Treatment of nonalcoholic fatty liver: present and emerging therapies

Treatment of patients with nonalcoholic fatty liver has typically been focused on the management of associated conditions such as obesity, diabetes mellitus, and hyperlipidemia as well as discontinuation of potentially hepatotoxic drugs. Nonalcoholic fatty liver associated with obesity may resolve with weight reduction, although the benefits of weight loss have been inconsistent. Appropriate metabolic control for patients with diabetes mellitus or hyperlipidemia is always recommended but not always effective in reversing nonalcoholic fatty liver. Promising results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, and alpha-tocopherol suggest that these medications may be of potential benefit in the treatment of patients with nonalcoholic fatty liver. These medications, however, need first to be tested in well-controlled trials with clinically relevant end points and extended follow-up. A better understanding of the pathogenesis and natural history of this condition will help to identify the subset of patients with nonalcoholic fatty liver at risk of progressing to advanced liver disease and, hence, the subgroup of patients who should derive the most benefit from medical therapy. In this article, we review (1) the existing medical therapy for patients with nonalcoholic fatty liver, (2) the emerging data from clinical trials evaluating potentially useful medications, and (3) the potential therapeutic implications of recent studies on the pathogenesis of this liver disease.     

Insulin sensitizers and atherosclerosis

It is surprising that only about ten years after the concept of insulin resistance in diabetes mellitus was established, the role of insulin resistance in the development of atherosclerosis has been discussed and clarified. Insulin resistance predisposes the development of glucose intolerance, hyperlipidemia, and hypertension; the cluster of these abnormalities is referred to as multiple risk factor syndrome and it increases the risk of atherosclerosis. A few insulin sensitizers have recently begun to be used in the therapy for diabetic patients. However, the inhibitory effects of these insulin sensitizers against atherosclerosis have not been studied in large-scale clinical trials because these drugs were approved for clinical treatment only several years ago. Accordingly, this review presents a summary of the previous studies on the anti-atherogenic effects of insulin sensitizers by different strategies and provides information on why it is expected that insulin sensitizers will be used as anti-atherogenic drugs.     

Metabolic changes with antihypertensive therapy of the salt-sensitive patient

Recent evidence suggests that metabolic changes that occur with antihypertensive agents may influence cardiovascular risk. Diuretic therapy is particularly appropriate for the salt-sensitive hypertensive patient. However, diuretic-induced electrolyte abnormalities may lead to ventricular arrhythmias, even in patients with uncomplicated essential hypertension. Antihypertensive drugs may change circulating lipoprotein levels, which may influence the development of atherosclerosis. Therefore, serum cholesterol and triglyceride levels should be monitored when antihypertensive drugs are administered that can cause hyperlipidemia. Weight reduction and diet therapy should be used because these may have a greater effect on reducing hyperlipidemia, though choice of antihypertensive agents is important. In addition, glucose tolerance may worsen with thiazide therapy, perhaps because newer evidence suggests that insulin resistance is common in essential hypertension. This glucose intolerance may be corrected with potassium repletion or substitution of bumetanide for thiazide. The calcium antagonists may be substituted for diuretic therapy, or other classes of antihypertensive drugs may be used with a reduced dose of diuretic drug if these metabolic changes persist. Thus, attention to metabolic changes may be as important as blood pressure reduction in treatment of the salt-sensitive hypertensive patient.     

