Improvement of clinical and radiological outcomes of root repair patients with advanced articular cartilage degeneration and osteoarthritis.

PURPOSE: The main purpose of this study was to investigate clinical and radiological outcomes of medial meniscus posterior root tear (MMPRT) repair in knees with advanced articular cartilage degeneration and osteoarthritis compared to those with minimal degenerative change. METHODS: Thirty-three knees underwent MMPRT repair using an arthroscopic pullout repair tibial tunnel technique. Clinical scores including Lysholm Score, International Knee Documentation Committee (IKDC) Score and Knee injury and Osteoarthritis Outcome (KOOS) Score were collected preoperatively and sequentially at 6 months, 12 months and mean final follow-up of 39.4 months. Kellgren-Lawrence (K-L) osteoarthritis grade, Outerbridge classification of cartilage degeneration and the presence of bone marrow oedema on MRI were also evaluated. RESULTS: All clinical scores improved at final follow-up for knees with K-L grade ≥ 2 osteoarthritis (p < 0.001), with no significant difference compared to K-L 0/1. Patients with Outerbridge class 3/4 cartilage degeneration also reported improvements in clinical scores, albeit lower than those with class 2 degeneration (p < 0.05). During recovery, the majority of patients reported clinical improvements by 6 months, and six patients further improved by at least 15 points in IKDC score between 6 and 12 months. Osteoarthritis progressed in 10 of 31 knees (32%), with an overall mean pre-operative K-L grade of 1.6 ± 0.9 compared to 2.0 ± 0.9 at final follow-up (n.s.). No knees progressed to K-L 4 or underwent re-operation. Pre-operative bone marrow oedema was present in 17 knees (52%), all of which had signal localised to the medial tibia or femur. Oedema had resolved in all but 5 knees post-operatively (p < 0.01). CONCLUSION: Arthroscopic repair of medial meniscus posterior root tears is associated with improved outcomes in knees with advanced cartilage degeneration and osteoarthritis. Meaningful improvements in clinical outcomes can be achieved beyond 6 months, thus success of the operation is best determined at the 12-month mark. Oedema signal significantly improved post-operatively, however a relatively high proportion of knees had K-L progression. LEVEL OF EVIDENCE: IV - Case Series.

Plasma 25-hydroxyvitamin D and risk of metabolic syndrome: an ancillary analysis in the Diabetes Prevention Program.

BACKGROUND/OBJECTIVES: Low blood levels of 25-hydroxyvitamin D (25OHD) have been associated with cardiometabolic disease but results are inconsistent. The objective of the study was to investigate the association of 25OHD with metabolic syndrome in a population at increased risk for diabetes. SUBJECTS/METHODS: Using baseline data from the placebo and lifestyle intervention arms of the Diabetes Prevention Program (N=2000), multivariable logistic regression models were used to estimate the odds of prevalent metabolic syndrome and each of its individual components across 25OHD tertiles. Multivariable linear regression was used to estimate the adjusted mean difference of insulin secretion and sensitivity across the same 25OHD tertiles. In participants free of metabolic syndrome at baseline (N=546), incident metabolic syndrome in the first 2 years of follow-up was assessed using discrete-time proportional hazards regression to test its association with 25OHD concentration. RESULTS: After multivariate adjustment, participants in the highest tertile of 25OHD had lower odds of prevalent metabolic syndrome (odds ratio=0.62; 95% confidence interval (CI)=0.45-0.84), smaller waist circumference, higher high-density lipoprotein and lower fasting plasma glucose compared with participants in the lowest tertile of 25OHD. Higher plasma 25OHD concentration was associated with greater insulin sensitivity and lower insulin secretion. After multivariate adjustment, there was a nonsignificant lower risk of metabolic syndrome in the highest tertile of 25OHD (hazard ratio=0.79; 95% CI=0.48-1.32) compared with the lowest tertile. CONCLUSIONS: In a population at increased risk for diabetes, higher plasma 25OHD concentration was inversely associated with prevalent metabolic syndrome and nonsignificantly with incident metabolic syndrome.

