Peter Linz

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

BACKGROUND We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction). CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

Cognitive Function and Brain Structure in Persons With Type 2 Diabetes Mellitus After Intensive Lowering of Blood Pressure and Lipid Levels: A Randomized Clinical Trial

IMPORTANCE Persons with type 2 diabetes mellitus (T2DM) are at increased risk for decline in cognitive function, reduced brain volume, and increased white matter lesions in the brain. Poor control of blood pressure (BP) and lipid levels are risk factors for T2DM-related cognitive decline, but the effect of intensive treatment on brain function and structure is unknown. OBJECTIVE To examine whether intensive therapy for hypertension and combination therapy with a statin plus a fibrate reduces the risk of decline in cognitive function and total brain volume (TBV) in patients with T2DM. DESIGN, SETTING, AND PARTICIPANTS A North American multicenter clinical trial including 2977 participants without baseline clinical evidence of cognitive impairment or dementia and with hemoglobin A1c (HbA1c) levels less than 7.5% randomized to a systolic BP goal of less than 120 vs less than 140 mm Hg (n = 1439) or to a fibrate vs placebo in patients with low-density lipoprotein cholesterol levels less than 100 mg/dL (n = 1538). Participants were recruited from August 1, 2003, through October 31, 2005, with the final follow-up visit by June 30, 2009. MAIN OUTCOME MEASURES Cognition was assessed at baseline and 20 and 40 months. A subset of 503 participants underwent baseline and 40-month brain magnetic resonance imaging to assess for change in TBV and other structural measures of brain health. RESULTS Baseline mean HbA1c level was 8.3%; mean age, 62 years; and mean duration of T2DM, 10 years. At 40 months, no differences in cognitive function were found in the intensive BP-lowering trial or in the fibrate trial. At 40 months, TBV had declined more in the intensive vs standard BP-lowering group (difference, -4.4 [95% CI, -7.8 to -1.1] cm(3); P = .01). Fibrate therapy had no effect on TBV compared with placebo. CONCLUSIONS AND RELEVANCE In participants with long-standing T2DM and at high risk for cardiovascular events, intensive BP control and fibrate therapy in the presence of controlled low-density lipoprotein cholesterol levels did not produce a measurable effect on cognitive decline at 40 months of follow-up. Intensive BP control was associated with greater decline in TBV at 40 months relative to standard therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000620.

Prevalence of Kawasaki Disease in Young Adults With Suspected Myocardial Ischemia

Background— Up to 25% of patients with untreated Kawasaki disease (KD) and 5% of those treated with intravenous immunoglobulin will develop coronary artery aneurysms. Persistent aneurysms may remain silent until later in life when myocardial ischemia can occur. We sought to determine the prevalence of coronary artery aneurysms suggesting a history of KD among young adults undergoing coronary angiography for evaluation of possible myocardial ischemia. Methods and Results— We reviewed the medical histories and coronary angiograms of all adults <40 years of age who underwent coronary angiography for evaluation of suspected myocardial ischemia at 4 San Diego hospitals from 2005 to 2009 (n=261). History of KD-compatible illness and cardiac risk factors were obtained by medical record review. Angiograms were independently reviewed for the presence, size, and location of aneurysms and coronary artery disease by 2 cardiologists blinded to the history. Patients were evaluated for number of risk factors, angiographic appearance of their coronary arteries, and known history of KD. Of the 261 young adults who underwent angiography, 16 had coronary aneurysms. After all clinical criteria were assessed, 5.0% had aneurysms definitely (n=4) or presumed (n=9) secondary to KD as the cause of their coronary disease. Conclusions— Coronary sequelae of KD are present in 5% of young adults evaluated by angiography for myocardial ischemia. Cardiologists should be aware of this special subset of patients who may benefit from medical and invasive management strategies that differ from the strategies used to treat atherosclerotic coronary artery disease.

Paradoxical Reduction in HDL-C With Fenofibrate and Thiazolidinedione Therapy in Type 2 Diabetes: The ACCORD Lipid Trial

OBJECTIVE To determine the occurrence of extremely low HDL cholesterol (HDL-C) among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial and to examine the relationship of this finding with treatment with fenofibrate and thiazolidinedione (TZD). RESEARCH DESIGN AND METHODS The ACCORD Lipid Trial was a randomized, double-blind, placebo-controlled study conducted in patients with type 2 diabetes at 77 clinical centers across the U.S. and Canada in a 5,518-patient subset of the larger 10,251 ACCORD Glycemia Trial. Patients were enrolled from 11 January 2001 to 29 October 2005 and followed until the end of study visits between 1 March and 30 June 2009. Follow-up in the ACCORD Lipid Trial was 4–8 years (mean 4.7 years). Patients were treated with blinded fenofibrate or placebo on a background of simvastatin therapy. The main outcome measures for these descriptive, post hoc analyses was the occurrence of extremely low HDL-C (defined as <25 mg/dL [0.647 mmol/L]) during the trial. RESULTS Among ACCORD Lipid Trial participants, the occurrence of extremely low HDL-C ever during study follow-up was 106% higher among those randomized to fenofibrate (10.1% fenofibrate vs. 4.9% placebo, P < 0.001). The occurrence of low HDL-C was associated with concurrent treatment with fenofibrate and TZD (7.0% for both vs. 2.2% for neither at 48 months postrandomization). CONCLUSIONS Idiosyncratic and marked reduction in HDL-C can occur in some patients treated with both fenofibrate and TZD. Practitioners should recognize this important potential idiosyncratic reaction and take appropriate corrective action.

