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Election! Election!! Election!!! 
This is to inform all medical     
Students Around the World    
of our first Election impending
 
This page will have a copy of our latest organization newsletter. We will update the page each month.
 
 

Author Spotlight
 
James Mulinda, MD
Consulting Staff
Department of Internal Medicine, Division of Endocrinology
Pennsylvania Hospital
University of Pennsylvania
 

DYSLIPIDEMIA AND METABOLIC SYNDROME

Summary of the state of affairs

Metabolic syndrome refers to a group of risk factors that includes dyslipidemia, hypertension, and abnormal glycemic metabolism due to insulin resistance and abdominal obesity (Grundy, 2004). Metabolic syndrome is increasingly recognized as a harbinger of excess morbidity and a higher mortality rate predominantly from cardiovascular disease. Cardiovascular mortality in metabolic syndrome is increased 2-fold compared to people without metabolic syndrome.

With the increasing incidence of obesity in the United States, the prevalence of metabolic syndrome is on the rise. In the adult US population, 20% are estimated of have metabolic syndrome, with prevalence approaching 50% in elderly individuals. Prevalence of metabolic syndrome among overweight US adolescents exceeds 30% (Duncan, 2004). Prevalence of metabolic syndrome in adult Europeans is 15%, with double the risk of cardiovascular disease mortality and a 40% greater risk of all-cause mortality compared to adults without metabolic syndrome (Hu, 2004).

Dyslipidemia is an established independent cardiovascular risk factor. Risk of cardiovascular morbidity is increased when additional components of metabolic syndrome are present. Recent studies suggest that the dyslipidemia in metabolic syndrome is more atherogenic even at similar levels of total cholesterol. In a study of 2225 men with cardiovascular disease, Onat found that dyslipidemic hypertension increased cardiovascular risk attributable to metabolic syndrome by 50% (2005).

The typical profile in metabolic syndrome is one of more atherogenic small, dense LDL-C particles, a low HDL-C level, and elevated triglyceride levels. This knowledge has led to further elucidation of culprit lipid subfractions that are increasingly targeted for optimal risk reduction.

Recent guidelines

The Adult Treatment Panel (ATP) III diagnostic criteria define metabolic syndrome as a constellation of any 3 or more of the following factors: obesity with waist circumference greater than 35 inches (88 cm) in women and greater than 40 inches (102 cm) in men, hypertension with blood pressure greater than 130/85 mm Hg, a fasting triglyceride level greater than 150 mg/dL (1.69 mmol/L), an HDL-C level lower than 50 mg/dL (1.29 mmol/L) in women and lower than 40 mg/dL (1.04 mmol/L) in men, and a fasting glucose level greater than 110 mg/dL (6.1 mmol/L) (Grundy, 2004). Metabolic syndrome is now a recognized reimbursable diagnostic entity, making it clinically treatable. The more components of metabolic syndrome an individual has, the higher the likelihood of cardiovascular morbidity in that individual. The presence of dyslipidemia and hypertension with metabolic syndrome increases the risk of cardiovascular morbidity (Onat, 2005; Lindblad, 2001). Smoking increases the cardiovascular risk.

Role of the expanded lipid profile and emerging risk factors

Recognition of the differences in cardiovascular morbidity in metabolic syndrome has led to further elucidation of the relative contribution of culprit cholesterol particles Small, dense LDL-C particles (pattern B) are more atherogenic than large, fluffy, buoyant LDL-C particles (pattern A) (Gotto, 2001; Hulthe, 2000). Using particle size centrifugation from commercially available laboratories in clinical practice to distinguish individuals with the more atherogenic pattern B from those with the less atherogenic pattern A makes setting more stringent lipid control targets clinically feasible. A recent study found that patients with metabolic syndrome had higher levels of oxidized LDL-C that was associated with more myocardial infarctions (Holvoet, 2004). Differences in HDL-C subtypes show HDL-C type 2 is more cardioprotective. Higher levels of VLDL-C contribute to a worse outcome. Elevated levels of lipoprotein(a) (Lp[a]) and apolipoprotein B (apoB) increase atherogenesis.