C-reactive protein in 2005. Interview by Peter C. Block

Acute coronary events strike nearly 1.4 million Americans annually. This includes an estimated 700,000 new coronary events, 500,000 recurrent events, and 175,000 silent first events each year. Adding to the clinical challenge is the fact that while conventional risk factors remain an important means of predicting who is at risk of developing coronary heart disease (CHD), it's unwise to rely on conventional risk factors alone for estimating patient risk. A 2003 evaluation of 122,458 patients enrolled in 14 international trials was meant to underscore that conventional risk factors are still important, yet one in five men with CHD in these trials (n=87,869) had none of the four conventional risk factors analyzed: smoking, hypertension, diabetes, and hyperlipidemia. Another challenge: Despite the overwhelming effectiveness of HMG-CoA reductase inhibitors in lipid lowering, 60% to 70% of cardiovascular events continue to occur despite statin therapy. This is in stark contrast to a 1996 prediction that statin therapy might eliminate heart attacks by the year 2000. It should be noted that in the large review of international trials mentioned above, only 34.1% of men with CHD had hyperlipidemia. If the lipid hypothesis of atherosclerosis is still correct, why do so few CHD patients have hyperlipidemia and why are so many events still occurring in patients on statin therapy? The seemingly anomalous data have led investigators to question whether the accepted target levels for low-density lipoprotein (LDL) cholesterol are low enough. Recent trials, including REVERSAL and PROVE IT/TIMI-22, have shown that lower target LDL levels, particularly in high-risk patients, are effective in further reducing cardiovascular events. (The implications of these studies were discussed in a 2004 update of clinical guidelines.) Yet, even intensive statin therapy is not the complete answer. In the PROVE-IT TIMI-22 study, for example, high-dose statin therapy still was associated with a 25% recurrent event rate at 2.5 years.     

NIH conference. Membranous nephropathy.

Membranous nephropathy is a worldwide problem that accounts for about 20% of the cases of the adult-onset nephrotic syndrome. This disease places many patients at risk for both end-stage renal failure and the complications of hyperlipidemia. Immune-mediated injury to the glomerular capillary wall in patients with membranous nephropathy is characterized by subepithelial immune complex formation and generation of the membrane attack complex of complement. Glomerular capillary hypertension, hyperlipidemia, and possibly cytokines could contribute to the glomerular sclerosis seen in the advanced stages of the disorder. In some cases, production of pathogenic antibody can be suppressed by treating the underlying condition. The mechanisms of action of immunosuppressive agents are being investigated and treatments are being tested in clinical trials to optimize the balance of efficacy and toxicity. Alternate-day treatment with corticosteroids is often recommended for nephrotic patients with idiopathic membranous nephropathy, but this approach has not been proved beneficial. Ongoing studies are evaluating whether cytotoxic drugs or cyclosporin A combined with prednisone is more effective than treatment with corticosteroids alone. Lipid-lowering drug therapy is warranted in cases of the persistent nephrotic syndrome to avert the cardiovascular sequelae of hyperlipidemia.     

Effects of pravastatin on left ventricular mass in patients with hyperlipidemia and essential hypertension

Left ventricular (LV) mass is a powerful predictor for future cardiovascular events. Epidemiologic studies have shown that hyperlipidemia is associated with higher LV mass. The effects of statin therapy for hyperlipidemia on LV mass have not been studied. To determine the effects of statin therapy on LV mass, we prospectively studied 3 groups of age and body surface area-matched patients: group 1 (n = 20), patients with systemic hypertension and hyperlipidemia treated with pravastatin plus anti-hypertensive drugs; group 2 (n = 20), patients with hypertension and hyperlipidemia treated with hypertensive agents and diet control alone; and group 3 (n = 20), hypertensive patients with normolipidemia treated with antihypertensive agents. A group of controls without hypertension or hyperlipidemia was used for comparison. Echocardiograms were recorded at baseline and after 6-month therapy. All hypertensive groups showed significant decreases in LV mass index after treatment. Group 1 had the greatest decrease in LV mass and it was significantly higher than in groups 2 and 3. Multivariate analysis revealed that regression of LV mass was significantly correlated only with the use of statins and sex (p = 0.005 and 0.01, respectively, R(2) = 0.47). Linear regression analysis in group 1 showed a significant correlation between changes in arterial compliance and LV mass regression (r = 0.57, p = 0.01). Thus, the addition of a statin may have an additional effect on reducing LV mass, independent of lipid-lowering effects.     

