Observational study of kidney function and albuminuria in patients with type 2 diabetes treated with exenatide BID versus insulin glargine.

BACKGROUND: Kidney disease is common among patients with type 2 diabetes (T2DM). Treatment of diabetes seeks to minimize negative kidney impact. OBJECTIVE: To assess the changes in kidney function and incidence of albuminuria in patients with T2DM treated for 1 year with exenatide twice daily (BID) or insulin glargine. METHODS: Retrospective analyses were performed using an electronic medical record database. Patients inititating treatment with either exenatide BID or insulin glargine between November 2006, and April 2009 comprised the study cohort. The 2 groups were 1:1 propensity score matched on baseline variables yielding 2683 pairs. Measures of kidney function included estimated glomerular filtration rate (eGFR,) and urinary albumin/creatinine ratio (UACR). RESULTS: Mean baseline eGFR was identical between the groups (79 ± 23 mL/min/1.73 m(2)). At 1-year follow-up, there was no significant difference in mean eGFR between the groups (78 mL/min/1.73 m(2) for exenatide BID vs 80 mL/min/1.73 m(2) for insulin glargine; P = .39). Despite matching of multiple characteristics, mean baseline UACR was lower in the exenatide BID group (mean = 34 ± 71 mg/g) compared with the insulin glargine group (183 ± 509 mg/g; P = .03). At follow-up, exenatide BID patients had a mean increase in UACR of 104 mg/g, insulin glargine patients had a decrease of 47 mg/g, but the difference was not significant (P = .19). CONCLUSION: There were no significant differences in change in kidney function or albuminuria at 1 year in patients treated with exenatide BID compared with insulin glargine as administered in routine practice.

The effect of ruboxistaurin on nephropathy in type 2 diabetes.

OBJECTIVE: Ruboxistaurin selectively inhibits protein kinase C-beta and ameliorates kidney disease in animal models of diabetes. The purpose of this study was to evaluate the effects of ruboxistaurin on diabetic nephropathy in humans. RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled, multicenter, pilot study was performed to evaluate the effects of 32 mg/day ruboxistaurin for 1 year in persons (n = 123) with type 2 diabetes and persistent albuminuria (albumin-to-creatinine ratio [ACR] 200-2,000 mg/g), despite therapy with renin-angiotensin system inhibitors. The primary end point was a change in the ACR. Estimated glomerular filtration rate (eGFR) (four-component equation from the Modification of Diet in Renal Disease study) was also calculated. RESULTS: At baseline, urinary ACR was 764 +/- 427 mg/g (means +/- SD), and eGFR was 70 +/- 24 ml/min per 1.73 m2. Systolic and diastolic blood pressures were 135 +/- 14 and 75 +/- 9 mmHg, respectively. HbA(1c) was 8.0 +/- 1.2%. After 1 year, urinary ACR decreased significantly (-24 +/- 9%) in participants treated with ruboxistaurin (P = 0.020) and nonsignificantly (-9 +/- 11%) in the placebo group (P = 0.430). The ACR-lowering effect of ruboxistaurin appeared by 1 month. eGFR did not decline significantly in the ruboxistaurin group (-2.5 +/- 1.9 ml/min per 1.73 m2) (P = 0.185), whereas the placebo group lost significant eGFR over 1 year (-4.8 +/- 1.8 ml/min per 1.73 m2) (P = 0.009). Between-group differences for changes in ACR and eGFR were not statistically significant, but this pilot study was underpowered to determine such differences. CONCLUSIONS: In persons with type 2 diabetes and nephropathy, treatment with ruboxistaurin reduced albuminuria and maintained eGFR over 1 year. Ruboxistaurin may add benefit to established therapies for diabetic nephropathy.

Effect of raloxifene on serum triglycerides in women with a history of hypertriglyceridemia while on oral estrogen therapy.

