Comparison of testosterone, alendronate, and a combination of both therapies in men with low bone mineral density.

BACKGROUND: Both bisphosphonates and testosterone are known to improve bone mineral density (BMD) in men with low bone mass, but whether combination therapy is superior to these agents used alone is not clear. We compared the changes in lumbar spine BMD when men with low bone mass were treated with each agent alone or as combination therapy. METHODS: In a retrospective study, we analyzed serum and BMD data from 149 men who had been evaluated in the Endocrinology Clinic at the Dallas Veterans Affairs Medical Center, Dallas, Texas. The subjects were divided into three cohorts: 59 men receiving testosterone therapy alone, 68 men receiving alendronate therapy alone, and 22 receiving combination therapy. RESULTS: Compared with the baseline values, the lumbar spine and BMD increased significantly in each of the testosterone, alendronate, and combination therapy cohorts (median annualized rate of change: 2.1% [p < .001], 2.6% [p < .001], and 2.5% [p = .04], respectively). The combination therapy group did not demonstrate any additional increase in BMD at the lumbar spine or total hip compared with either agent alone. The results did not change after adjusting for differences in baseline weight, age, BMD, or baseline testosterone level. CONCLUSION: The results suggest that the combination of testosterone and alendronate does not appear to be superior to single-drug therapy in our patient population.

Ezetimibe added to ongoing statin therapy improves LDL-C goal attainment and lipid profile in patients with diabetes or metabolic syndrome.

This analysis of the Ezetimibe Add-on to Statin for Effectiveness (EASE) trial examined the effectiveness and safety of ezetimibe 10 mg added to ongoing statin therapy in patients with diabetes, metabolic syndrome without diabetes, or neither disorder who had low-density lipoprotein cholesterol (LDL-C) levels exceeding National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) goals. After six weeks of treatment, ezetimibe added to statin reduced LDL-C in patients with diabetes by 28%, metabolic syndrome by 24%, or neither by 26%, compared with a 3% reduction for placebo for each group. In each group, more patients receiving ezetimibe plus statin reached LDL-C goal (67-74%) compared with those receiving placebo plus statin (19-22%). Other parameters demonstrating greater improvement with ezetimibe included triglycerides, apolipoprotein (Apo)B/Apo A-I ratio, high-density lipoprotein cholesterol (HDL-C), and C-reactive protein. Ezetimibe plus statin was well tolerated in each group. Ezetimibe added to ongoing statin therapy offers a new treatment option that is consistently effective in improvement of lipid profiles and attainment of LDL-C goals in patients with without diabetes or metabolic syndrome.

Dietary fats, fatty acids, and their effects on lipoproteins.

All saturated fatty acids, with the notable exception of stearic acid (C18:0), raise low-density lipoprotein (LDL) cholesterol levels. A few less ubiquitous fatty acids also have LDL cholesterol effects. Trans-monounsaturated fatty acids, at equivalent doses of saturated fatty acids, raise LDL cholesterol. Polyunsaturated fatty acids, at three times the dose of saturated fatty acids, lower LDL cholesterol. Higher intakes of most fatty acids raise high-density lipoprotein (HDL) cholesterol, with the notable exception of trans-monounsaturated fatty acids, which lower HDL cholesterol to the same extent as carbohydrate when either is substituted for other dietary fatty acids. Conjugated linoleic acids containing both cis and trans bonds and cis-monounsaturated fatty acids neither raise nor lower cholesterol concentrations of lipoproteins. The omega-3 fatty acids from fish lower triglyceride levels. Although dietary composition remains an important, modifiable predictor of dyslipidemia, overconsumption of any form of dietary energy may replace overconsumption of saturated fat as the primary factor that increases lipid and lipoprotein levels.

Effectiveness of ezetimibe added to ongoing statin therapy in modifying lipid profiles and low-density lipoprotein cholesterol goal attainment in patients of different races and ethnicities: a substudy of the Ezetimibe add-on to statin for effectiveness trial.

