Contributions of increasing obesity and diabetes to slowing decline in subclinical coronary artery disease.

BACKGROUND: Our previous study of nonelderly adult decedents with nonnatural (accident, suicide, or homicide) cause of death (96% autopsy rate) between 1981 and 2004 revealed that the decline in subclinical coronary artery disease (CAD) ended in the mid-1990s. The present study investigated the contributions of trends in obesity and diabetes mellitus to patterns of subclinical CAD and explored whether the end of the decline in CAD persisted. METHODS AND RESULTS: We reviewed provider-linked medical records for all residents of Olmsted County, Minnesota, who died from nonnatural causes within the age range of 16 to 64 years between 1981 and 2009 and who had CAD graded at autopsy. We estimated trends in CAD risk factors including age, sex, systolic blood pressure, diabetes (qualifying fasting glucose or medication), body mass index, smoking, and diagnosed hyperlipidemia. Using multiple regression, we tested for significant associations between trends in CAD risk factors and CAD grade and assessed the contribution of trends in diabetes and obesity to CAD trends. The 545 autopsied decedents with recorded CAD grade exhibited significant declines between 1981 and 2009 in systolic blood pressure and smoking and significant increases in blood pressure medication, diabetes, and body mass index ≥30 kg/m(2). An overall decline in CAD grade between 1981 and 2009 was nonlinear and ended in 1994. Trends in obesity and diabetes contributed to the end of CAD decline. CONCLUSIONS: Despite continued reductions in smoking and blood pressure values, the previously observed end to the decline in subclinical CAD among nonelderly adult decedents was apparent through 2009, corresponding with increasing obesity and diabetes in that population.

Impact of data from recent clinical trials on strategies for treating patients with type 2 diabetes mellitus.

Type 2 diabetes is associated with increased risk for the development of cardiovascular disease (CVD) secondary to hyperglycemia's toxicity to blood vessels. The escalating incidence of CVD among patients with type 2 diabetes has prompted research into how lowering glycated hemoglobin (HbA(1c)) may improve CVD-related morbidity and mortality. Data from recent studies have shown that some patients with type 2 diabetes actually have increased mortality after achieving the lowest possible HbA(1c) using intensive antidiabetes treatment. Multiple factors, such as baseline HbA(1c), duration of diabetes, pancreatic beta-cell decline, presence of overweight/obesity, and the pharmacologic durability of antidiabetes medications influence diabetes treatment plans and therapeutic results. Hypertension and dyslipidemia are common comorbidities in patients with type 2 diabetes, which impact the risk of CVD independently of glycemic control. Consideration of all of these risk factors provides the best option for reducing morbidity and mortality in patients with type 2 diabetes. Based on the results of recent trials, the appropriate use of current antidiabetes therapies can optimize glycemic control, but use of intensive glucose-lowering therapy will need to be tailored to individual patient needs and risks.

Efficacy and safety of ursodeoxycholic acid in primary, type IIa or IIb hypercholesterolemia: a multicenter, randomized, double-blind clinical trial.

BACKGROUND: Ursodeoxycholic acid (UDCA) is a therapeutic bile acid used in dissolution of gallstones and treatment of several cholestatic liver diseases. Results obtained from primary biliary cirrhosis patients treated with UDCA suggested that this agent exerts significant cholesterol-lowering effects and justifies evaluation in primary hypercholesterolemic patients without liver disease. Purpose of this study was to determine whether UDCA had potential to be an effective, safe cholesterol-lowering agent in primary type IIa or IIb hypercholesterolemia. METHODS: This was a multicenter randomized, double blind, placebo-controlled trial. After a 6-week placebo lead-in period during which two qualifying lipid profiles were obtained, patients with a mean serum LDL-cholesterol (LDL-C) between 130 and 190mg/dL, triglycerides <400mg/dL and HDL-cholesterol >30mg/dL were randomized to UDCA or matching placebo for 24 weeks. RESULTS: Seven sites screened 200 patients with 134 patients meeting the entry criteria who were randomized to the two treatments. There were 125 patients meeting the efficacy evaluation criteria, 57 on UDCA and 68 on placebo. LDL-C change from weeks 0 to 24 showed no significant difference between groups. No significant differences in changes for total cholesterol, HDL-cholesterol and triglycerides were observed. Both groups had similar adverse event profiles. CONCLUSIONS: UDCA did not show intrinsic cholesterol-lowering properties and therefore is not a useful therapy in treating type IIa or type IIb hypercholesterolemic patients. UDCA was confirmed as a well tolerated and safe drug in this population.

Metabolic risk factors, endothelial dysfunction, and erectile dysfunction in men with diabetes.