Other emerging risk factors shown to contribute to cardiovascular morbidity include prothrombotic and proinflammatory markers. Elevated levels of homocystine and type-1 plasminogen activator inhibitor (PAI-1) are prothrombotic cardiovascular risk markers, while highly sensitive cardioselective C-reactive protein is used as a proinflammatory marker. The outcome of treating emerging dyslipidemia risk factors is not as firmly established as is the outcome of targeting LDL-C.

Treatment guidelines for dyslipidemia in metabolic syndrome

The treatment of metabolic syndrome focuses on both general measures and targeted treatment of the different components of the metabolic syndrome. Goals of treatment for dyslipidemia in metabolic syndrome are similar to established goals for individuals with diabetes mellitus: target LDL-C level under 100 mg/dL, triglyceride level under 150 mg/dL, and HDL-C level greater than 40 mg/dL in men and 50 mg/dL in women.

  • Lifestyle changes of weight loss, diet, and exercise should be initiated and continued.
  • Persistent elevated LDL-C levels may require therapy with statins with or without ezetimibe (Zetia).
  • LDL-C particle size can be favorably altered with exercise and niacin and thiazolidinedione therapy.
  • Persistent elevated triglyceride levels may require therapy with fibrates.
  • Persistently low HDL-C, however, is more difficult to treat and may require addition of niacin, statins, and fibrates (Gotto, 2001).
  • Clinical trials targeting elevation of HDL-C levels are underway.
  • Elevated apoB levels may be reduced with statins.
  • Lp(a) levels may be lowered through treatment with statins, niacin, and estrogen but with much less reliability than treatment for reduction of apoB levels.

Prevention

Epidemiologic studies such as the Diabetes Prevention Program that emphasize lifestyle changes have shown regression of metabolic syndrome features. The Bogalusa Heart Study suggests that preventing the progression of metabolic syndrome requires starting early in life (Chen, 2004). A multifaceted approach spanning from the individual to the national level and facilitating favorable lifestyle changes is important. Further studies involving unconventional risk factors and personalized medications are still needed.

References

Chen W, Srinivasan SR, Li S, et al. Metabolic syndrome variables at low levels in childhood are beneficially associated with adulthood cardiovascular risk: the Bogalusa Heart Study. Diabetes Care. 2004;28(1):126-131.

Duncan GE, Li SM, Zhou XH. Metabolic syndrome among US adolescents: An emerging public health problem. Diabetes Care. 2004;27(10):2438-2443.

Hu G, Qiao Q, Tuomilehto J, et al. Metabolic syndrome predicts higher cardiovascular and all-cause mortality. Archives of Internal Medicine. 2004;164:1066-1076.

Gotto AM. Low high-density lipoprotein cholesterol as a risk factor in coronary heart disease: A working group report. Circulation. 2001;103(17): 2213-2218.

Grundy SM, Cleeman JI, Merz NB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227-239.

Holvoet P, Kritchevsky SB, Tracy RP, et al. The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the Health, Aging, and Body Composition Cohort. Diabetes. 2004;53:1068-1073.

Hulthe J, Bokemark L, Wikstrand J,et al. The metabolic syndrome, LDL particle size, and atherosclerosis: the Atherosclerosis and Insulin Resistance (AIR) study. Arteriosclerosis, Thrombosis, and Vascular Biolog. 2000;20(9):2140-2147.

Lindblad U, Langer RD, Wingard DL, et al. Metabolic syndrome and ischemic heart disease in elderly men and women. American Journal of Epidemiology. 2001;153(5):481-489.

Onat A, Herenç G, San I, et al. Dyslipidemic hypertension: Distinctive features and cardiovascular risk in a prospective population-based study. American Journal of Hypertension. 2005;18:409-416.

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Carmen Landaverde MD
Department of Medicine
Olive View – UCLA Medical Center

Francisco Durazo MD
Assistant Clinical Professor of Medicine and Surgery
Division of Digestive and Liver Diseases
Dumont-UCLA Liver Transplant Center

HEPATITIS C MANAGEMENT: EFFICACY OF PEGINTERFERON AND STANDARD INTERFERON COMBINATION VERSUS MONOTHERAPY

Background

Hepatitis C virus (HCV) infection is the most common blood-borne infection worldwide and an important health care problem (National Center for Health Statistics, 1996; National Institutes of Health, 1997), as it represents the leading indication for liver transplantation. Nearly 4 million Americans are estimated to have hepatitis C, and deaths from HCV-associated chronic liver disease are estimated to range from 8,000-10,000 each year (National Center for Health Statistics, 1996; Alter, 1997). Approximately 20-30% of patients with chronic hepatitis C develop cirrhosis (Hoofnagle, 1997). The course of hepatitis C is variable among individuals, but it eventually can lead to chronic hepatitis, decompensated cirrhosis, and hepatocellular carcinoma.