Optimal management of hyperlipidemia in primary prevention of cardiovascular disease

Cardiovascular disease (CVD) in the developed countries continues to grow at an epidemic proportion. There are a significant number of young adults with no clinical evidence of CVD, but who have two or more risk factors that predispose them to CV events and death. Many of these risk factors are modifiable, and by controlling these factors, the CVD burden can be decreased significantly. Recent statistics have shown that, if all major forms of CVD were eliminated, the life expectancy would rise by almost 7 years. Hence it is imperative that primary prevention efforts should be initiated at a young age to avert decades of unattended risk factors. Hyperlipidemia has been linked to CVD almost a century ago. Since then various clinical trials have not only supported this link, but have also shown the CV benefits in aggressively treating patients with hyperlipidemia. In this generation, we have various therapeutic agents that are capable of reducing the elevated lipid levels. With drugs like statins, we are able to reduce the risk of CVD by about 30% and avoid major adverse events. Newer drugs are being researched and introduced in the treatment of hyperlipidemia in humans. These can be used in combination therapy resulting in optimal levels of lipids. The new National Cholesterol Education Program (NCEP)/Adult Treatment Panel III (ATP III) guidelines have come as a wake-up call to clinicians about primary prevention of CVD through strict lipid management and multifaceted risk management approach in the prevention of CVD.     

Statins, ACE inhibitors and ARBs in cardiovascular disease

Several trials have indicated that classical cardiovascular risk factors, including hyperlipidemia and hypertension, are not associated with a great number of acute cardiovascular events. Given the crucial role of inflammation in atherogenesis, inflammatory factors have been proposed to better define and predict acute cardiovascular events. In this promising context, treatments with lipid-lowering drugs (statins) and anti-hypertensive drugs (ACE inhibitors and ARBs) have been also investigated from an ‘anti-inflammatory’ point of view, with some encouraging results. At present, statins are recommended by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines as the first-line choice for drug therapy lowering LDL cholesterol in high-risk patients (LDL goal <70 mg/dL, <1.8 mmol/L). In moderate-risk patients (LDL goal <100 mg/dL, <2.6 mmol/L), statin therapy is indicated mainly in metabolic syndrome and in diabetic patients. Treatment with ACE inhibitors or ARBs is recommended in both hypertension and cardiovascular diseases, particularly in diabetic patients. The use of ACE inhibitors is recommended in all patients with ST-elevation myocardial infarction with LVEF ≤40%, with normal LVEF in the presence of well-controlled cardiovascular risk factors and revascularization, hypertension, diabetes or chronic kidney disease. On the other hand, the use of ARBs is recommended in patients intolerant of ACE inhibitors or who have heart failure or hypertension. In the future, these recommendations will probably be frequently updated as the pleiotropic activities of statins, ACE inhibitors and ARB are also taken into account.     

New drugs for metastatic kidney cancer

Systemic therapy of metastatic kidney cancer has undergone dramatic changes over the past years. One reason for this is our increasing knowledge of different histological subtypes and associated genetic aberrations. Furthermore, signalling pathways have been identified to be relevant for tumour progression and therapeutic intervention. Until some years ago, systemic therapy for kidney cancer consisted of cytokines. In this review, new drugs for the treatment of metastatic kidney cancer are discussed. These drugs predominantly interact the VEGF, EGFR and mTOR signalling pathways. Four drugs have been studied in phase III trials and were (or will soon be) approved for treatment of metastatic kidney cancer. Additionally, many drugs are currently being tested in phase I and phase II trials. At present, the following scenarios have an impact on therapy decisions: different prognostic groups, first-line and second-line therapy, combination therapies and the impact of different histological subtypes.     