OBJECTIVE: To examine whether the improvements in lipid profiles and low-density lipoprotein cholesterol (LDL-C) goal attainment found in the Ezetimibe Add-On to Statin for Effectiveness trial occurred equally in the black, Hispanic, and white patient populations enrolled in the study. PATIENTS AND METHODS: In this double-blind, placebo-controlled study, patients were recruited from 299 community-based practices across the United States (January to August 2003). Patients with, hypercholesterolemia and LDL-C levels exceeding National Cholesterol Education Program Adult Treatment Panel III goals were randomized (2:1) to receive either ezetimibe (10 mg/d) or placebo in addition to their ongoing statin therapy for 6 weeks. RESULTS: A total of 5802 patients were screened at baseline for the Ezetimibe Add-On to Statin for Effectiveness study. Of these, 2772 were excluded, and the remaining 3030 eligible patients were randomized. Ezetimibe, compared with placebo, added to statin therapy significantly reduced LDL-C levels from statin-treated baseline by 23.0% (white patients), 23.0% (black patients), and 21.0% (Hispanic patients). This effect was consistent across race and ethnicity groups (P > .50 for treatment-by-race interactions). Ezetimibe added to statin therapy also statistically significantly (P < .001) increased the percentage of patients attaining their LDL-C goal for their National Cholesterol Education Program Adult Treatment Panel III risk category in black (63.0%), Hispanic (64.8%), and white (72.3%) patients compared with placebo plus statin (32.9% black patients, 19.0% Hispanic patients, and 19.7% white patients). Ezetimibe treatment improved other lipid parameters across groups, including triglyceride, high-density lipoprotein cholesterol, non-high-density ilpoprotein cholesterol, and total cholesterol levels. Finally, the addition of ezetimibe reduced high-sensitivity C-reactive protein levels overall, and no significant interaction of treatment by race occurred (P = .83), Indicating a consistent effect across races. Ezetimibe was generally well tolerated, and no detectable differences occurred in the adverse event profile by race or ethnicity. CONCLUSION: Ezetimibe added to statin therapy is effective and well tolerated for improving the lipid profile and LDL-C goal attainment of patients regardless of race or ethnicity.

The impact of physician attitudes and beliefs on treatment decisions: lipid therapy in high-risk patients.

BACKGROUND: Despite clinical guidelines, many patients with hypercholesterolemia do not achieve treatment goals in clinical practice. OBJECTIVES: This study examined physician attitudes and beliefs about hyperlipidemia and whether they are associated with lipid treatment decisions. METHODS: This was a cross-sectional study of 107 physicians who completed a validated survey of attitudes and beliefs about hyperlipidemia and provided treatment histories for 1187 statin-treated patients with coronary heart disease (CHD) or who were CHD risk-equivalent. Logistic regressions (using generalized estimating equation) estimated the impact of patient characteristics and physician attitudes and beliefs on whether a patient received increases in the statin dose. RESULTS: Approximately 70% of the 843 patients who were not at low-density lipoprotein cholesterol goal (<100 mg/dL) with initial statin therapy received a dose increase, although only one-half attained goal. Controlling for patient characteristics, patients whose physicians believed "close enough to goal is good enough" had 47% lower odds of having a dose increase (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.34-0.82), whereas patients whose physicians believed "statins are effective" had almost twice the odds of having a dose increase (OR, 1.78; 95% CI, 1.05-3.00). CONCLUSIONS: Although the understanding of basic and clinical science remains fundamental, clinical guideline authors may want to consider the importance of physician attitudes and beliefs in determining translation of their guidelines into clinical practice.

Diet, lifestyle, and nonstatin trials: review of time to benefit.

How rapidly benefits accrue from nonstatin, lipid-lowering therapies is a 21st-century question posed to data collected in the 20th century. The 3 early dietary trials conducted in institutional settings where diet was strictly controlled demonstrate that, compared with a control diet, cholesterol-lowering diets reduce coronary event rates over several years. These data do not reveal whether a more homogeneous high-risk population would demonstrate an earlier time to benefit. Dietary counseling trials of men with coronary disease conducted in the 1950s and 1960s failed to demonstrate a consistent benefit from dietary therapy, in part because of confounding factors from methodologic flaws in trial design. By the 1980s and 1990s, improvements in trial design, such as larger numbers of subjects, control of confounding risk factors, and limiting trial end points to those directly attributable to atherosclerotic events, were in place. Subsequently, 5 randomized clinical trials showed a consistent benefit of dietary therapy, with significant reductions by 1 to 2 years in fatal events, nonfatal events, and total mortality; 2 of these studies, each including omega-3 fatty acids as part of the dietary intervention, reported a rapid and significant time to benefit (within 3 to 6 months). Additional lifestyle benefits of cardiac rehabilitation (a surrogate for physical activity) and smoking cessation clearly show long-term benefit at 1 and 5 years, respectively. Nonstatin drug and surgical therapies either have shown no significant benefit (estrogen, dextrothyroxine) or benefit after 1 to 5 years of therapy (intestinal bypass surgery, cholestyramine, clofibrate, niacin, and a combination of niacin and clofibrate). In conclusion, rapid time to benefit has been observed in older lifestyle and nonstatin trials that have included omega-3 fatty acids as a component of dietary therapy. Lifestyle changes in diet, physical activity, weight loss, and smoking cessation remain important and effective therapies with which significant long-term benefits can be expected.