OS 12-03 SGLT-2-INHIBITION WITH DAPAGLIFLOZIN REDUCES TISSUE SODIUM CONTENT.

Objective: Sodium tissue content by 23Na magnetic resonance imaging (Na-MRI) has been validated in experimental and human studies. SGLT-2 inhibition blocks the reabsorption of glucose and, in parallel, of sodium in the proximal tubular cells in a 1:1 fashion. We hypothesized that SGLT-2 inhibition in patients with type 2 diabetes leads to decreased tissue sodium content due to its pharmacological action. Design and Method: In a prospective, double blind, placebo controlled, cross-over trial 59 patients (61 ± 7.6 years) with type 2 diabetes were randomized to dapagliflozin 10 mg o.d. and placebo for 6 weeks each. In addition to metabolic parameters and ambulatory blood pressure (BP) we analyzed the sodium content in the skin and muscles of the lower leg by the Na-MRI at baseline, after the first and second treatment phase of 6 weeks. Results: Compared to baseline 6 weeks treatment with the SGLT-2 inhibitor dapagliflozin decreased fasting (132 ± 28 vs. 114 ± 19 mg/dl, p < 0.001), postprandial blood glucose (178 ± 66 mg/dl vs. 153 ± 46 mg/dl, p < 0.001), body weight (87.6 vs. 86.6 kg, p < 0.001) and systolic (129 ± 12 vs. 126 ± 11, p = 0.010) and diastolic (77.4 ± 9 vs. 75.6 ± 8 mmHg, p = 0.024) 24-hour ambulatory BP. Tissue sodium content in the skin was reduced after 6 weeks treatment with dapagliflozin compared to baseline (24.1 ± 6.6 vs.22.7 ± 6.4 mmol/L; p = 0.013). No significant reduction of tissue sodium content was observed in the muscle (M. triceps surae: 20.5 ± 3.5 vs. 20.4 ± 3.7 mmol/L, p = 0.801). No clear significant difference in tissue water content of muscle and skin was observed after 6 weeks of treatment with dapagliflozin, compared to baseline. Conclusions: SGLT-2 inhibition with dapagliflozin resulted in a significant decrease in sodium tissue content of the skin after 6 weeks. This observation point to a decrease of total sodium content in patients with type 2 diabetes known to be salt sensitive and prone to cardiovascular complications, that might be mitigated by SGLT-2 inhibition.

Quantitative assessment of muscle injury by 23Na magnetic resonance imaging

Background23Na magnetic resonance imaging (23Na-MRI) is able to measure Na+ in vivo in humans and allows quantification of tissue sodium distribution. We now tested the utility of 23Na-MRI technique in detecting and assessing sports-related acute muscular injury.Case presentationWe assessed tissue Na+ of both lower legs with a 3T MRI scanner using a customized 23Na knee coil. The affected left calf muscle in an injured volleyball player showed a hyperintense Na+ signal. Follow-up measurements revealed persistently increased muscle Na+ content despite complete clinical recovery.ConclusionsOur findings suggest that 23Na-MRI could have utility in detecting subtle muscular injury and might indicate when complete healing has occurred. Furthermore, 23Na-MRI suggests the presence of substantial injury-related muscle electrolyte shifts that warrant more detailed investigation.

Complex reinnervation pattern after unilateral renal denervation in rats

Renal denervation (DNX) is a treatment for resistant arterial hypertension. Efferent sympathetic nerves regrow, but reinnervation by renal afferent nerves has only recently been shown in the renal pelvis of rats after unilateral DNX. We examined intrarenal perivascular afferent and sympathetic efferent nerves after unilateral surgical DNX. Tyrosine hydroxylase (TH), CGRP, and smooth muscle actin were identified in kidney sections from 12 Sprague-Dawley rats, to distinguish afferents, efferents, and vasculature. DNX kidneys and nondenervated kidneys were examined 1, 4, and 12 wk after DNX. Tissue levels of CGRP and norepinephrine (NE) were measured with ELISA and mass spectrometry, respectively. DNX decreased TH and CGRP labeling by 90% and 95%, respectively (P < 0.05) within 1 wk. After 12 wk TH and CGRP labeling returned to baseline with a shift toward afferent innervation (P < 0.05). Nondenervated kidneys showed a doubling of both labels within 12 wk (P < 0.05). CGRP content decreased by 72% [3.2 ± 0.3 vs. 0.9 ± 0.2 ng/gkidney; P < 0.05] and NA by 78% [1.1 ± 0.1 vs. 0.2 ± 0.1 pmol/mgkidney; P < 0.05] 1 wk after DNX. After 12 wk, CGRP, but not NE, content in DNX kidneys was fully recovered, with no changes in the nondenervated kidneys. The use of phenol in the DNX procedure did not influence this result. We found morphological reinnervation and transmitter recovery of afferents within 12 wk after DNX. Despite morphological evidence of sympathetic regrowth, NE content did not fully recover. These results suggest a long-term net surplus of afferent influence on the DNX kidney may be contributing to the blood pressure lowering effect of DNX.

Constrictive Pericarditis From a Severely Calcified Pericardium

A 42-year-old otherwise healthy woman presented with palpitations and gradual dyspnea on exertion. Her ECG showed normal sinus rhythm, an incomplete left bundle-branch block, and multiple premature atrial contractions. A posterior-anterior and lateral chest x-ray (Figure 1) demonstrated severe, dense calcification of the pericardium. The patient had been having palpitations for the past year and indolent dyspnea …