OBJECTIVE: Raloxifene hydrochloride is a selective estrogen receptor modulator that to date has not been shown to cause hypertriglyceridemia in normal, diabetic, or hypertriglyceridemic women. This study was designed to assess the effect of raloxifene on serum triglycerides in postmenopausal women who have a history of increased hypertriglyceridemia with oral estrogen therapy. RESEARCH DESIGN AND METHODS: This was a single-center, uncontrolled, open-label study investigating the effects of 8 weeks of raloxifene (60 mg/day) therapy on plasma lipids. The study subjects were 12 postmenopausal women, ages 49-73 years, with a documented history of oral estrogen-induced hypertriglyceridemia (serum triglycerides > or =3.39 mmol/l [> or =300 mg/dl]). RESULTS: At week 2 of the study, three (25%) of the subjects withdrew from the trial because they developed marked hypertriglyceridemia (>or =11.3 mmol/l [> or =1,000 mg/dl]) during raloxifene therapy. These three women had higher baseline triglyceride and glucose levels, were not being treated with lipid-lowering agents, and were more likely to have diabetes than the other study subjects. The remaining nine patients (75%) completed the 8-week trial and experienced a nonsignificant increase in mean triglyceride levels from baseline to end point. Raloxifene treatment also resulted in a significant 16% decrease in hepatic lipase activity and a 26% increase in HDL(2) levels (P = 0.013 and 0.03, respectively). CONCLUSIONS: Patients with a previous history of hypertriglyceridemia on oral estrogen therapy should have serum triglyceride levels monitored closely after beginning raloxifene therapy and may even require fibrate therapy before beginning raloxifene.

Raloxifene does not affect insulin sensitivity or glycemic control in postmenopausal women with type 2 diabetes mellitus: a randomized clinical trial.

Little is known about the metabolic or cardiovascular effects of selective ER modulators (SERMs), such as raloxifene hydrochloride (RLX), in postmenopausal women with type 2 diabetes mellitus (DM). Therefore, the effect of RLX vs. placebo (PL) on glycemic control, insulin sensitivity, as well as effects on a number of hormone, lipid, coagulation, and safety factors were determined in 30 postmenopausal women with type 2 DM in a randomized, double blind, cross-over trial. All participants had a SHBG serum concentration below 60 nmol/liter at baseline and had stable diabetes controlled by either oral hypoglycemic agents or diet for 1 month. In the first treatment period, participants received 12 wk of either PL or RLX, followed by an 8-wk washout before the second treatment period. In the second treatment period, participants were crossed over to the other treatment. Compared with PL, RLX did not significantly affect fasting blood glucose, hemoglobin A(1c), lipids, fasting insulin, or insulin sensitivity (as measured by the euglycemic clamp technique). Compared with PL, RLX reduced fibrinogen levels by 0.77 g/liter (P < 0.001), IGF-I by 2.4 nmol/liter (P < 0.001), and free T by 0.73 pmol/liter (P = 0.038) and increased SHBG by 5.5 nmol/liter (P = 0.001) and IGF-binding protein-3 by 0.57 ng/ml (P = 0.007). Our results demonstrate that RLX does not significantly affect glycemic control and has favorable or neutral effects on selected surrogate markers of cardiovascular risk in postmenopausal women with type 2 diabetes mellitus while decreasing hyperandrogenicity in these patients.

Baseline characteristics of participants in the Raloxifene Use for The Heart (RUTH) trial.

The Raloxifene Use for The Heart (RUTH) trial is a randomized, placebo-controlled, double-blind trial designed to determine whether raloxifene 60 mg/day compared with placebo lowers the risk of coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI) and reduces the risk of invasive breast cancer in women at risk for a major coronary event. Raloxifene is a selective estrogen receptor modulator that improves cardiovascular risk factors, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. Between June 1998 and August 2000, 10,101 women were enrolled at 187 sites in 26 countries. Approximately half of the women had documented coronary heart disease (CHD) (n = 5,031); the remainder had multiple CHD risk factors that increased their risk for a CHD event (n = 5,070). The mean age of participants was 68 years (39% were >70 years old), and did not differ between those with documented CHD and those at increased CHD risk. Most women were Caucasian (84%); 60% had a body mass index >/=27 kg/m(2), 46% had diabetes mellitus, 78% had systemic hypertension, and 14% had low-density lipoprotein cholesterol >160 mg/dl. Compared with women at increased CHD risk, women with documented CHD had higher cardiovascular risk scores, a higher prevalence of abnormal electrocardiograms, greater use of cardiovascular medications, were more likely to have had cardiac rehabilitation, and were more likely to have previously used estrogen or oral contraceptives, but had a slightly lower prevalence of CHD risk factors such as smoking, obesity, diabetes mellitus, and systemic hypertension, and had lower serum levels of total and low-density lipoprotein cholesterol. The RUTH cohort is the largest group of postmenopausal women at increased risk of CHD events ever assembled in a clinical trial, and is the first trial designed to determine the effect of a selective estrogen receptor modulator on the risk of CHD events.