A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial.

OBJECTIVE: To determine the extent of reduction in low-density lipoprotein cholesterol (LDL-C) level and improvement in National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goal attainment when ezetimibe was added to ongoing statin therapy in a diverse population of community-based patients. PATIENTS AND METHODS: In this multicenter, double-blind, placebo-controlled trial (from January 2003 to August 2003), hypercholesterolemic patients (from 299 US primary care and specialty practices) with LDL-C levels exceeding NCEP ATP III goals were randomized (2:1) to receive ezetimibe (10 mg/d) or placebo in addition to their ongoing statin therapy for 6 weeks. RESULTS: In a study of 3030 randomized patients, ezetimibe added to statin therapy significantly reduced the LDL-C level by an additional 25.8% in the total population, compared with an additional 2.7% reduction with placebo plus statin (treatment difference, -23.1%; P<.001); the treatment difference ranged from -19.9% to -24.0% (P<.001) in each NCEP ATP III risk category subgroup. Significantly (P<.001) more patients (71.0%) treated with ezetimibe added to statin reached their NCEP ATP III target LDL-C level compared with those treated with placebo plus statin (20.6%). The addition of ezetimibe also resulted in improvement in other lipid parameters and high-sensitivity C-reactive protein levels. These benefits were consistent across sex, race, age, statin brand, and dose subgroups. Ezetimibe plus statin therapy was well tolerated, with a safety profile similar to placebo plus statin. CONCLUSION: Across multiple subgroups, ezetimibe added to statin therapy consistently produced significant additional improvements in LDL-C levels and goal attainment, as well as in other lipoproteins, compared with addition of placebo. The addition of ezetimibe to statin therapy should be considered for patients not achieving their NCEP ATP III LDL-C goals while receiving statin therapy alone.

Effectiveness of the addition of ezetimibe to ongoing statin therapy in modifying lipid profiles and attaining low-density lipoprotein cholesterol goals in older and elderly patients: subanalyses of data from a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The Ezetimibe Add-on to Statin for Effectiveness (EASE) trial examined the effectiveness and safety profile of ezetimibe (EZE) added to ongoing statin therapy in 3030 patients with low-density lipoprotein cholesterol (LDL-C) levels exceeding National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP 111) goals. OBJECTIVE: Because people aged > 65 years are at increased risk for development of coronary heart disease (CHD), these subgroup analyses of data from the EASE trial were conducted to determine the extent of change in LDL-C levels and attainment of NCEP ATP III LDL-C goals with the addition of EZE to ongoing statin therapy in patients aged 65 to 74 years (the older group) and > or = 75 years (the elderly group). METHODS: In the multicenter (299 sites), community-based, double-blind, placebo-controlled EASE trial, patients were randomly assigned in a 2:1 ratio to receive EZE 10 mg/d or placebo in addition to their ongoing statin therapy for 6 weeks. The primary efficacy end point was the percent reduction in LDL-C levels, and the principal secondary end point was the proportion of patients achieving NCEP ATP III target LDL-C levels. The effects of the addition of EZE on additional lipid and lipoprotein measures and high-sensitivity C-reactive protein were also examined, as was tolerability. Study analyses were performed in the modified intent-to-treat population. RESULTS: This subgroup analysis included data from 841 patients in the older age group (579 EZE + statin, 262 placebo + statin), which constituted 27.8% of the overall EASE population, and 466 in the elderly group (307 EZE + statin, 159 placebo + statin), which constituted 15.4% of the overall EASE population. The former group included 436 (51.8%) men and 405 (48.2%) women, with a mean (SD) age of 69.2 (3.0) years; the latter group included 227 (48.7%) men and 239 (51.3%) women, with a mean age of 78.5 (3.2) years. The characteristics of the 2 groups were comparable at baseline. In the older group, 717 (85.3%) had CHD or a CHD risk equivalent, as did 421 (90.3%) of those in the elderly group. Thirty-two patients in the older group and 17 in the elderly group discontinued the study. The reasons for discontinuation included clinical adverse events (n = 23), withdrawal of consent (n = 15), loss to follow-up (n = 4), protocol deviation (n = 2), and other reasons (n = 5). EZE + statin significantly reduced LDL-C compared with placebo + statin (older group: mean [SE] treatment difference, -25.1% [1.4]; P < 0.001; elderly group: treatment difference, -22.0% [1.8]; P < 0.001). The LDL-Glowering effects of treatment were consistent in the 2 groups. EZE + statin therapy significantly improved other lipid parameters (triglycerides, non high density lipoprotein cholesterol, and total cholesterol, P < 0.001 in both age groups; high-density lipoprotein cholesterol, P < 0.03 in the older group only) and high-sensitivity C-reactive protein levels compared with EZE + placebo (P < 0.03). The attainment of LDL-C goals also was significantly increased with EZE + statin compared with placebo + statin (older group: 72.3% vs 18.9%, respectively; odds ratio [OR] = 14.59; 95% CI, 9.55 to 22.28; P < 0.001; elderly group: 73.3% vs 18.9%; OR = 13.44; 95% CI, 7.72 to 23.41; P < 0.001). EZE + statin therapy was well tolerated by patients in both age groups, with a safety profile comparable to that of placebo + statin. CONCLUSIONS: In these older and elderly patients, many of them at high risk for CHD, EZE added to ongoing statin therapy was well tolerated and was an effective treatment option for improving lipid profiles and attainment of LDL-C goals. Adding EZE improved rates of attainment of NCEP ATP III LDL-C goals without increases in the dose or potency of statin therapy. Further studies are necessary to determine whether these results can be generalized to other older and elderly populations.