Intensification of diabetes medication and risk for 30-day readmission.

AIM: To examine the association of in-hospital diabetes regimen intensification with subsequent 30-day risk for unplanned readmission/emergency department admission. METHODS: We retrospectively studied 1949 adults with Type 2 diabetes receiving primary care within an academic health network admitted to the hospital between January 2007 and December 2009. Glucose therapy intensification was defined as new start of insulin or oral hypoglycaemic agents, or addition of prandial insulin or insulin mixtures. The association of glucose therapy intensification with subsequent 30-day risk for unplanned readmission/emergency department admission was examined, with focus on medicine service patients with poorly controlled glycaemia (baseline HbA(1c) ≥ 64 mmol/mol). RESULTS: One in six patients (324/1949, 17%) had early readmission/emergency department admission. Compared with patients without early readmission, readmitted patients were more often male (58 vs. 52%, P = 0.03), had higher Charlson co-morbidity score [mean (sd) 3.0 (2.0) vs. 2.8 (1.8), P = 0.02], longer length of stay [5 (4.4) vs. 3.9 (3.3) days, P < 0.01] and were more often discharged home with nursing services (38 vs. 32%, P = 0.03). Overall, glucose therapy intensification was not associated with early hospital readmission/emergency department admission (odds ratio 0.94, 95% CI 0.64-1.37, P = 0.74). However, among medicine service patients with baseline HbA(1c) ≥ 64 mmol/mol (8%), glucose therapy intensification was associated with a significantly decreased early readmission risk (adjusted odds ratio 0.33, 95% CI 0.12-0.88, P = 0.03) and lower post-discharge HbA(1c) {mean decrease (sd): 20 (26) mmol/mol [1.8 (2.4)%] vs. 7 (15) mmol/mol [0.6 (1.4)%], P < 0.01}. CONCLUSIONS: Diabetes medical regimen intensification during hospitalization was not associated with early readmission. Among patients with elevated HbA(1c) , glucose therapy intensification was associated with a decreased 30-day readmission/emergency department admission risk and lower outpatient HbA(1c) levels. Our findings support the safety and durable impact of diabetes regimen optimization during hospital admission.

Insulin resistance influences the association of adiponectin levels with diabetes incidence in two population-based cohorts: the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study and the Framingham Offspring Study.

AIMS/HYPOTHESIS: Lower adiponectin levels are associated with higher risk of incident type 2 diabetes. Most analyses have been adjusted for confounding factors, but few have taken into account insulin resistance per se. We tested the hypothesis that the association of adiponectin levels with incident type 2 diabetes differs between insulin-resistant and insulin-sensitive individuals. METHODS: We studied two prospective cohorts: the Framingham Offspring Study (n = 2,023) and the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study (n = 887) cohorts. Insulin resistance was estimated by HOMA-insulin resistance (HOMA-IR). We used logistic regression analysis to test the association between adiponectin and incident type 2 diabetes overall and in insulin-resistant vs insulin-sensitive individuals (defined by ≥ vs <75th percentile of HOMA-IR). RESULTS: At baseline, Framingham's participants were 60 ± 9 years old and 56% were women; KORA's participants were 63 ± 5 years old and 49% were women. Type 2 diabetes incidence was 5.4% over 6.5 years (n = 109) in Framingham and 10.5% over 8 years (n = 93) in KORA. Lower adiponectin levels were associated with type 2 diabetes incidence in both cohorts. In insulin-resistant individuals, lower adiponectin levels were associated with higher risk of type 2 diabetes incidence (OR 1.60 [95% CI 1.10-2.31] per SD decrease in Framingham, p = 0.01; and OR 2.34 [95% CI 1.16-4.73] in KORA, p = 0.02); while this was not observed in insulin-sensitive individuals (OR 1.10 [95% CI 0.73-1.67] in Framingham, p = 0.64; and OR 1.34 [95%CI: 0.88-2.03] in KORA, p = 0.18). CONCLUSIONS/INTERPRETATION: We conclude that lower adiponectin levels are associated with higher risk of type 2 diabetes in insulin-resistant but not in insulin-sensitive individuals. This suggests that some level of insulin resistance is needed to see deleterious effects of low adiponectin.