A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C beta inhibition.

Diabetic nephropathy is one of the most common microvascular complications of diabetes mellitus and the leading cause of end-stage renal disease in developed countries. Current treatment includes glycemic control, blood pressure control (with special emphasis on agents targeting the renin-angiotensin system), a low-protein (0.6 to 0.8 g/kg) diet, and the use of hypolipidemic agents. Although these therapeutic options may slow progression, the burden of disease remains large, and additional therapeutic agents are urgently needed. Ruboxistaurin (LY333531) mesylate is a bisindolylmaleimide that shows a high degree of specificity within the protein kinase C (PKC) gene family for inhibiting PKC beta isoforms. In animal models of diabetes, including the streptozotocin (STZ) rat, Lepr(db)/Lepr(db) mouse, and STZ-Ren 2 rat models, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, and reduced glomerular transforming growth factor-beta1 and extracellular matrix protein production. As a result, improvements were noted in mesangial expansion, glomerulosclerosis, tubulointerstitial fibrosis, and renal function. Other studies using less specific probes of PKC activity also have shown an important role for PKC in the development of diabetic nephropathy and a close relationship to pathways believed to be important in its pathogenesis. Inhibition of PKC beta, a common signaling molecule in diabetes-related renal and vascular injury, holds promise as a novel strategy to improve microvascular and macrovascular outcomes in diabetes. Such therapies are needed to reduce the occurrence of devastating diabetic complications.

Post hoc analysis of data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial on the effects of three years of raloxifene treatment on glycemic control and cardiovascular disease risk factors in women with and without type 2 diabetes.

BACKGROUND: The long-term effects of the selective estrogen-receptor modulator raloxifene hydrochloride on glycemic control and markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes mellitus are unknown. OBJECTIVE: The aim of this analysis was to compare the effects of 3-year treatment with raloxifene 60 mg/d versus placebo on glycemic control and markers of cardiovascular disease risk in osteoporotic postmenopausal women with and without type 2 diabetes. METHODS: In this analysis, we included women from the Multiple Outcomes of Raloxifene Evaluation trial (a multicenter, double-masked trial) who were randomized to receive raloxifene 60 mg/d (n = 2557) or placebo (n = 2576). Baseline and 36-month fasting plasma glucose (FPG) and total cholesterol (TC) were measured for all participants. Glycated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), apolipoprotein (apo) A-I, apo B, and fibrinogen were assessed in approximately 1800 participants from selected larger sites. RESULTS: At baseline, 202 of all 5133 women (3.9%) had type 2 diabetes. Of the approximately 1800 women who were assessed for HbA1c, LDL-C, TGs, apo A-I, apo B, and fibrinogen, 70 (3.9%) had type 2 diabetes at baseline. Compared with placebo, raloxifene did not significantly affect HbA1c, FPG, HDL-C, or TGs in women with or without diabetes. Raloxifene produced statistically significant reductions in TC, LDL-C, and fibrinogen both in women with diabetes (all P < or = 0.004) and without diabetes (all P < 0.001). Raloxifene significantly increased apo A-I (P < 0.001) and reduced apo B (P < 0.001) in women without diabetes. In the raloxifene-treated group, body weight increased by a mean 0.31 kg (P < 0.001) in women without diabetes. CONCLUSIONS: In osteoporotic postmenopausal women with or without type 2 diabetes, raloxifene 60 mg/d did not affect glycemic control and had favorable effects on TC, LDL-C, and fibrinogen levels.

Exenatide twice daily: analysis of effectiveness and safety data stratified by age, sex, race, duration of diabetes, and body mass index.