Utility of currently available modes of therapy in reaching lipid goals.

The National Cholesterol Education Program Adult Treatment Panel III lipid management guidelines emphasize the importance of matching the intensity of lipid modification therapy to each patient's risk of coronary heart disease. For many patients who are at low risk, nonpharmacologic interventions such as diet, exercise, and smoking cessation can be effective lipid-lowering strategies. However, many patients require the addition of drug therapy to achieve lipid targets. Currently available lipid-modifying drugs include bile acid sequestrants, fibrates, nicotinic acid, cholesterol absorption inhibitors, and statins. In addition, nonprescription agents such as plant stanols and sterols are available to modify plasma lipid levels. These agents can be used individually or coadministered to achieve lipid goals.

Coadministration of multidrug therapy to achieve lipid goals.

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the drug of first choice for lowering low-density lipoprotein cholesterol (LDL-C) levels and reducing risk of coronary heart disease (CHD). Current therapeutic use of statins, however, has resulted in only a small percentage of patients reaching their LDL-C treatment goal. Despite the clinical trial data supporting early aggressive use of statins, prescribing physicians are more likely to use lower doses of statins, leaving many patients at high risk of CHD short of goals. The barrier to achieving cholesterol treatment goals does not appear to be the decision to initiate statin therapy, but the failure of prescribers to titrate statin therapy to a dose sufficient to achieve goals. An alternative to statin monotherapy is coadministration of a statin and a second agent that has a different mechanism of action. This approach can increase the likelihood of achieving target lipid levels and may be more acceptable to physicians. The coadministration of ezetimibe and simvastatin reduces cholesterol derived from both endogenous and exogenous sources. Simvastatin reduces the hepatic production of cholesterol, and ezetimibe decreases the intestinal absorption of dietary and biliary free cholesterol. The coadministration of low doses of these agents has been proved to be as effective as high-dose statin therapy in reducing LDL-C levels and assisting patients achieve their treatment goals.

Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.