HbA1(c) and mean blood glucose show stronger associations with cardiovascular disease risk factors than do postprandial glycaemia or glucose variability in persons with diabetes: the A1C-Derived Average Glucose (ADAG) study.

AIMS: Increased glucose excursions and postprandial hyperglycaemia have been suggested as unique risk factors for cardiovascular disease (CVD) and mortality in patients with diabetes mellitus. Much of the evidence is based on a single 2 h glucose value after oral glucose tolerance testing in epidemiological studies. We examined the association between various indices of glycaemia measured during everyday activities and metabolic CVD risk factors in the A1C-Derived Average Glucose (ADAG) study. METHODS: Participants (268 with type 1 diabetes, 159 with type 2 diabetes) completed 16 weeks of intensive continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG). From these data, common indices of postprandial glycaemia, overall hyperglycaemia, glucose variability and HbA1(c) were derived. The associations between glycaemic indices and known CVD risk factors (lipids, high-sensitivity C-reactive protein and blood pressure) were explored in linear regression models. RESULTS: For both diabetes types, the overall strongest associations with CVD risk factors were seen for the measures of average glycaemia (mean blood glucose and HbA1(c)). Associations between self-monitored postprandial and fasting glucose and CVD risk factors were weaker, but significant. Measurements of blood glucose variability showed non-significant associations. Overall, calculations based on CGM were not more informative than those based on frequent SMBG. CONCLUSIONS/INTERPRETATION: Mean glycaemia and HbA1(c) show consistent and stronger associations with CVD risk factors than fasting glucose or postprandial glucose levels or measures of glucose variability in patients with diabetes.

Disparity in management of diabetes and coronary heart disease risk factors by sex in DCCT/EDIC.

AIMS: Coronary heart disease (CHD) is a major cause of morbidity and mortality in patients with diabetes. Sex disparity in the treatment of modifiable CHD risk factors in patients with Type 2 diabetes has been reported previously; however, there is little comparable information in Type 1 diabetes. METHODS: We performed a cross-sectional analysis of 1153 subjects with Type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort to compare achievement of metabolic and CHD risk factor goals and use of recommended risk factor interventions between the sexes. RESULTS: Women were less likely than men to achieve glycated haemoglobin (HbA1c)<7.0% [adjusted odds ratio (AOR) 0.76, 95% confidence interval (CI) 0.57-0.995] or<8.0% (AOR 0.74, 95% CI 0.58-0.95). Achievement of target lipid levels was not significantly different between the sexes. As in the non-diabetic population, men had higher blood pressure. Women were significantly less likely than men to report using aspirin (AOR 0.77, 0.60-0.99) and angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) (AOR 0.62, 0.49-0.80) and statins (AOR 0.56, 0.43-0.73), even after adjusting for blood pressure and lipid levels, respectively. Reported use of statins was also lower in women than men in the subset that developed a low-density lipoprotein (LDL) cholesterol level>3.4 mmol/l (39% vs. 60%, P<0.05). CONCLUSIONS: In Type 1 diabetes, women report lower frequency than men in the use of interventions that decrease CHD risk. These findings are consistent with reports in the Type 2 diabetic population, showing that risk-reducing measures are underused in women with diabetes.

Real-life glycaemic profiles in non-diabetic individuals with low fasting glucose and normal HbA1c: the A1C-Derived Average Glucose (ADAG) study.