BACKGROUND: Exenatide, a glucagon-like peptide-1 receptor agonist, is used twice daily (BID) as monotherapy or adjunctive therapy for the improvement of glycemic control in patients with type 2 diabetes mellitus. The purpose of this pooled analysis was to evaluate the safety and efficacy of exenatide BID in patients stratified by various demographic characteristics. METHODS: This post hoc analysis included data from 16 randomized controlled trials in which patients with type 2 diabetes mellitus were treated with 10-µg exenatide BID. Each patient was classified into subgroups on the basis of his or her baseline values for age (< 65 or ≥ 65 years), sex (male or female), race (white, black, Asian, or Hispanic), duration of diabetes (< 10 years or ≥ 10 years), and body mass index (BMI; ≥ 20 to < 25, ≥ 25 to < 30, ≥ 30 to < 35, or ≥ 35 kg/m(2)). RESULTS: A total of 2067 patients were included. All groups experienced significant improvements in glycated hemoglobin, fasting plasma glucose levels (other than black patients, who had a relatively low baseline fasting plasma glucose level), and body weight from baseline to endpoint. Most groups had significant improvements in systolic blood pressure. All of the age, sex, and duration of diabetes groups experienced significant improvements in lipid levels (other than high-density lipoprotein cholesterol). Whites and Asians generally experienced significant improvements in lipid levels, whereas blacks and Hispanics did not. Significant improvements in lipid levels were generally seen across BMI groups. The most common adverse events overall were nausea (38.6%), hypoglycemia (28.4%), and vomiting (14.0%). Hypoglycemia was more common overall in patients who were taking a concomitant sulfonylurea than it was in patients who were not. CONCLUSION: In this pooled analysis, exenatide BID improved glycemic control and body weight, and had generally beneficial effects on blood pressure and lipid levels in patients regardless of baseline age, sex, race, duration of diabetes, or BMI. Gastrointestinal events were the most common adverse events. TRIAL REGISTRATION: www.ClinicalTrials.gov [NCT00039026, NCT00039013, NCT00082381, NCT00035984, NCT00082407, NCT00381342, NCT00360334, NCT00375492, NCT00603239, NCT00765817, NCT00577824, NCT00434954].

Randomized, open-label, parallel-group evaluations of basal-bolus therapy versus insulin lispro premixed therapy in patients with type 2 diabetes mellitus failing to achieve control with starter insulin treatment and continuing oral antihyperglycemic drugs: a noninferiority intensification substudy of the DURABLE trial.

