Level One Evidence to Treat Metabolic Syndrome Largely Ignored

I read with great interest the recent paper by Dr. Scott M. Grundy, Metabolic Syndrome: Connecting and Reconciling Cardiovascular and Diabetes Worlds, published in the March 21, 2006, Journal of the American College of Cardiology. My writing today is going to be long, but I hope you'll bear with me since this is important information.

In part, the summary is short, concise and on point:

The metabolic syndrome is a constellation of risk factors that carry increased risk for cardiovascular disease and type 2 diabetes. These risk factors are atherogenic dyslipidemia, elevated blood pressure, elevated plasma glucose, a prothrombotic state, and a proinflammatory state. The two major underlying risk factors are obesity and insulin resistance. Primary treatment is lifestyle therapy - weight loss, increased physical activity, and anti-atherogenic diet. As the syndrome worsens, drug therapies directed toward individual risk factors might be required. Ultimately, drugs might be developed that will simultaneously modify all of the risk factors, but such drugs are not currently available.

First let me applaud Dr. Grundy's frank discussion of many of the pressing issues clouding progress to effectively diagnose and treat individuals presenting with features of Metabolic Syndrome - ineffective communication and lack of agreement between the diabetes and cardiology researchers and organizations; pharmaceutical agents that only target individual risk factors and often do not ameliorate the features effectively; pointing to the long-term, geometric increases to risk individuals face as each feature of Metabolic Syndrome presents and/or advances; and the continued neglect in clinical practice of the single best intervention - diet and lifestyle.

He makes it a point to state that the long-term risk for antherosclerotic cardiovascular disease is greater than the sum of the risk factors associated with Metabolic Syndrome individually. As Dr. Grundy also points out clearly, "primary treatment is lifestyle therapy - weight loss, increased physical activity, and anti-atherogenic diet."

When Dr. Grundy included a section dedicated to the evidence for lifestyle intervention, I was hopeful he would include evidence that provides a comprehensive presentation of the most effective lifestyle interventions supported by hard data. To sum up my expectations - level one evidence, randomly controlled studies, investigation that includes the primary risk factors (BMI and/or waist circumference; total cholesterol, HDL, LDL, triglycerides, TC/HDL ratio, fasting glucose, insulin levels, and blood pressure) or included individuals with Metabolic Syndrome specifically; studies at least six months in length with good compliance rates and overall statistically significant results.

So, which studies did he include to support his statement that "Beyond reducing risk for cardiovascular disease, weight reduction and increased physical activity slows progression to type 2 diabetes in individuals with the metabolic syndrome."

J. Tuomilehto, J. Lindstrom, J.G. Eriksson et al. and Finnish Diabetes Prevention Study Group, Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, N Engl J Med 344 (2001), pp. 1343–1350.

W.C. Knowler, E. Barrett-Connor, S.E. Fowler et al. and Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N Engl J Med 346 (2002), pp. 393–403.

To say I was disappointed by the two studies he included is an understatement. To be clear, both were indeed level one studies - randomly controlled, long-term and with controls to compare the intervention group results. Neither, however, is clear and convincing that the lifestyle interventions were effective for the features of Metabolic Syndrome.

Let me explain why. In the first, Tuomilehto et al, indeed had two groups with multiple features of Metabolic Syndrome. While the findings support that the intervention group did better than the control, they continued to have Metabolic Syndrome as evidenced by their waist circumferance, cholesterol levels, fasting glucose and blood pressure. This particular study also did not provide enough key data for cholesterol since it did not evaluate impacts on LDL cholesterol.

In the second, Knowler et al investigate how lifestyle intervention compares with a pharmaceutical intervention to delay diabetes and conclude that lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. But, the lifestyle intervention was more effective than metformin. Unfortunately this study, again, did not look at enough risk markers to effectively communicate its value as an intervention for Metabolic Syndrome. The investigators did not look at total cholesterol, LDL, HDL, triglycerides, blood pressure or insulin values. Without a complete investigation of these risk markers, this data lacks and is inappropriate to use in support of lifestyle intervention because it leaves too many questions unanswered.