AIMS/HYPOTHESIS: Real-life glycaemic profiles of healthy individuals are poorly studied. Our aim was to analyse to what extent individuals without diabetes exceed OGTT thresholds for impaired glucose tolerance (IGT) and diabetes. METHODS: In the A1C-Derived Average Glucose (ADAG) study, 80 participants without diabetes completed an intensive glucose monitoring period of 12 weeks. From these data, we calculated the average 24 h glucose exposure as time spent above different plasma glucose thresholds. We also derived indices of postprandial glucose levels, glucose variability and HbA(1c). RESULTS: We found that 93% of participants reached glucose concentrations above the IGT threshold of 7.8 mmol/l and spent a median of 26 min/day above this level during continuous glucose monitoring. Eight individuals (10%) spent more than 2 h in the IGT range. They had higher HbA(1c), fasting plasma glucose (FPG), age and BMI than those who did not. Seven participants (9%) reached glucose concentrations above 11.1 mmol/l during monitoring. CONCLUSIONS/INTERPRETATION: Even though the non-diabetic individuals monitored in the ADAG study were selected on the basis of a very low level of baseline FPG, 10% of these spent a considerable amount of time at glucose levels considered to be 'prediabetic' or indicating IGT. This highlights the fact that exposure to moderately elevated glucose levels remains under-appreciated when individuals are classified on the basis of isolated glucose measurements.

The clinical application of genetic testing in type 2 diabetes: a patient and physician survey.

AIMS/HYPOTHESIS: Advances in type 2 diabetes genetics have raised hopes that genetic testing will improve disease prediction, prevention and treatment. Little is known about current physician and patient views regarding type 2 diabetes genetic testing. We hypothesised that physician and patient views would differ regarding the impact of genetic testing on motivation and adherence. METHODS: We surveyed a nationally representative sample of US primary care physicians and endocrinologists (n = 304), a random sample of non-diabetic primary care patients (n = 152) and patients enrolled in a diabetes pharmacogenetics study (n = 89). RESULTS: Physicians and patients favoured genetic testing for diabetes risk prediction (79% of physicians vs 80% of non-diabetic patients would be somewhat/very likely to order/request testing, p = 0.7). More patients than physicians (71% vs 23%, p < 0.01) indicated that a 'high risk' result would be very likely to improve motivation to adopt preventive lifestyle changes. Patients favoured genetic testing to guide therapy (78% of patients vs 48% of physicians very likely to request/recommend testing, p < 0.01) and reported that genetic testing would make them 'much more motivated' to adhere to medications (72% vs 18% of physicians, p < 0.01). Many physicians (39%) would be somewhat/very likely to order genetic testing before published evidence of clinical efficacy. CONCLUSIONS/INTERPRETATION: Despite the paucity of current data, physicians and patients reported high expectations that genetic testing would improve patient motivation to adopt key behaviours for the prevention or control of type 2 diabetes. This suggests the testable hypothesis that 'genetic' risk information might have greater value to motivate behaviour change compared with standard risk information.

Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

Retinal haemodynamics in individuals with well-controlled type 1 diabetes.

AIMS/HYPOTHESIS: Abnormalities in retinal haemodynamics have been reported in patients with type 1 diabetes in advance of clinical retinopathy. These abnormalities could therefore be useful as early markers or surrogate endpoints for studying the microangiopathy. Since the DCCT, the increased focus on good glycaemic control is changing the natural history of diabetic retinopathy. Based on this, the aim of this study was to investigate whether patients with type 1 diabetes treated entirely or mostly in the post-DCCT era and tested in the absence of confounding factors show retinal haemodynamic abnormalities. METHODS: We measured retinal haemodynamics by laser Doppler flowmetry in 33 type 1 diabetic individuals with no or minimal retinopathy (age 30+/-7 years, duration of diabetes 8.8+/-4.6 years, 9% showing microaneurysms), and 31 age- and sex-matched non-diabetic controls. The study participants were not taking vasoactive medications, and blood glucose at the time of haemodynamic measurements was required to be between 3.8 and 11.1 mmol/l. RESULTS: HbA1c was 7.5+/-1.2% and blood glucose 7.7+/-2.8 mmol/l in these type 1 diabetic individuals, indicating relatively good glycaemic control. Retinal blood speed, arterial diameter and blood flow were not different between the diabetic individuals and the matched controls. CONCLUSIONS/INTERPRETATION: Type 1 diabetic patients with no or minimal retinopathy who maintain relatively good glycaemic control do not show abnormalities of the retinal circulation at steady state, even after several years of diabetes. In such patients it may be necessary to test the vascular response to challenges to uncover any subtle abnormalities of the retinal vessels.