Several advances in the management of chronic HCV infection have occurred in the last decade. More recent research has propelled a shift from interferon alfa monotherapy to combination therapy with pegylated interferon (peginterferon) and ribavirin as the standard treatment for chronic hepatitis C. Numerous clinical studies and review articles have been published in the recent literature, the aim of which is to investigate the efficacy of peginterferon versus standard interferon as monotherapy and combination therapy with ribavirin. Clearly defining the terminology of the treatment endpoints to better understand the clinical findings in these studies is important. An earlier review article used the following definitions:

  • End-of-treatment response occurs on the basis of having no detectable HCV RNA (virologic response) at the end of the treatment.

  • Sustained response occurs based on reference range ALT levels and no detectable HCV RNA at the end of the treatment and throughout the observation period after stopping the therapy. Sustained virologic response (SVR) is defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy.

  • Nonresponse to treatment is when ALT levels remain abnormal at all time points evaluated during the study period or ALT levels become elevated (or HCV RNA appears) after having been in the reference range (or having no detectable HCV RNA) on treatment.

  • A histologic response is defined as a reduction in the Knodell score of 2 or more points compared to the baseline (Lindsay, 1997).

Peginterferon alfa-2a and ribavirin versus interferon alfa-2b and ribavirin combination therapy

A multicenter, randomized, controlled clinical trial was conducted involving 1121 interferon-naïve patients that compared the efficacy of peginterferon (180 µg SC each week) plus ribavirin (1000-1200 mg) with standard interferon alfa-2b plus ribavirin (Rebetron) and peginterferon alfa-2a monotherapy (Fried, 2002). Patients were treated for 48 weeks. All patients had abnormal ALT levels within 6 months of the initiation of the study and liver biopsies demonstrating chronic hepatitis, while 12-15% had cirrhosis. Approximately 65% of patients had genotype 1.

A greater proportion of patients who received peginterferon alfa-2a plus ribavirin were observed to have an SVR compared to patients who received interferon alfa-2b plus ribavirin (56% vs 44%) or peginterferon alfa-2a monotherapy (56% vs 29%). Patients with all HCV genotypes were more likely to have an SVR when treated with peginterferon alfa-2a plus ribavirin than with the other 2 regimens. The response rate was significantly higher for patients with genotype 2 or 3 compared to genotype 1 (76% vs 46%) with the peginterferon alfa-2a regimen. The overall safety profiles of the 3 treatment regimens were similar. In addition, patients with a 2-log decline in their HCV RNA titer or those who became HCV RNA negative within 12 weeks of initiation of the therapy had a 65% chance of achieving an SVR, which was subsequently termed as having an early virologic response. In contrast, of the patients who did not have a 2-log decline or undetectable levels of HCV RNA at week 12, 97% did not achieve an SVR. Other studies since have substantiated these findings (Ferenci, 2001; Ferenci, 2005). Thus, stopping therapy after 3 months in those patients who do not achieve an early virologic response should be considered. Therapy is generally discontinued in patients who have persistent detectable HCV RNA at the 24 week mark after initiation of therapy, even if those patients are considered responders.

Another study investigated the optimal duration of treatment with peginterferon alfa-2a and dosage of ribavirin (Hadziyannis, 2004). In this study, 1311 interferon-naïve patients were randomly assigned to peginterferon alfa-2a (180 µg SC/wk) plus ribavirin (either 800 or 1200 mg/d) for 24 or 48 weeks. Among patients with genotype 1, the highest SVR rate (52%) occurred after 48 weeks of treatment using the higher dose of ribavirin. In contrast, in patients with genotype 2 or 3 (80%), a shorter duration of treatment (24 weeks) and low-dose ribavirin (800 mg/d) was sufficient to achieve an SVR. Therefore, the National Institutes of Health Consensus conference recommends that patients with genotypes 2 and 3 should be treated with the lower dose of ribavirin for only 24 weeks.

