such recommendations for general usage.

Pharmacological strategies to prevent macrovascular disease in NIDDM.

The pathogenesis of atherosclerosis and vascular thrombosis in NIDDM is reviewed. Evidence that suggests a role for chronic hyperglycemia, in association with other vascular risk markers, is presented. Based on this framework, a multifactorial approach to the prevention of progression of macrovascular disease in NIDDM is discussed. Results from a recent consensus conference sponsored by the American Diabetes Association regarding approaches to glycemic regulation in people with NIDDM are reviewed. It is concluded that preventive approaches will materially alter the course of macrovascular disease, reduce health care costs, and improve the quality of life for people with NIDDM.