BACKGROUND: Insulin glargine and lispro mix 75/25 (75% insulin lispro protamine suspension and 25% insulin lispro injection [LM75/25]) represent 2 common starter insulin regimen classes: basal and premixed. After initiation of starter insulin therapy, if patients with type 2 diabetes mellitus (DM) are unable to achieve a glycosylated hemoglobin (HbA1c) level <7.0%, insulin intensification may be indicated. The DURABLE (Assessing Durability of Basal Versus Lispro Mix 75/25 Insulin Efficacy) trial was designed to compare initiating insulin therapy with analogue basal insulin versus premixed analogue insulin in patients unable to achieve good glycemic control while taking multiple oral antihyperglycemic drugs (OADs). OBJECTIVE: To provide objective information about insulin intensification, the DURABLE trial also included a substudy evaluating a systematic approach to advancing insulin therapy in those patients who did not achieve glycemic control with their initial insulin regimen. This substudy, the results of which are reported here, tested the hypothesis that advancing insulin therapy with premixed insulin is noninferior to basal-bolus therapy (BBT) in patients with type 2 DM unable to achieve an HbA1c level < or = 7.0% after 6 months of starter insulin therapy. METHODS: In the main DURABLE study, 2091 patients (age range, 30-80 years) with type 2 DM and HbA1c values >7.0% receiving > or = 2 OADs were randomized to receive insulin glargine (n = 1046) or LM75/25 (n = 1045), both in combination with prestudy OADs. After 6 months, patients with HbA1c levels >7.0% could enter this intensification substudy; OADs except sulfonylureas were continued. Patients originally receiving insulin glargine were enrolled in intensification arm A and were randomized to receive BBT (insulin glargine once daily plus mealtime insulin lispro TID) or LM75/25 BID. Patients originally receiving LM75/25 were enrolled in intensification arm B and randomized to receive BBT or mealtime 50% insulin lispro protamine suspension and 50% insulin lispro injection (LM50/50) TID. Insulin doses were adjusted based on preprandial plasma glucose levels. The primary end point was noninferiority of premixed therapy versus BBT with respect to end-point HbA1c. Secondary end points included change in HbA1c and weight, percentage of patients reaching HbA1c target levels, total daily insulin dose, and rates of hypoglycemia. The safety profile was also assessed. RESULTS: Of the 475 patients in the insulin glargine + OAD arm of the main study who had HbA1c levels >7.0% at 6 months, 399 (84%) entered intensification arm A. The mean age was 57 years, 53% of the patients were male, and mean (SD) HbA1c was 8.0% (1.0%) at baseline. Of those patients, 199 were randomly assigned to receive BBT and 200 were assigned to receive LM75/25. Of the 411 patients in the LM75/25 + OAD arm of the main study who had an HbA1c level >7.0% at 6 months, 345 (84%) entered intensification arm B. The mean age was 55 years, 51% of the patients were male, and mean (SD) HbA1c was 8.0% (0.9%) at baseline. Of those patients, 171 were randomly assigned to receive BBT and 174 were assigned to receive LM50/50. At end point, noninferiority of LM75/25 or LM50/50 to BBT was supported, with a 95% CI of -0.10 to 0.37 and -0.25 to 0.25, respectively. At 6 months, HbA1c did not differ significantly from baseline in any group. Regardless of treatment group, <20% of patients achieved an HbA1c level <7.0%. There were no significant differences between groups in total daily insulin dose, weight gain, incidence or rate of hypoglycemia, or incidence of serious adverse events. CONCLUSIONS: No group had significant improvement from baseline in HbA1c. Our study results suggest that premixed therapy, dosed 2 times per day (LM75/25) or 3 times per day (LM50/50), was noninferior to BBT (4 injections/d) in this population of adult patients with type 2 DM previously uncontrolled with OADs plus basal insulin or twice-daily premixed insulin. Clinical-Trials.gov identifier: NCT00279201.

Protein kinase C beta inhibition: the promise for treatment of diabetic nephropathy.

PURPOSE OF REVIEW: The prevalence of diabetes mellitus is increasing rapidly worldwide. The number of patients with diabetic nephropathy is also expected to increase considerably in the future despite currently available treatments that may prevent or slow kidney disease progression. Additional therapeutic agents are therefore urgently needed. RECENT FINDINGS: Ruboxistaurin mesylate is a bisindolylmaleimide that specifically inhibits the beta-isoform of protein kinase C. In animal models of diabetic nephropathy, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, preserved renal function and reduced mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis. In humans with type 2 diabetes and nephropathy already treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, treatment with ruboxistaurin for 1 year reduced albuminuria and urinary transforming growth factor-beta, and maintained estimated glomerular filtration rate. Ruboxistaurin has so far been shown to be well tolerated at the doses tested. SUMMARY: Inhibition of protein kinase C beta may represent a novel strategy to improve kidney outcomes in patients with diabetes mellitus. Large-scale, prospective trials are needed to confirm the safety and potential benefits of ruboxistaurin in patients with diabetic nephropathy.

Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease.

BACKGROUND: A pilot study showed that ruboxistaurin (RBX), a protein kinase C beta inhibitor, significantly decreased albuminuria and stabilized kidney function over 1 yr in patients who had diabetic nephropathy and persistent macroalbuminuria despite receiving the current standard of care, including renin-angiotensin system inhibition. In contrast, in a trial of patients with diabetic retinopathy, investigators reported the adverse event "diabetic nephropathy" more frequently in patients who received RBX. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: The purpose of this study was to evaluate long-term effects of RBX on kidney outcomes among patients with diabetic eye disease in three diabetic retinopathy trials (n = 1157). Baseline-to-study end changes in estimated GFR (eGFR) were calculated. Kidney outcomes included doubling of serum creatinine, development of advanced chronic kidney disease (stages 4 to 5), and death. RESULTS: Baseline eGFR was 81.6 +/- 26.0 ml/min per 1.73 m(2). In the combined placebo and RBX treatment groups, eGFR decreased by 11.0 +/- 19.6 ml/min per 1.73 m(2) during median follow-up of 33 to 39 mo. At least one kidney outcome occurred in 11.3% of patients. Frequency of doubling of serum creatinine was 6.0%, progression to advanced chronic kidney disease was 4.1%, and death was 4.1%. Kidney outcome rates did not differ by treatment assignment. CONCLUSIONS: Long-term kidney outcomes in patients with diabetic eye disease were similar in placebo and RBX groups. In conclusion, large-scale, prospective trials in patients with diabetic nephropathy are needed to confirm safety and potential benefits of RBX on clinical outcomes.