Peginterferon alfa-2a versus interferon alfa-2a in monotherapy trials

In a study comparing peginterferon alfa-2a (180 µg/wk) and standard interferon alfa-2a (6 mU 3 times per week for 12 weeks followed by 3 mU 3 times per week for 36 weeks), the mean SVR rates were 39% and 19%, respectively (Zeuzem, 2000). In addition, histologic scores improved in both groups but were not significantly different, and genotype 1 was less likely to be associated with an SVR. In a more recent study, peginterferon alfa-2a 135 µg/wk and 180 µg/wk produced similar SVR rates, both of which were significantly higher than that achieved with interferon alfa-2a 3 times per week (Pockros, 2004). Furthermore, a significantly higher proportion of patients treated with the 180-µg dose of peginterferon alfa-2a had clinically significant histologic improvement. The results of this study are similar to those reported in the pivotal peginterferon alfa-2a trials, which have consistently demonstrated significantly greater SVR rates compared with the rates from treatment with interferon alfa-2a (Zeuzem, 2000; Heathcote, 2000; Reddy, 2001).

An earlier study found that an SVR to interferon therapy is associated with regression of fibrosis (Shiratori, 2000). In addition, it has been demonstrated that histologic improvement is more common in patients treated with interferon and ribavirin than in patients treated with interferon alone (McHutchison, 1998). Both observations support the findings that a greater proportion of patients treated with peginterferon alfa-2a combination therapy would have a histologic response, as stated earlier.

Future targets of therapy

Combining peginterferons with ribavirin considerably improves efficacy but at the expense of poor tolerability attributable to ribavirin, and a significant proportion of patients in these trials did not respond to treatment. Given the significant adverse effects attributed to interferon-ribavirin therapy, patients need to be screened carefully to assess their candidacy for this therapy. Future therapeutic developments may include 1 or more of the following approaches: understanding the HCV genomic organization, elucidating the viral life cycle and HCV replication strategy, and understanding the immune mechanisms required for viral propagation or infectivity (Sookoian, 2003). Therapies under development and evaluation for patients with hepatitis C include adjunctive use of the antiviral agent amantadine and the immunomodulatory agent thymalfasin as well as novel small molecules, which include the ribavirin analogs, viramidine and levovirin, and BILN 2061, an inhibitor of HCV serine protease (Foster, 2004).

References

Alter MJ. Epidemiology of Hepatitis C. Hepatology 1997;26 Suppl 1:62S-65S.

Ferenci P, Shiffman ML, Fried MW, et al. Early prediction of response to 40 Kd Peginterferon alfa-2a (Pegasys) plus ribavirin in patients with chronic hepatitis C (abstract). Hepatology 2001;34:351A.

Ferenci P, Fried MW, Shiffman ML et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a/ribavirin. J of Hepatol 2005;43(3):425-433.

Foster GR. Past, present, and future hepatitis C treatments. Semin Liver Dis 2004;24 Suppl 2:97-104 (Abstract).

Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975.

Hadziyannis SJ, Sette H Jr, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346.

Heathcote EJ, Shiffman ML, Cooksley WGE, et al. Peginterferon alpha-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343:1673-1680.

Hoofnagle JH. Hepatitis C: The clinical spectrum of disease. Hepatology 1997;26 Suppl 1:15S-20S.

Lindsay KL. Therapy of hepatitis C: Overview. Hepatology 1997;26 Suppl 1: 71S-77S.

McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;139:1493-1499.

National Center for Health Statistics. Third National Health and Nutrition Examination Survey: 1988-1994. Hyattsville, MD: Center for Disease Control and Prevention, 1996.

National Institutes of Health Consensus Development Conference Panel statement: management of hepatitis C. Hepatology 1997;26 Suppl 1:2S-10S.

Pockros PJ, Carithers R, Desmond P, et al. Efficacy and safety of two-dose regimens of peginterferon alpha-2a compared with interferon alpha-2a in chronic hepatitis C: a multicenter, randomized controlled trial. Am J Gastroenterol. 2004 Jul;99(7):1298-1305.

Reddy KR, Wright TL, Tockros PJ, et al. Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C. Hepatology 2001;33:433-438.

Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann of Intern Med 2000;132(7):517-524.

Sookoian SC. New therapies on the horizon for hepatitis C. Ann Hepatol 2003 Oct-Dec;2(4):164-170.

Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666-1672.

 
     
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