Relationship between glycated haemoglobin levels and mean glucose levels over time.

AIMS/HYPOTHESIS: HbA(1c), expressed as the percentage of adult haemoglobin that is glycated, is the most widely used measure of chronic glycaemia. Achieving near-normal HbA(1c) levels has been shown to reduce long-term complications and the HbA(1c) assay is recommended to determine whether treatment is adequate and to guide adjustments. However, daily adjustments of therapy are guided by capillary glucose levels (mmol/l). We determined the relationship between an accurate measure of mean glucose levels over time and the HbA(1c) level, and whether HbA(1c) can be expressed in the same units as self-monitoring results. METHODS: Twenty-two participants with diabetes and three non-diabetic participants were included in this longitudinal observational study. Mean glucose levels were measured by continuous glucose monitoring (CGM), which measures interstitial glucose levels every 5 min, for 12 weeks. Capillary measurements were obtained four times per day to confirm the accuracy of CGM. HbA(1c) was measured at baseline and every 4 weeks. RESULTS: The HbA(1c) results at weeks 8 and 12 correlated strongly (r = 0.90) with the CGM results during the preceding 8 and 12 weeks. A curvilinear (exponential) relationship and a linear regression captured the relationship with similarly high correlations, which allowed transformation of HbA(1c) values to a calculated mean glucose level. CONCLUSIONS AND INTERPRETATION: HbA(1c) correlates closely with a complete measure of average glycaemia over the preceding 8-12 weeks. The translation of HbA(1c) to an average glucose level for reporting and management purposes is feasible.

[Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. (A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes)].

This Russian translation and reprint of the original article published with authors permissions. Original article published in the Diabetes Care. 2006;29(8). Translation to Russian prepared by Yu. Sych. An abridged version of the article was prepared by A. Gorbovskaya. These recommendations and the algorithm are based on data from clinical studies of various treatment options for type 2 diabetes and on the personal experience of consensus participants, taking into account the main goal of treatment - to achieve and maintain glucose levels as close as possible to glycemia in healthy people. The lack of evidence of high levels of glycemia obtained in comparative clinical trials with a direct comparison of different treatment options for diabetes remains the main obstacle to isolating one main class of drugs or combination of drugs that have advantages over others.

Clinical inertia in the management of Type 2 diabetes metabolic risk factors.

AIMS: Delays in the initiation and intensification of medical therapy may be one reason patients with diabetes do not reach evidence-based goals for metabolic control. We assessed intensification of medical therapy over time, comparing the management of hyperglycaemia, hypertension, and hyperlipidaemia. METHODS: Prospective cohort study of 598 adults with Type 2 diabetes receiving primary care in an academic medical centre from May 1997 to April 1999. We assessed whether patients failing to achieve standard treatment goals for haemoglobin A1c (HbA1c), systolic blood pressure (SBP), or low density lipoprotein (LDL) cholesterol when last measured during 12 months (Year 1, 5/97-4/98) had increases in their corresponding medical regimen during the following 12 months (Year 2, 5/98-4/99). RESULTS: Among untreated patients in Year 1, seven of 12 (58%) of those above goal for HbA1c were initiated on medical therapy in Year 2, compared with 16 of 48 (34%) above SBP goal (P=0.02) and 26 of 115 (23%) above LDL cholesterol goal (P=0.02). Among patients on therapy and above goal, 124 of 244 (51%) patients with elevated HbA1c had their regimen increased in Year 2, compared with 85 of 282 (30%) with elevated SBP (P<0.001) and 22 of 79 (30%) with elevated LDL cholesterol (P<0.001). From Year 1 to Year 2 there was a decline in the overall proportion of patients above goal for LDL cholesterol (from 58% to 45%, P=0.002) but not for HbA1c or blood pressure. CONCLUSIONS: Greater initiation and intensification of pharmaceutical therapy, particularly for elevated blood pressure or cholesterol, may represent a specific opportunity to improve metabolic control in Type 2 diabetes.

