Trevor J. Orchard, MD; Marinella Temprosa, MS; Ronald Goldberg, MD; Steven Haffner, MD; Robert Ratner, MD; Santica Marcovina, PhD, DSc; Sarah Fowler, PhD; Diabetes Prevention Program Research Group
Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, et al. The Effect of Metformin and Intensive Lifestyle Intervention on the Metabolic Syndrome: The Diabetes Prevention Program Randomized Trial. Ann Intern Med. 2005;142:611-619. doi: 10.7326/0003-4819-142-8-200504190-00009
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Published: Ann Intern Med. 2005;142(8):611-619.
Numbers are numbers of participants at baseline. The shaded sections represent participants meeting the metabolic syndrome criteria as defined by the National Cholesterol Education Program Adult Panel II. BP = blood pressure; HDL-C = high-density lipoprotein cholesterol; TG = triglyceride.
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Frank A. Anania
Emory University School of Medicine
April 21, 2005
Metabolic Syndrome and Fatty Liver
TO THE EDITOR: It would be remiss of practitioners in the Digestive Disease community not to point out that the most recent results published by Orchard and colleagues in association with the Diabetes Prevention Program failed to present laboratory data of the patients' serum alanine aminotransferase (ALT) values at entry, and upon completion of either pharmacologic intervention with metformin or the intensive lifestyle modifications tested in this study. Non-alcoholic fatty liver disease (NAFLD) is now the commonest reason patients are referred to a gastroenterologist for abnormal liver function tests (1). Results from the NHANES III database also suggest that up to 28% of patients have NAFLD and there is a strong association in such patients with obesity and type II diabetes mellitus (2). Clearly, impaired glucose intolerance and the presence of NAFLD are the unfortunate consequence of insulin resistance. Hence, it is concerning that NAFLD was not mentioned in this recent article. NAFLD, steatohepatitis, and disease progression will become the leading cause of chronic liver disease and cirrhosis in the United States. Given that the population of the Diabetes Prevention Program is highly selected for impaired glucose intolerance, it would be of great value to monitor this cohort for the incidence and prevalence of NAFLD. We would be curious to know whether the authors have data indicating an improvement in serum ALT values of their patients and whether or not metformin resulted in a significant improvement or not? While Diehl and colleagues found that metformin reversed steatosis in the ob/ob mouse model of obesity (3), they did not find sustained improvement in non- alcoholic steatohepatitis when the drug was tested in a small open-label clinical trial. (4). We, Gong and colleagues, recently identified an ALT isoenzyme (ALT2) that was highly expressed in the fatty livers of ob/ob mice (5), which also has a human homologue. We agree with the authors that multivariable models may be better predictors of various outcomes from the metabolic syndrome. Future studies should include examination of serum ALT or other predictors of NAFLD, particularly in subjects with impaired glucose tolerance. While it is reasonable to speculate, given the results from the lifestyle intervention arm, that reduction in waist circumference and increased activity is prudent advice for patients with NAFLD; the spiraling health-care costs that are a direct consequence of insulin resistance, requires urgent interdisciplinary use of the Diabetes Prevention Program to assess risk from NAFLD.
1. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003; 37:1202- 19. [PMID: 12717402] 2. Yu AS, Keeffe EB. Nonalcoholic fatty liver disease. Rev Gastroenterol Disord. 2002; 2:11-19. [PMID: 12122975] 3. Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000; 6:998-1003. [PMID: 10973319] 4. Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004; 20:23-8. [PMID: 15225167] 5. Jadhao SB, Yang RZ, Lin Q, Hu H, Anania FA, Shuldiner AR, Gong DW. Murine alanine aminotransferase: cDNA cloning, functional expression, and differential gene regulation in mouse fatty liver. Hepatology. 2004 May; 39:1297-302. [PMID: 15122758]
Vasilios G Athyros
May 5, 2005
Multitargeted treatment for metabolic syndrome
Multitargeted treatment for metabolic syndrome
TO THE EDITOR: Orchard et al  report that diet and exercise was more effective than metformin alone or neither intervention in preventing the development of the metabolic syndrome (MetS) in patients with impaired fasting glucose (IFG). Furthermore, patients in the diet and exercise group who had MetS at baseline were more likely to be free of MetS at the end of the 3.2 year follow up .
Is it possible to improve on these impressive results since, as mentioned by Orchard et al. , MetS is associated with a high risk of cardiovascular disease (CVD) ?
In a prospective, randomized, open label, intention-to-treat and parallel study  we followed up 300 non-diabetic patients with MetS, free of CVD at baseline, for a period of 12 months. Age- and gender- matched subjects without MetS (n=100) acted as controls. All patients received strict lifestyle advice (the same as in DPP ) and a stepwise- implemented drug treatment for hypertension (mainly ACE inhibitors and angiotensin II receptor blockers), IFG (metformin) and obesity (orlistat if BMI >30 Kg/m2). The patients were also randomly allocated to atorvastatin (n=100, 20 mg/day), micronized fenofibrate (n=100, 200 mg/day) or both drugs (n=100). After 12-months, 76% of patients no longer had MetS (46% only had one MetS diagnostic component). The remaining patients (24%) had two diagnostic factors less than at baseline. Since there is an association between the number of MetS features and CVD mortality [4,5] all participants probably benefited from the intervention. The secondary endpoint was the reduction in estimated (Framingham) 10-year CVD risk. This was 14.6% for all MetS patients at baseline and was significantly reduced in the atorvastatin group (to 6.4%), in the fenofibrate group (to 9.2%) and in the combination group (to 5.5%) (p<0.0001 for all vs baseline). The 10-year risk in the atorvastatin and combination groups was not different from that of the controls (5.0%).