BACKGROUND: The prevalence of men with erectile dysfunction (ED) and concomitant diabetes mellitus continues to increase. ED, diabetes, hypertension, and dyslipidemia (components of the metabolic syndrome) are associated with endothelial dysfunction. ED has been reported to be a marker for cardiovascular arterial disease. Effective treatment of ED requires recognition of the condition and its associated comorbidities, including endothelial dysfunction. METHODS: An electronic search of the literature was conducted to review information concerning the prevalence of ED, diabetes, metabolic syndrome, endothelial dysfunction, and treatment of ED. RESULTS: Phosphodiesterase type 5 (PDE5) inhibitors are effective vasodilating agents with a predominant effect on penile vasculature and are therefore first-line treatment for men with ED. These agents have also been demonstrated to have a beneficial effect in other vascular beds. PDE5 inhibitors have not been shown to have an adverse effect on cardiovascular morbidity or mortality or on glycemic control in men with diabetes. In addition, no causal association has been established between nonarteritic ischemic optic neuropathy and PDE5 inhibitors. CONCLUSIONS: PDE5 inhibitors have a beneficial effect on endothelial dysfunction and ED in men with diabetes and metabolic risk factors.

Temporal trends in prevalence of diabetes mellitus in a population-based cohort of incident myocardial infarction and impact of diabetes on survival.

OBJECTIVE: To determine the temporal trends in prevalence of confirmed diabetes mellitus (DM), time from the date DM criteria were met to myocardial infarction (MI), and impact of DM on survival. SUBJECTS AND METHODS: A retrospective cohort design was used to identify residents of Olmsted County, Minnesota, with incident MI from 1979 to 1998. The MI cases were characterized according to prevalent DM. Cases with and without DM were followed up for vital status until January 1, 2003. RESULTS: Of 2171 MI cases, 364 (17%) met criteria for prevalent DM. In the age- and sex-adjusted logistic regression models, the odds of prevalent DM Increased 3% with each Increasing year between 1979 and 1998 (95% confidence Interval [CI], 1%-5%; P=.007). Survival for MI cases with DM was unchanged between 1979-1983 and 1994-1998 (P=.74). For all MI cases, age-, sex-, and DM-adjusted risk of death decreased 3% from 1979 to 1998 (95% CI, 1%-5%) per year for 28-day survival (P=.02) and 2% (95% CI, 1%-3%) per year for 5-year survival (P=.02). There was a significant adverse effect of DM on 5-year survival after MI (age-, sex-, and calendar year-adjusted hazard ratio, 1.70; 95% CI, 1.38-2.09; P<.001). The adverse effect of DM persisted after adjusting for other cardiovascular disease risk factors, MI severity, and reperfusion therapy (hazard ratio, 1.66; 95% CI, 1.34-2.05; P<.001) and was unchanged over time (interaction between DM and calendar year, P=-.63). CONCLUSION: These data indicate that the prevalence of DM among patients with MI is increasing and that its adverse impact on survival after MI remains unchanged.

Addition of insulin to oral therapy in patients with type 2 diabetes.

BACKGROUND: A majority of individuals with type 2 diabetes will eventually require exogenous insulin therapy to achieve or maintain glycemic control. This review provides practical recommendations for adding insulin therapy for patients with type 2 diabetes whose glucose levels are inadequately controlled with oral medications. METHODS: We used a systematic review of MEDLINE to retrieve relevant articles from 1990 to 2004 using the search terms insulin therapy, combination oral therapy, glycemic control, insulin analogs, insulin glargine, and basal insulin, which we supplemented with a review of clinical practice guidelines from the American Diabetes Association and the American Association of Clinical Endocrinologists. RESULTS: Type 2 diabetes mellitus is becoming more common in the United States and is likely to increase in prevalence as obesity, a risk factor for type 2 diabetes, likewise increases. Treatment often begins with oral monotherapy, but after 3 years of treatment, more than half of patients will require more than one pharmacological agent, and eventually most patients will require insulin. Adding insulin to oral therapy at an earlier stage in treatment provides improved glycemic control without promoting increased hypoglycemia or weight gain, lowers the risk of microvascular complications by 25%, and reduces the amount of insulin patients require. Various insulin preparations, including the newer analog insulins, with different onsets and durations of action are available to help meet individual patients' dosing needs. CONCLUSIONS: The addition of insulin to oral antidiabetic therapy can improve glycemic control. Newer insulin analogs can emulate normal physiologic insulin secretion and potentially limit diabetes-related comorbidity.

Relative risk of mortality associated with diabetes as a function of birth weight.