Clinical and cost outcomes of medical nutrition therapy for hypercholesterolemia: a controlled trial.

OBJECTIVE: To compare the results and cost-effectiveness of a cholesterol lowering protocol implemented by registered dietitians with cholesterol lowering advice by physicians. DESIGN: Six month randomized controlled trial, cost-effectiveness analysis. Subjects included 90 ambulatory care patients (60 men, 30 women), age range 21 to 65 years, with hypercholesterolemia and not taking hypolipidemic drugs. Patients were randomly assigned to receive medical nutrition therapy (MNT) from dietitians using a NCEP based lowering protocol or usual care (UC) from physicians. Outcome measures were plasma lipid profiles, dietary intake, weight, activity, patient satisfaction, and costs of MNT. Changes from baseline for each variable of interest were compared between treatment groups using analysis of covariance controlling for baseline value of the variable and gender. RESULTS: MNT achieved a 6% decrease in total and LDL cholesterol levels at 3 and 6 months compared with a 1% increase and a 2% decrease in both values at 3 and 6 months with UC (P<.001 and P<.05, respectively). Weight loss (1.9 vs 0 kg, P<.001) and dietary intake of saturated fat (7% of energy vs 10%, P<.001) were better in the MNT than the UC group. The additional costs of MNT were $217 per patient to achieve a 6% reduction in cholesterol and $98 per patient to sustain the reduction. The cost-effectiveness ratio for MNT was $36 per 1% decrease in cholesterol and LDL level. APPLICATIONS/CONCLUSIONS: MNT from registered dietitians is a reasonable investment of resources because it results in significantly better lipid, diet, activity, weight, and patient satisfaction outcomes than UC.

Sample exchange to compare insulin measurements between the San Antonio Heart Study and the Framingham Offspring Study.

Lack of assay standardization has precluded cross-study comparison of insulin levels. We exchanged blood samples between the San Antonio Heart and Framingham Offspring Studies to compare insulin measurements. Two randomly selected specimens were chosen for each non-diabetic man and woman in each of the bottom four quintiles and top two deciles of the originally assayed fasting and 2-hour post-challenge insulin distributions: 48 plasma samples from Framingham, and after further stratification by ethnicity, 96 serum samples from San Antonio. Total immunoreactive insulin was originally measured in both studies; we repeated the identical assay on exchanged samples. Repeat assays were performed a mean (SD) of 7.0 (0.8) years after collection in the Framingham study and 4.6 (1.1) years in the San Antonio study. Repeat insulin levels were highly correlated with original levels for both San Antonio samples repeated in Framingham (Pearson r=0.923) and for Framingham samples repeated in San Antonio (r=0.959). Original and repeat San Antonio serum insulin levels were similar (mean fasting and 2-hour combined original level 154 pmol/l vs. 142 pmol/l on repeat in Framingham). Framingham plasma insulin levels repeated in San Antonio were substantially lower than original levels (120 pmol/l vs. 336 pmol/l), as were an additional 12 samples repeat assayed in Framingham (93 pmol/l vs. 320 pmol/l). Repeat rank ordering in both studies was excellent: over 90% of subjects originally classified as hyperinsulinemic (top tertile of the combined distribution) were again classified as hyperinsulinemic upon repeat assay. We conclude that sample exchange for insulin measurement is simple and feasible. Original and repeat insulin levels are highly correlated; subjects originally classified as hyperinsulinemic remain so classified upon repeat assay. Associated regression curves can be used to calibrate insulin levels to a common reference standard, allowing epidemiology studies to compare levels of insulin and associated risk factors.

The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up.