CONTEXT: Patients with serum thyroid-stimulating hormone (TSH) levels outside the reference range and levels of free thyroxine (FT4) and triiodothyronine (T3) within the reference range are common in clinical practice. The necessity for further evaluation, possible treatment, and the urgency of treatment have not been clearly established. OBJECTIVES: To define subclinical thyroid disease, review its epidemiology, recommend an appropriate evaluation, explore the risks and benefits of treatment and consequences of nontreatment, and determine whether population-based screening is warranted. DATA SOURCES: MEDLINE, EMBASE, Biosis, the Agency for Healthcare Research and Quality, National Guideline Clearing House, the Cochrane Database of Systematic Reviews and Controlled Trials Register, and several National Health Services (UK) databases were searched for articles on subclinical thyroid disease published between 1995 and 2002. Articles published before 1995 were recommended by expert consultants. STUDY SELECTION AND DATA EXTRACTION: A total of 195 English-language or translated papers were reviewed. Editorials, individual case studies, studies enrolling fewer than 10 patients, and nonsystematic reviews were excluded. Information related to authorship, year of publication, number of subjects, study design, and results were extracted and formed the basis for an evidence report, consisting of tables and summaries of each subject area. DATA SYNTHESIS: The strength of the evidence that untreated subclinical thyroid disease is associated with clinical symptoms and adverse clinical outcomes was assessed and recommendations for clinical practice developed. Data relating the progression of subclinical to overt hypothyroidism were rated as good, but data relating treatment to prevention of progression were inadequate to determine a treatment benefit. Data relating a serum TSH level higher than 10 mIU/L to elevations in serum cholesterol were rated as fair but data relating to benefits of treatment were rated as insufficient. All other associations of symptoms and benefit of treatment were rated as insufficient or absent. Data relating a serum TSH concentration lower than 0.1 mIU/L to the presence of atrial fibrillation and progression to overt hyperthyroidism were rated as good, but no data supported treatment to prevent these outcomes. Data relating restoration of the TSH level to within the reference range with improvements in bone mineral density were rated as fair. Data addressing all other associations of subclinical hyperthyroid disease and adverse clinical outcomes or treatment benefits were rated as insufficient or absent. Subclinical hypothyroid disease in pregnancy is a special case and aggressive case finding and treatment in pregnant women can be justified. CONCLUSIONS: Data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few. The consequences of subclinical thyroid disease (serum TSH 0.1-0.45 mIU/L or 4.5-10.0 mIU/L) are minimal and we recommend against routine treatment of patients with TSH levels in these ranges. There is insufficient evidence to support population-based screening. Aggressive case finding is appropriate in pregnant women, women older than 60 years, and others at high risk for thyroid dysfunction.

A novel therapeutic approach.

Since 1988, the National Cholesterol Education Program has identified low-density lipoprotein cholesterol (LDL-C) as the target of therapy; the new Adult Treatment Panel III (ATP III) guidelines continue the tradition of matching the aggressiveness of LDL-lowering therapy according to the risk of coronary heart disease (CHD). A significant change in the new guidelines is the definition of.CHD risk equivalents. and the inclusion of a modified Framingham global risk score. These revisions significantly raise the number of patients who qualify for lipid-lowering therapy. ATP III recognizes statins as the drug of first choice for LDL-C lowering. Statins are proven to be safe and effective for LDL-C reduction and are proven to reduce CHD event rates and mortality. Some patients are not candidates for statin therapy, however, and must rely on nonstatin agents that are less effective in reducing LDL-C, less safe, or poorly tolerated. Consequently, new cholesterol-lowering therapies are needed. Ezetimibe, approved by the U.S. Food and Drug Administration (FDA) in October 2002, is the first in a new class of selective cholesterol absorption inhibitors and offers a novel approach to the treatment of dyslipidemia. Phase 2 data demonstrated that ezetimibe lowers LDL-C by 18% and has a tolerability and short-term safety profile similar to placebo. This paper reviews the cholesterol metabolic pathways and the mechanism of action of the currently available lipid-modifying agents and introduces ezetimibe, the first selective cholesterol absorption inhibitor.

Combination therapy.

Adult Treatment Panel III (ATP III) guidelines recommend specific treatment targets for low-density lipoprotein cholesterol (LDL-C) levels according to an individual.s short-term and long-term risk for coronary heart disease (CHD). Therapeutic lifestyle changes are recommended for all patients at any level of risk for CHD. Although most patients will achieve some LDL-C lowering with lifestyle modification, ATP III recognizes that a majority of patients with dyslipidemia will require drug therapy to reach their LDL goal. Surveys of physicians. practices suggest that only a small percentage of patients enrolled in an active treatment program actually achieve their LDL-C target. In addition, other surveys suggest that not all patients who are treatment candidates are receiving assessment. From a medication perspective, either up-titration of statin dose or the use of drug combinations should further enhance the likelihood of achieving target lipid levels. Combination therapies that target both the endogenous and exogenous pathways of cholesterol synthesis are particularly attractive. This paper reviews the pharmacotherapeutic effects of combination therapy, summarizes the strengths and weaknesses of current lipid-lowering drug combinations, and identifies the potential contribution of the novel cholesterol absorption inhibitor, ezetimibe, to the LDL-C treatment algorithm.

Metabolic syndrome.

The metabolic syndrome is like an elephant, and any literary review of its importance is shamefully reduced to an examination of tusks, trunk, and tail. Evidence continues to mount that this diminutive approach is an incorrect management strategy for such a large problem. Diet and lifestyle are effective strategies, but they must effectively compete with behaviors that have instant gratification. Our society has turned its focus away from the long-term rewards of good sustainable behaviors and has instead focused on short-term rewards of unsustainable behaviors. To tame the behaviors that promote the metabolic syndrome, simple answers from diet and drug therapy will require support from society to be effective.