Use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in various forms of dyslipidemia

The inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase are highly effective in treating severe elevations of serum cholesterol, and are being widely used for this purpose. In our laboratory, these drugs have been used for the treatment of other forms of dyslipidemia including primary moderate hypercholesterolemia, primary mixed hyperlipidemia, diabetic dyslipidemia, hyperlipidemia of the nephrotic syndrome, and primary hypoalphalipoproteinemia. In these conditions, the HMG CoA reductase inhibitors proved effective in substantially decreasing levels of both low-density lipoproteins and very low density lipoproteins, as well as apolipoprotein B. In some patients, they may even increase levels of high-density lipoproteins. The primary mode of action of HMG CoA reductase inhibitors appears to be to increase the synthesis of hepatic receptors for lipoproteins containing apolipoprotein B, although a reduction in synthesis of these lipoproteins has not been ruled out with certainty. Regardless of mechanisms, drugs of this type appear to have the potential for effective therapy of various forms of dyslipidemia beyond primary severe hypercholesterolemia.     

Projected life-expectancy gains with statin therapy for individuals with elevated C-reactive protein levels

OBJECTIVES: We sought to estimate the potential gains in life expectancy achieved with statin therapy for individuals without overt hyperlipidemia but with elevated C-reactive protein (CRP) levels. BACKGROUND: Persons with low-density lipoprotein (LDL) cholesterol levels below current treatment guidelines and elevated CRP levels are at increased risk of cardiovascular disease and may benefit from statin therapy. METHODS: We constructed a decision-analytic model to estimate the gains in life expectancy with statin therapy for individuals without overt hyperlipidemia but with elevated CRP levels. The annual risks of myocardial infarction (MI) and stroke, as well as the efficacy of statin therapy, were based on evidence from randomized trials. Estimates of prognosis after MI or stroke were derived from population-based studies. RESULTS: We estimated that 58-year-old men and women with CRP levels >or=0.16 mg/dl but LDL cholesterol <149 mg/dl would gain 6.6 months and 6.4 months of life expectancy, respectively, with statin therapy. These gains were similar to those for patients with LDL cholesterol >or=149 mg/dl (6.7 months for men and 6.6 months for women). In sensitivity analyses, we identified the baseline risk of MI and the efficacy of statin therapy for preventing MI as the most important factors in determining the magnitude of benefit with statin therapy. CONCLUSIONS: Our results suggest that individuals with elevated CRP levels, many of whom do not meet current National Cholesterol Education Program guidelines for drug treatment, may receive a substantial benefit from statin therapy. This analysis supports a crucial need for direct intervention trials aimed at subjects with elevated CRP levels.     

Efficacy and safety of statin and fibrate combination therapy in lipid management

Adequate control of hyperlipidemia is of paramount importance for prevention of vascular events. Statins and fibrates are well established treatments for hyperlipidemia. Combination therapy with a statin and fibrate offers significant therapeutic advantage for the treatment of severe or refractory mixed hyperlipidemia. Although such a combination does increase the risk of myopathy, with an incidence of approximately 0.12%, this small risk of myopathy rarely outweighs the established morbidity and mortality benefits of achieving lipid goals. Nevertheless, a higher incidence of myopathy has been reported with statin monotherapy. Statin + fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids or nicotinic acid) did not achieve lipid targets or is impractical. The current article focuses on recent studies highlighting the beneficial effects of this combination.     

The patient at risk of sudden death:value of drug therapy]

The evaluation of antiarrhythmic therapy should be based on its effects on total mortality assessed by controlled trials. The author reviews the large trials on antiarrhythmic drugs, during the past ten years, and concludes with the current importance of such therapy. Trials have been conducted in three kinds of high-risk populations: patients with malignant ventricular arrhythmias, survivors of myocardial infarction and patients with congestive heart failure. The results have been disappointing, showing either an increase in mortality with antiarrhythmic drugs (class I, d-sotalol) or a neutral effect (amiodarone). Trials conducted in patients with malignant arrhythmias have shown that the implantable cardioverter-defibrillator was superior to the best available antiarrhythmic therapy. In other high-risk populations, the only drugs that consistently reduced mortality were betablockers, which might have other mechanisms of action besides the antiarrhythmic effect. Amiodarone, the most potent suppressor of ventricular arrhythmias, is indicated in highly symptomatic patients; dl-sotalol is a good alternative to amiodarone. We may conclude from these large trials that study endpoints must be correctly chosen in order to assess the real value of an antiarrhythmic drug. The study population must have a high risk of sudden death and be within an appropriate time window of maximal risk. Antiarrhythmic trials must proceed, learning the lessons from the old studies, trying to test new drugs or new therapeutic strategies, better selecting study populations and new risk markers superior to those currently available.     