How the diabetic eye loses vision.

The objective is to review the most common causes of vision loss in patients with diabetes with the goal of better managing patients with diabetic eye disease. In this review, the causes of vision loss, and the clinical evaluation and management of diabetic retinopathy (DR) and diabetic macular edema (DME) are outlined. Patients with diabetes mellitus have an increased risk of vision loss and blindness. In patients with diabetes, the primary mechanism responsible for vision loss is centrally involved DME or clinically significant macular edema (CSME), defined as vascular leakage resulting in fluid accumulation that affects the center of the macula. DR and DME are thought to result from the effects of excessive blood glucose on the vessels that produces microvascular damage. The progression of DR can be slowed by intensive glycemic and blood pressure control. Severe visual loss from proliferative DR and moderate visual loss from DME can be reduced by laser photocoagulation. DR and DME are diagnosed on dilated retinal examination and confirmed with diagnostic testing. Many experts and associations recommend that patients with diabetes have an yearly, thorough, dilated eye exam. This manuscript describes the case history of a patient with diabetes and vision loss.

Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial.

CONTEXT: Raloxifene, a selective estrogen receptor modulator, improves cardiovascular risk factors, but its effect on cardiovascular events is unknown. OBJECTIVE: To determine the effect of raloxifene on cardiovascular events in osteoporotic postmenopausal women. DESIGN: Secondary analysis of data from the Multiple Outcomes of Raloxifene Evaluation trial, a randomized, double-blind, placebo-controlled trial conducted between November 1994 and September 1999. SETTING: Outpatient and community settings at 180 sites in 25 countries. PARTICIPANTS: A total of 7705 osteoporotic postmenopausal women (mean age, 67 years). INTERVENTION: Patients were randomly assigned to receive raloxifene, 60 mg/d (n = 2557), or 120 mg/d (n = 2572), or placebo (n = 2576) for 4 years. MAIN OUTCOME MEASURES: Cardiovascular events, including coronary events (myocardial infarction, unstable angina, or coronary ischemia) and cerebrovascular events (stroke or transient ischemic attack), collected as safety end points and subsequently adjudicated by a cardiologist blinded to therapy. Cardiovascular risk at study entry was determined by the presence of multiple cardiovascular risk factors or prior coronary events or revascularization procedure. RESULTS: In the overall cohort, there were no significant differences between treatment groups in the number of combined coronary and cerebrovascular events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/d of raloxifene, and 94 (3.7%) with 120 mg/d of raloxifene. Relative risks (RRs) were 0.86 (95% confidence interval [CI], 0.64-1.15) and 0.98 (95% CI, 0.74-1.30) for 60 mg/d and 120 mg/d of raloxifene, respectively. Similar results were obtained when coronary and cerebrovascular events were analyzed separately. Among the subset of 1035 women with increased cardiovascular risk at baseline, those assigned to raloxifene had a significantly lower risk of cardiovascular events compared with placebo (RR, 0.60; 95% CI, 0.38-0.95 for both raloxifene groups). The number of cardiovascular events during the first year was not significantly different across groups in the overall cohort (P =.94), or among women at increased cardiovascular risk (P =.86) or with evidence of established coronary heart disease (P =.60). CONCLUSIONS: Raloxifene therapy for 4 years did not significantly affect the risk of cardiovascular events in the overall cohort but did significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk. There was no evidence that raloxifene caused an early increase in risk of cardiovascular events. Before raloxifene is used for prevention of cardiovascular events, these findings require confirmation in trials with evaluation of cardiovascular outcomes as the primary objective.