BACKGROUND: Few data are available on the long-term impact of type 2 diabetes mellitus on total mortality and fatal coronary heart disease (CHD) in women. METHODS: We examined prospectively the impact of type 2 diabetes and history of prior CHD on mortality from all causes and CHD among 121 046 women aged 30 to 55 years with type 2 diabetes in the Nurses' Health Study who were followed up for 20 years from 1976 to 1996. RESULTS: During 20 years of follow-up, we documented 8464 deaths from all causes, including 1239 fatal CHD events. Compared with women with no diabetes or CHD at baseline, age-adjusted relative risks (RRs) of overall mortality were 3.39 (95% confidence interval [CI], 3.08-3.73) for women with a history of diabetes and no CHD at baseline, 3.00 (95% CI, 2.50-3.60) for women with a history of CHD and no diabetes at baseline, and 6.84 (95% CI, 4.71-9.95) for women with both conditions at baseline. The corresponding age-adjusted RRs of fatal CHD across these 4 groups were 1.0, 8.70, 10.6, and 25.8, respectively. Multivariate adjustment for body mass index and other coronary risk factors only modestly attenuated the RRs. Compared with nondiabetic persons, the multivariate RRs of fatal CHD across categories of diabetes duration (< or =5, 6-10, 11-15, 16-25, >25 years) were 2.75, 3.63, 5.51, 6.38, and 11.9 (P< .001 for trend), respectively. The combination of prior CHD and a long duration of clinical diabetes (ie, >15 years) was associated with a 30-fold (95% CI, 20.7-43.5) increased risk of fatal CHD. CONCLUSIONS: Our data indicate that among women, history of diabetes is associated with dramatically increased risks of death from all causes and fatal CHD. The combination of diabetes and prior CHD identifies particularly high-risk women.

Fasting plasma homocysteine levels in the insulin resistance syndrome: the Framingham offspring study.

OBJECTIVE: Insulin resistance, associated metabolic abnormalities, and elevated homocysteine levels are risk factors for cardiovascular disease (CVD). We examined relationships between homocysteine levels and features of insulin resistance syndrome (IRS). RESEARCH DESIGN AND METHODS: We measured clinical characteristics, plasma levels of fasting homocysteine, folate, B vitamins, creatinine, and fasting and 2-h insulin and glucose levels after a 75-g oral glucose tolerance test in 2,214 subjects without CVD at the fifth examination (1991-1995) of the Framingham Offspring Study. After excluding 203 subjects with diabetes, the remaining 2,011 subjects were categorized as having none, one, two, or all three of the phenotypes of IRS: impaired glucose tolerance, hypertension, and/or a central metabolic syndrome (two or more traits: obesity, dyslipidemia, or hyperinsulinemia). In addition, in 1,592 subjects attending the sixth examination (1995-1998), we measured the urine albumin/creatinine ratio (UACR). Age-, sex-, creatinine-, vitamin-, and UACR-adjusted mean homocysteine levels or proportions with homocysteine >14 micromol/l in each phenotypic category and differences between categories were assessed with regression models. RESULTS: The mean age of the subjects was 54 years (range 28-82); 55% were women, 12.3% had hyperinsulinemia, and 15.9% had two or more of the IRS phenotypes. Adjusted mean homocysteine levels were higher comparing those with hyperinsulinemia (9.8 micromol/l) and those without (9.4 micromol/l, P = 0.04) and were higher among subjects with two or more IRS phenotypes (9.9 micromol/l) compared with those with 1 or no phenotype (9.3 micromol/l, P = 0.003). Mean UACR levels were also higher among subjects with two or more IRS phenotypes (7.2 mg/g) compared with those with 1 or no phenotype (5.5 mg/g, P = 0.007). CONCLUSIONS: Hyperhomocysteinemia and abnormal urinary albumin excretion are both associated with hyperinsulinemia and may partially account for increased risk of CVD associated with insulin resistance. Because hyperhomocysteinemia and microalbuminuria also reflect endothelial injury, these observations also support the hypothesis that endothelial dysfunction is associated with expression of the IRS.