Management of hypertension in patients with type 2 diabetes mellitus: guidelines based on current evidence.

Hypertension and diabetes are becoming increasingly common. Most patients with both disorders have a markedly worsened risk for premature microvascular and macrovascular complications. The appropriate management of the hypertension seen in almost 70% of patients with type 2 diabetes mellitus remains controversial. However, over the past few years, many randomized, controlled trials have provided guidance for more effective therapy. These trials have established the need for a lower goal blood pressure (<130/80 mm Hg) than has previously been recommended. In addition, they have proven the efficacy of drugs from three major classes of antihypertensive agents; however, comparative trials have failed to show definite superiority of any particular class in either lowering blood pressure or reducing cardiovascular morbidity and mortality. To achieve therapy goals, multiple antihypertensive drugs are usually needed. On the basis of their apparent superiority in slowing diabetic nephropathy, angiotensin-converting enzyme inhibitors should probably be the first choice. Second and third choices should be a long-acting diuretic and a calcium-channel blocker or a beta-blocker, respectively. Attention should also be directed toward nonpharmacologic and pharmacologic control of hyperglycemia and dyslipidemia.     

Cardiovascular and medical ramifications of treatment of subclinical hypothyroidism

Subclinical hypothyroidism can be diagnosed in 1% to 10% of the adult population, is more common in women, and increases with age. In many patients, treatment with L-thyroxine reduces low-density lipoprotein cholesterol, improves cardiac function, reduces symptoms of hypothyroidism, and diminishes neuropsychiatric symptoms. Treatment also reduces the likelihood of statin-induced myopathy. However, in double-blind, placebo-controlled trials of L-thyroxine therapy in subclinical hypothyroidism, cardiovascular and symptomatic benefits have been neither uniform nor definitive. In the absence of a large-scale, multicenter, randomized trial, physicians have to individualize therapy for each patient. Benefits of therapy are most likely to be realized in patients with thyroid-stimulating hormone levels greater than 10 mU/L on repeated measures, those with hypothyroid symptoms, those who are pregnant, those with a documented family history of hypothyroidism, and those with severe hyperlipidemia.     

Dietary therapy for different forms of hyperlipoproteinemia

Diet is the first line of therapy for hypercholesterolemia. The major dietary factors raising the plasma cholesterol are saturated fatty acids, cholesterol, and excess total calories. For almost all forms of hyperlipidemia, the first principle of dietary therapy is to reduce saturated fatty acids, decrease cholesterol, and curtail excess calories. In patients with severe hypercholesterolemia, marked restrictions of diet may be necessary. For these patients, drugs may be required to control cholesterol levels. However, the majority of patients with elevated plasma cholesterol can achieve a satisfactory reduction of cholesterol levels by diet, and drugs will not be necessary. Dietary therapy alone is adequate for most patients with familial forms of hypertriglyceridemia, but for a few patients drugs are required.     