We suggest that in subjects with MetS, multiple risk factor intervention reduces the number of MetS diagnostic criteria and the estimated CVD risk, more than diet and exercise alone.
1. Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, et al for the Diabetes Prevention Program Research Group. The Effect of Metformin and Intensive Lifestyle Intervention on the Metabolic Syndrome: The Diabetes Prevention Program Randomized Trial. Ann Intern Med 2005;142: 611-9. 2. Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;52:1210-4. 3. Athyros VG, Mikhailidis DP, Papageorgiou AA, Didangelos TP, Peletidou A, Kleta D, et al. Targeting vascular risk in patients with metabolic syndrome but without diabetes. Metabolism 2005 (in Press). 4. Ford ES. The metabolic syndrome and mortality from cardiovascular disease and all-causes: findings from the National Health and Nutrition Examination Survey II Mortality Study. Atherosclerosis 2004:173:307-12. 5. Klein BE, Klein R, Lee KE. Components of the metabolic syndrome and risk of cardiovascular disease and diabetes in Beaver Dam. Diabetes Care 2002:25:1790-4.
PRISCILLA S. SARINAS M.D. FACP
VA Palo Alto Health Care System and Stanford University
May 19, 2005
Sleep Related Breathing Disorders and the Metabolic Syndrome
To the Editor,
With respect to Trevor et al.(1) We would like to comment that several studies have also suggested that sleep-related breathing disorder (SRBD) is independently associated with insulin resistance, endothelial dysfunction, and hypertension (2). Furthermore, impairment in glucose tolerance seems to be related to the severity of oxygen desaturation associated with SRBD independently of age, gender, body mass index, and waist circumference and may be mediated by elevated release of epinephrine. (2, 3) These abnormalities are corrected with positive pressure ventilation.(4) Thus, sleep is a "missing link" that should be included as a variable of the syndrome-X.(5) Notwithstanding the omission of sleep as an important variable, the demonstration that exercise and diet are superior to metformin in the resolution of the metabolic syndrome is counter to the orthodox strategies adopted in the treatment of syndromes such as diabetes or hypertension that are clinically considered to have 'well defined' abnormalities. In vitro evidence suggests that hypertension, and insulin resistance are very complex disorders with multiple metabolic derangements whose measurement is poorly served by the contemporary indices used to gauge them such as blood sugar or blood pressure. It seems logical that intrinsic biochemical counteractive measures provoked by exercise or balanced nutritional homeostasis would better counteract the abnormalities thought to be operational in these syndromes. As has been historically contended, the absence of these syndromes in agrarian societies supports the conclusion that syndromes of insulin resistance, obesity and acquired hyperlipidemia are a reflection of the modern distortion of the organism-environmental equilibrium attained throughout human evolution in which energy utilization was balanced with physiological demands for survival. Thus, exercise, control of caloric utilization, and sleep may fall in the realm of processes that coax intrinsic bio-physiological machinery to balance protein-energy utilization. In consonance with the findings of this important study we support an integrated and multifaceted approach to the treatment of the metabolic syndromes. This study has extensive ramifications with regards to managing insulin resistance, hypertension, and obesity and requires careful scrutiny.
1. Trevor J. Orchard, Marinella Temprosa, Ronald Goldberg, Steven Haffner, Robert Ratner, Santica Marcovina, Sarah Fowler for the Diabetes Preventi Program Research Group The Effect of Metformin and Intensive Lifestyle Intervention on the Metabolic Syndrome: The Diabetes Prevention Program Randomized Trial. Ann Intern Med. 2005; 142: 611 - 619.
2. Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE; Sleep Heart Health Study Investigators.: Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol. 2004; 160(6):521-30.
3. Oltmanns KM, Gehring H, Rudolf S, Schultes B, Rook S, Schweiger U, Born J, Fehm HL, Peters A. Hypoxia causes glucose intolerance in humans. Am J Respir Crit Care Med. 2004 ;169(11):1231-7. Epub 2004 Mar 24.
4. Babu AR, Herdegen J, Fogelfeld L, Shott S, Mazzone T. Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea. Arch Intern Med. 2005;165(4):447-52.
5. Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J. 2004 ;25(9):735-41.
Trevor J Orchard
Institute for Biostatistics, George Washington University
June 16, 2005
We thank Drs Sarinas, Dube and Anania for their interesting letters concerning Sleep Related Breathing Disorders (SRBD) and Fatty Liver, respectively, as they relate to the Metabolic Syndrome. In terms of SRBD unfortunately we have no specific data to provide, but agree this is an interesting field for future study. We do however, have data concerning liver enzymes. While these were not provided in our current report, as they do not form part of the NCEP definition, we consider this topic so relevant and important that a full, separate, paper is in preparation to address this whole issue and both the impact on, and associations, of our interventions on these measures.
Yours sincerely ,
Trevor J Orchard, Marinella Temprosa and Robert Ratner. for the Diabetes Prevention Program
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism, Obesity.
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