N-of-1 (single-patient) trials for statin-related myalgia.

BACKGROUND: Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation. OBJECTIVE: To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results. DESIGN: N-of-1 trial with 3 double-blind, crossover comparisons separated by 3-week washout periods. (Clinicaltrials.gov: NCT01259791) SETTING: Tertiary care lipid clinic. PATIENTS: Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels. INTERVENTION: Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo. MEASUREMENTS: Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm). RESULTS: Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months. LIMITATION: Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation. CONCLUSION: In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability. PRIMARY FUNDING SOURCE: Western University, London, Ontario, Canada.

The effectiveness of beta-blockers after myocardial infarction in patients with type 2 diabetes.

OBJECTIVE: Beta-blocker therapy has been proven to reduce mortality and reinfarction after myocardial infarction (MI), but the impact of beta-blockers on cardiac outcomes in patients with type 2 diabetes in routine practice is not clear. The purpose of this study was to determine the effectiveness of beta-blockers after MI in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using the Saskatchewan Health Databases, 12,272 patients with newly treated diabetes were identified between 1991 and 1996; 625 patients were subsequently admitted for MI. Beta-blocker exposure within 30 days of discharge was identified in 298 patients, and all were followed until death, coverage termination, or 31 December 1999. Multivariate proportional hazards models were used to assess differences in all-cause mortality, recurrent MI, and 30-day all-cause rehospitalization (the latter a proxy measure for drug safety). RESULTS: Patients were aged 69 +/- 11 years old, 66% were male, and mean follow-up was 2.7 +/- 2.1 years. Overall, beta-blockers were prescribed for 48% of patients. There were fewer deaths in the beta-blocker group versus control subjects (55 of 298 [18.5%] vs. 126 of 327 [38.5%], respectively, P < 0.001). However, beta-blockers were not associated with improved survival in multivariate analyses (hazard ratio [HR] 0.89 [95% CI 0.63-1.25]). There were no differences in rates of recurrent MI (adjusted HR 1.35 [0.93-1.95]) or rehospitalizations (adjusted odds ratio 1.40 [0.83-2.37]) between the groups. CONCLUSIONS: Beta-blocker therapy post-MI was not associated with reduced mortality or fewer recurrent events in people with type 2 diabetes in routine practice, although these medications were safe in this population.

Coronary artery disease is common in nonuremic, asymptomatic type 1 diabetic islet transplant candidates.

OBJECTIVE: Coronary artery disease (CAD) is the most common cause of death in patients with type 1 diabetes. Asymptomatic CAD is common in uremic diabetic patients, but its prevalence in nonuremic type 1 diabetic patients is unknown. The prevalence of CAD was determined by coronary angiography and the performance of noninvasive cardiac investigation evaluated in type 1 diabetic islet transplant (ITX) candidates with preserved renal function. RESEARCH DESIGN AND METHODS: A total of 60 consecutive type 1 diabetic ITX candidates (average age 46 years [mean 24-64], 23 men, and 47% ever smokers) underwent coronary angiography, electrocardiographic stress testing (EST), and myocardial perfusion imaging (MPI) in a prospective cohort study. CAD was indicated on angiography by the presence of stenoses >50%. Models to predict CAD were examined by logistic regression. RESULTS: Most subjects (53 of 60) had no history or symptoms of CAD; 23 (43%) of these asymptomatic subjects had stenoses >50%. CAD was associated with age, duration of diabetes, hypertension, and smoking. Although specific, EST and MPI were not sensitive as predictors of CAD on angiography (specificity 0.97 and 0.93, sensitivity 0.17 and 0.04, respectively) but helped identify two of three subjects requiring revascularization. EST and MPI did not enhance logistic regression models. A clinical algorithm to identify low-risk subjects who may not require angiography was highly sensitive but was applicable only to a minority (n = 8, sensitivity 1.0, specificity 0.27, negative predictive value 1.0). CONCLUSIONS: Nonuremic type 1 diabetic patients with hypoglycemic unawareness and/or metabolic lability referred for ITX are at high risk for asymptomatic CAD despite negative noninvasive investigations. Aggressive management of cardiovascular risk factors and further investigation into optimal cardiac risk stratification in type 1 diabetes are warranted.

Cross-sectional and prospective association between proinsulin secretion and graft function after clinical islet transplantation.

Proinsulin levels as a marker of beta-cell dysfunction have not been described after clinical islet transplantation. Proinsulin secretion was studied in 23 type 1 diabetic patients after islet allotransplantation and in 20 age-matched nondiabetic controls. Fasting serum insulin, total proinsulin (TP), intact proinsulin, proinsulin fragments (PFs) and their ratios to insulin were determined 1 and 12 months after patients became insulin independent. TP, PF, and proinsulin/insulin ratios were lower in transplant recipients compared with controls, in patients who retained long-term insulin independence. Insulin, C-peptide, and intact proinsulin values were similar in transplant recipients and controls. Hormone levels remained stable over time in the group of patients who retained long-term insulin independence, but the TP and PF levels were higher at 12 months compared with 1 month in the group of patients who resumed insulin therapy. TP and PF levels were reduced in transplant recipients compared with controls but increased over time if insulin independence was lost.