OBJECTIVE: Birth weight is a risk factor for both diabetes and mortality. Diabetes is a risk factor for mortality. Whether the excess mortality observed for diabetes varies with birth weight is unclear. RESEARCH DESIGN AND METHODS: Among all 2,508 Rochester, Minnesota, residents who first met research criteria for adult-onset diabetes in 1960-1995, 171 were born locally in-hospital after 1922 (i.e., birth weights available) as singleton, term infants. Each case subject and two age- and sex-matched nondiabetic control subjects (born locally, residing locally when the case subject met the criteria for diabetes) were followed through 31 December 2000 for vital status. RESULTS: Of the diabetic case subjects, 16% (27 of 171) died vs. 7% (25 of 342) of control subjects (P = 0.004). The difference was less for normal-birth-weight (NBW) (2,948-<3,856 g) individuals (12% [12 of 102] vs. 8% [20 of 246], P = 0.31) than for abnormal-birth-weight individuals (low birth weight [LBW] 20% [8 of 39] vs. 2% [1 of 46], P = 0.01; high birth weight [HBW] 23% [7 of 30] vs. 8% [4 of 50], P = 0.16), as confirmed with age- and sex-adjusted Cox proportional hazards (diabetes-associated hazard ratio 1.4 [95% CI 0.69-2.90] for NBW vs. 4.8 [1.7-13.3] for abnormal birth weight, test for interaction P = 0.056). The observed diabetes deaths were greater than expected, based on mortality for the general population (27 vs. 13.3, P < 0.001), with 70% of excess deaths occurring among LBW (8 vs. 2.2, P < 0.001) and HBW (7 vs. 3.1, P = 0.03) individuals. CONCLUSIONS: The excess mortality observed for diabetes appears disproportionately concentrated among abnormal-birth-weight individuals, thus identifying a subset of at-risk diabetic individuals and reinforcing the importance of NBW deliveries.

Peripheral arterial disease, diabetes, and mortality.

OBJECTIVE: The aims of this study were to provide estimates of 1) the risk of mortality for individuals with both diabetes and peripheral arterial disease (PAD) relative to that for individuals with either condition alone and 2) the association between PAD progression and mortality for individuals with diabetes, PAD, and both conditions. RESEARCH DESIGN AND METHODS: This longitudinal cohort study was conducted in Rochester, Minnesota. Local residents age 50-70 years with a prior diagnosis of PAD and/or diabetes were identified from the Mayo Clinic diagnostic registry and invited to a baseline examination (1977-1978). Those who met inclusion criteria were assessed for PAD progression at 2 and 4 years and followed for vital status through 31 December 1999. RESULTS: The numbers who met criteria for PAD, diabetes, and both conditions at baseline were 149, 238, and 186, respectively. Within each group, observed survival was less than expected (P <0.001). The adjusted risk of death for both conditions was 2.2 times that for PAD alone. Among the 449 who returned at 4 years, the risk of subsequent death was greater for those whose PAD had progressed; among individuals with diabetes alone at baseline, 100% (17 of 17) who met criteria for PAD progression were dead by 31 December 1999 compared with 62% (111 of 178) of those who had not met criteria (adjusted relative hazard 2.29 [95% CI 1.30-4.02], P=0.004). The increased mortality associated with PAD progression was significant only for individuals with diabetes (alone or with PAD). CONCLUSIONS: Diabetes is a risk factor for both PAD and PAD-associated mortality, emphasizing the critical need to detect and monitor PAD in diabetic patients.

The case for insulin treatment early in type 2 diabetes.

Most patients with type 2 diabetes ultimately need insulin therapy. This paper presents the case for starting insulin therapy sooner rather than later, preferably without oral drugs and in a "basal/bolus" regimen consisting of a daily dose of a long-acting insulin for basal coverage plus preprandial doses of a short-acting insulin.

Trends in the mortality burden associated with diabetes mellitus: a population-based study in Rochester, Minn, 1970-1994.

BACKGROUND: The prevalence of diabetes mellitus (DM) has increased markedly in recent decades, but trends in the mortality burden associated with DM are unclear. Therefore, we analyzed population-based longitudinal data to address this issue. METHODS: The community-based medical records of all Rochester residents 45 years and older who died between January 1, 1970, and December 31, 1994, were reviewed to identify those who met the standardized criteria for DM before death. Trends over successive quinquenniums were assessed for the proportion of all deaths in the community of persons with prevalent DM, for mortality rates for persons with and without DM, and for the distribution of causes of death among decedents with and without DM. RESULTS: Of 10 152 total deaths in 1970-1994, 1384 (13.6%) met the criteria for prevalent DM. Between 1970-1974 and 1990-1994, the proportion of decedents with DM increased by 48.2%. Mortality rates for persons with and without DM declined by 13.8% and 21.4%, respectively. This disparity in mortality trends was most apparent for older women and younger men. There were temporal declines in the proportion of all persons dying of cardiovascular disease, but temporal declines in persons dying of cerebrovascular disease were found only in decedents without DM. CONCLUSIONS: The mortality burden associated with DM increased significantly between 1970 and 1994, probably due to increases in DM incidence and smaller declines in mortality for persons with DM relative to those without DM. In the absence of improved DM prevention and treatment, the steady declines in mortality observed for the general population since the 1960s will likely begin to slow or even reverse.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE EVALUATION AND TREATMENT OF HYPERTHYROIDISM AND HYPOTHYROIDISM.

