Fenofibrate-associated changes in renal function and relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) experience.

AIMS/HYPOTHESIS: Fenofibrate has been noted to cause an elevation in serum creatinine in some individuals. Participants in the Action to Control Cardiovascular Risk in Diabetes Lipid Study were studied to better characterise who is at risk of an increase in creatinine level and to determine whether those with creatinine elevation have a differential risk of adverse renal or cardiovascular outcomes. METHODS: A fenofibrate-associated creatinine increase (FACI) was defined as an increase in serum creatinine of at least 20% from baseline to month 4 in participants assigned to fenofibrate. Baseline patient characteristics, and baseline and 4-month drug, clinical, laboratory characteristics and study outcomes were examined by FACI status. RESULTS: Of the sample, 48% of those randomised to receive fenofibrate had at least a 20% increase in serum creatinine within 4 months. In multivariable analysis, participants who were older, male, used an ACE inhibitor at baseline, used a thiazolidinedione (TZD) at 4 months post-randomisation, had baseline CVD, and had lower baseline serum creatinine and LDL-cholesterol levels were all more likely to meet the criteria for FACI. Participants in the FACI group were also more likely to have a decrease in their serum triacylglycerol level from baseline to 4 months. No differences in study outcomes were seen by FACI criteria. CONCLUSIONS/INTERPRETATION: Several characteristics predict a rapid rise in serum creatinine upon starting fenofibrate. Participants who met the criteria for FACI also had a greater change in triacylglycerol levels. In the setting of careful renal function surveillance and reduction of fenofibrate dose as indicated, no increase in renal disease or cardiovascular outcome was seen in those individuals demonstrating FACI. TRIAL REGISTRATION: ClincalTrials.gov: NCT00000620. FUNDING: The ACCORD Trial was supported by grants (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035 and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; by General Clinical Research Centers and by the Clinical and Translational Science Awards. Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, sanofi-aventis US and Takeda Pharmaceuticals provided study medications, equipment or supplies.

The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomised trial.

AIMS/HYPOTHESIS: Recent clinical trials have found that the combination of conjugated equine oestrogen (CEO) and medroxyprogesterone has a protective effect on the incidence of type 2 diabetes. To determine the effect of CEO alone on the incidence of diabetes mellitus in postmenopausal women, we analysed the results of the Women's Health Initiative oestrogen-alone trial. METHODS: The Women's Health Initiative is a randomised, double-masked trial comparing the effect of daily 0.625 mg CEO with placebo during 7.1 years of follow-up of 10,739 postmenopausal women who were aged 50-79 years and had previously had a hysterectomy. Diabetes incidence was ascertained by self-report of treatment with insulin or oral hypoglycaemic medication. Fasting glucose, insulin and lipoproteins were measured in an 8.6% random sample of study participants, at baseline and at 1, 3 and 6 years. RESULTS: The cumulative incidence of treated diabetes was 8.3% in the oestrogen-alone group and 9.3% in the placebo group (hazard ratio 0.88, 95% CI 0.77-1.01, p=0.072). During the first year of follow-up, a significant fall in insulin resistance (homeostasis model assessment of insulin resistance) in actively treated women compared with the control subjects (Year 1 baseline between-group difference -0.53) was seen. However, there was no difference in insulin resistance at the 3- or 6-year follow-up. CONCLUSIONS/INTERPRETATION: Postmenopausal therapy with oestrogen alone may reduce the incidence of treated diabetes. The effect is smaller than that seen with oestrogen plus progestin. CEO should not, however, be used with the intention of preventing diabetes, as its well-described adverse effects preclude long-term use for primary prevention.

Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial.

AIMS/HYPOTHESIS: Studies examining the effect of postmenopausal hormone therapy on concentrations of glucose, insulin and diabetes incidence have been inconclusive, in part because many of the studies were too small. We examined the effect of oestrogen plus progestin on diabetes incidence and insulin resistance. METHODS: The study was a randomised, double-blind trial comparing the effect of daily 0.625 mg conjugated equine oestrogens plus 2.5 mg medroxyprogesterone acetate with that of placebo during 5.6 years of follow-up. The participants were 15,641 postmenopausal women enrolled in the Women's Health Initiative Hormone Trial. These women were aged 50 to 79 and all had an intact uterus. Diabetes incidence was ascertained by self-report of treatment with insulin or oral hypoglycaemic medication. Fasting glucose, insulin, and lipoproteins were measured in a random sample at baseline and at 1 and 3 years. RESULTS: The cumulative incidence of treated diabetes was 3.5% in the hormone therapy group and 4.2% in the placebo group (hazard ratio 0.79, 95% CI 0.67-0.93, p=0.004). There was little change in the hazard ratio after adjustment for changes in BMI and waist circumference. During the first year of follow-up, changes in fasting glucose and insulin indicated a significant fall in insulin resistance in actively treated women compared to the control subjects (Year 1 to baseline between-group difference -0.22+/-0.10, p=0.03). INTERPRETATIONS/CONCLUSION: These data suggest that combined therapy with oestrogen and progestin reduces the incidence of diabetes, possibly mediated by a decrease in insulin resistance unrelated to body size. Future studies of alternative postmenopausal hormone therapy regimens and selective oestrogen agonists and/or antagonists should consider the effects of these regimens on insulin resistance and diabetes.

Cost-effectiveness of prenatal screening for postpartum thyroiditis.

Five percent of all pregnant women and 25% of pregnant women with insulin-dependent diabetes mellitus (IDDM) develop postpartum thyroiditis (PPT) during the first year after delivery. PPT has significant morbidity and can be predicted prenatally by the presence of thyroid peroxidase (TPO) antibody. Our objective was to estimate the cost-effectiveness of screening pregnant women for the TPO antibody versus the current strategy of no screening test or an alternative strategy of a thyroid-stimulating hormone (TSH) test 6 weeks postpartum. We performed cost-effectiveness analysis using a decision tree model that accounted for cases of PPT detected, medical outcomes of screening, and costs of screening and care. Hypothetical cohorts of 1000 pregnant women with uncomplicated pregnancies and 1000 pregnant women with IDDM were used to determine direct medical costs, quality-adjusted life years, and cases of PPT detected. The cost of testing 1000 pregnant women for TSH at the 6 week postpartum visit was $75,000, with an effectiveness of 995.2 quality-adjusted life years resulting in a cost-effectiveness ratio of $48,000 per quality-adjusted life year. Checking a TPO antibody was more effective (995.5 quality-adjusted life years) but also more expensive ($93,000). The incremental cost-effectiveness ratio of the TPO antibody strategy was $60,000 per quality-adjusted life year. Results were most sensitive to changes in the test characteristics, incidence of disease, and percentage of women with PPT who were symptomatic. A separate analysis for women with IDDM resulted in an incremental cost-effectiveness ratio of $13,000 per quality-adjusted life year for the TSH strategy and $32,000 per quality-adjusted life year for the TPO strategy. Screening for PPT is likely to be reasonably cost-effective and should be considered for inclusion as part of routine pregnancy care.