Randomized Clinical Trials of Neurally Mediated Syncope

Evidence for therapy of neurally mediated syncope is generally weak. Many drugs have been used for the treatment of vasovagal syncope (beta-blockers, disopyramide, scopolamine, clonidine, theophylline, fludrocortisone, ephedrine, dihydroergotamine, etilefrine, midodrine, clonidine, serotonin reuptake inhibitors, enalapril). In general, although the results have been satisfactory in uncontrolled trials or short-term controlled trials, the majority of long-term placebo-controlled prospective trials have not been able to show a benefit of the active drug over placebo. Only two well-designed double-blind placebo-controlled randomized trials have been performed—one for etilefrine and the other for atenolol—and both were unable to show a superiority of the active drug versus placebo. Four randomized clinical trials of pacing therapy—three positive and one negative—have been performed in patients affected by vasovagal syncope. The relationship between carotid sinus hypersensitivity and spontaneous, otherwise unexplained, syncope has been demonstrated. Cardiac pacing appears to be beneficial in carotid sinus syndrome; its efficacy has been demonstrated by two randomized controlled trials and confirmed by several pre-post comparative studies, one controlled trial, and one prospective observational study. There is evidence and general agreement that cardiac pacing is useful in patients with cardioinhibitory or mixed carotid sinus syndrome. Usefulness of the treatment is less well established and divergence of opinion exists with regard to cardiac pacing in patients with cardioinhibitory vasovagal syncope. The evidence fails to support the efficacy of beta-blocking drugs. As yet there are insufficient data to support the use of any other pharmacologic therapy for vasovagal syncope. (J Cardiovasc Electrophysiol, Vol. 14, pp. S64-S69, September 2003, Suppl.)     

Potential Anti-Atherosclerotic Effects of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Mellitus

Cardiovascular disease (CVD) is the leading cause of mortality in patients with diabetes. Pharmacotherapy that can reduce hyperglycemia and also exhibit pleiotropic effects that can result in a reduction in cardiovascular disease will be a major advance. Recently, the dipeptidyl-peptidase-4 inhibitors were introduced as ant-hyperglycemic therapy. Studies from numerous groups have reported effects that could potentially result in a reduction in CVD. Some of the drugs in this class, especially vildagliptin and sitagliptin, have been shown to reduce postprandial hyperlipidemia following a fat load, improve endothelial function as evidenced by increased forearm blood flow, and also display anti-inflammatory effects. Their effects on platelet function, blood pressure, and oxidative stress are very preliminary and need to be confirmed. Finally, they have been shown to reduce subclinical atherosclerosis by reducing carotid intimal-medial thickness. However, the final arbiter with respect to a reduction in CVD will be the ongoing clinical trials.     

Management of diabetes mellitus in patients with angiopathies

Nowadays, about 6-8% of the German population suffers from diabetes mellitus mostly type 2 but in patients with angiopathies about 30% have known diabetes and a further 30% have newly diagnosed diabetes or impaired glucose tolerance. Therefore diagnosis and therapy of glucose impairment play a central role for management of these patients. The antidiabetic therapy for secondary prevention of cardiovascular disease has to be embedded in a multifactorial concept with management of hypertension, hyperlipidemia and hypercoagulability. The management of diabetes following guidelines is a stepwise therapy with lifestyle interventions (diet, exercise) and oral drugs or insulin. Metformin has shown favorable outcome in overweight patients if aware of side effects; insulin is a safe drug in multimorbid patients and with planned interventions or operations. We are awaiting the results of multiple endpoint studies with newer antidiabetic drugs which may change our current concept of management of diabetes mellitus in these patients in the near future.     

Lipid regulation: a clinician's view of patient management

Practicing physicians now have the capability as well as the responsibility to treat hyperlipidemia. Recent conclusive trials have demonstrated the link between lipid elevations and coronary heart disease, as well as the likelihood of reducing coronary heart disease risk by lowering blood lipids via diet and/or drug intervention. Screening criteria for hyperlipidemia in normal patients and in special patient subgroups are described, and recommendations for treatment are proposed. The diet recommended by the American Heart Association--which limits fat intake to 25% to 30% of all calories in a 1:1:1 ratio of saturated, monounsaturated and polyunsaturated fats, and limits cholesterol to less than 300 mg/day--is discussed. Guidelines are suggested for drug therapy with lipid-lowering agents to reduce abnormal lipid levels when diet alone proves insufficient after 2- to 3-month trial.