These clinical practice guidelines summarize the recommendations of the American Association of Clinical Endocrinologists for the diagnostic evaluation of hyperthyroidism and hypothyroidism and for treatment strategies in patients with these disorders. The sensitive thyroid-stimulating hormone (TSH or thyrotropin) assay has become the single best screening test for hyperthyroidism and hypothyroidism, and in most outpatient clinical situations, the serum TSH is the most sensitive test for detecting mild thyroid hormone excess or deficiency. Therapeutic options for patients with Graves' disease include thyroidectomy (rarely used now in the United States), antithyroid drugs (frequently associated with relapses), and radioactive iodine (currently the treatment of choice). In clinical hypothyroidism, the standard treatment is levothyroxine replacement, which must be tailored to the individual patient. Awareness of subclinical thyroid disease, which often remains undiagnosed, is emphasized, as is a system of care that incorporates regular follow-up surveillance by one physician as well as education and involvement of the patient.

Coronary atherosclerosis in diabetes mellitus: a population-based autopsy study.

OBJECTIVES: The study was conducted to test the hypothesis that the prevalence of coronary atherosclerosis is greater among diabetic than among nondiabetic individuals and is similar for diabetic individuals without clinical coronary artery disease (CAD) and nondiabetics with clinical CAD. BACKGROUND: Persons with diabetes but without clinical CAD encounter cardiovascular mortality similar to nondiabetic individuals with clinical CAD. This excess mortality is not fully explained. We examined the association between diabetes and coronary atherosclerosis in a geographically defined autopsied population, while capitalizing on the autopsy rate and medical record linkage system available via the Rochester Epidemiology Project, which allows rigorous ascertainment of coronary atherosclerosis, clinical CAD, and diabetes. METHODS: Using two measures, namely a global coronary score and high-grade stenoses, the prevalence of atherosclerosis was analyzed in a cohort of autopsied residents of Rochester, Minnesota, age 30 years or older at death, while stratifying on diabetes, clinical CAD diagnosis, age, and gender. RESULTS: In this cohort, diabetes was associated with a higher prevalence of atherosclerosis. Among diabetic decedents without clinical CAD, almost three-fourths had high-grade coronary atherosclerosis and more than half had multivessel disease. Without diabetes, women had less atherosclerosis than men, but this female advantage was lost with diabetes. Among those without clinical CAD, diabetes was associated with a global coronary disease burden and a prevalence of high-grade atherosclerosis similar to that observed among nondiabetic subjects with clinical CAD. CONCLUSIONS: These findings provide mechanistic insights into the excess risk of clinical CAD among diabetic individuals, thereby supporting the need for aggressive prevention of atherosclerosis in all diabetic individuals, irrespective of clinical CAD symptoms.

Impact of case ascertainment on recent trends in diabetes incidence in Rochester, Minnesota.

The authors previously reported an increase in the incidence of diabetes mellitus among Rochester, Minnesota, residents during the period 1970-1989. This study provides updated rates from data collected through 1994. Trends in diabetes surveillance, i.e., the proportion of residents who had a blood glucose measurement in each year between 1987 and 1994, are also provided. The authors reviewed medical records to identify residents aged 30 years or more who first met National Diabetes Data Group criteria for diabetes between January 1, 1970, and December 31, 1994. Age- and sex-adjusted incidence rates were calculated for successive quinquennia (5-year periods), and Poisson regression was used to test for an effect of calendar year; calendar period (1970-1989 vs. 1990-1994) was added to assess whether the association with calendar year varied in the most recent quinquennium. Altogether, 1,992 Rochester residents first met National Diabetes Data Group criteria for diabetes between 1970 and 1994. The age-adjusted incidence per 100,000 person-years increased 67% for males (267.0 vs. 444.8) and 42% for females (225.4 vs. 319.1) between 1970-1974 and 1990-1994. Calendar year (p < 0.001) and calendar period (p = 0.026) were significant, suggesting that rates accelerated during 1990-1994. The proportion of residents with at least one blood glucose measurement per year was unchanged (p = 0.181) from 1987 to 1994, while the incidence of diabetes increased (p = 0.033). Thus, the authors conclude that the increase in diabetes incidence accelerated over the last quinquennium and was not due to increased surveillance.