So, neither of these studies supports the idea that lifestyle intervention can reverse the features of Metabolic Syndrome effectively. The fact that Dr. Grundy didn't include evidence, from trials specifically looking at those with features of Metabolic Syndrome or studies that evaluated enough risk markers to reach conclusions about the features of Metabolic Syndrome begs the question - is there a lack of evidence?

The answer is clearly no!

We have dozens of studies that point to the efficacy of lifestyle interventions that not only delay progression of the features, but that can reverse the features! I am very disappointed that Dr. Grundy failed to include any of them. In fact, I would say, without hesitation, that his omission borders on negligence to his colleagues and those individuals seeking methods to improve their condition!

I know that's a very strong statement. But, it must be said if we are going to start to see evidence-based medicine in practice. Anything other than the use of strong evidence is mere speculation or wishful thinking and is nothing more than lip-service. Dr. Grundy has an obligation to his colleagues, clinicians and the public to fully explore the literature and present those studies that clearly indicate which lifestyle interventions work! He failed to do that. And he didn't just fail to find one study - he failed to find or include dozens of studies.

Case in point: Foster GD, Wyatt HR, Hill JO, McGuckin BG, Brill C, Mohammed BS, Szapary PO, Rader DJ, Edman JS, Klein S. A randomized trial of a low-carbohydrate diet for obesity N Engl J Med. 2003;348:2082–2090

Key aspects of the above study - one year, randomly controlled trial; measured cholesterol, insulin, blood pressure, weight, insulin response and glucose levels. The results are best summed up in a graphic:



Golay A, Eigenheer C, Morel Y, Kujawski P, Lehmann T, de Tonnac N. Weight-loss with low or high carbohydrate diet? Int J Obes Relat Metab Disord. 1996;20:1067–1072

Key aspects of the above study - one year, randomly controlled trial; compared low carbohydrate with a low fat diet; measured cholesterol, BMI, glucose, cholesterol, insulin and blood pressure. Again, the results are best summed up in a graphic:



Late last year, Volek & Feinman published a comprehensive review of the literature and found that the degree of carbohydrate restriction directly parallels improvement in the features of metabolic syndrome. As part of their paper, Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction, they included a table of one dozen studies of varying time lengths:



Notice in the above graphic the stunning improvements, across the board, when carbohydrate restriction is used as the dietary intervention.

They also review fourteen studies of ad libitum consumption of carbohydrate restricted diets compared with low-fat diets. The results again strongly support the use of carbohydrate restricted diets to specifically reduce or reverse the features of Metabolic Syndrome:



Now you may be thinking this is all fine and dandy, but surely the conventional wisdom and recommendation to follow a low-fat diet must have merit, otherwise the leading health organizations would stop recommending them since we're told things now are strictly evidence-based?

Unfortunately, the dogma that supports the low-fat paradigm finds little support in the evidence for the features of Metabolic Syndrome. And, sadly, the negative effect of low-fat diets on the risks have been long-known and ignored.

Our first key date in the history of understanding the negative effects of low-fat diets on the features of Metabolic Syndrome comes from data from none other than the "Father of Metabolic Syndrome," Gerald Reaven's work. In 1986, Dr. Reaven published Effect of dietary carbohydrate on the metabolism of patients with non-insulin dependent diabetes mellitus. (Nutr Rev. 1986;44:65–73) and found reducing carbohydrate to 40% of the calories improved individuals to a greater degree than when they consumed 55% of their diet as carbohydrate.

Little research was done to replicate the results or to explore if further reductions of carbohydrate would result in even greater improvements. The biggest reason for the stall in the research was, and remains, the fear of dietary fat. Yet, in 2004, Gannon and Nuttall published, Effect of a high-protein, low-carbohydrate diet on blood glucose control in people with type 2 diabetes. (Diabetes. 2004;53:2375–2382) and found that when carbohydrate is reduced to 20% of calories, the improvements exceed those seen in Reavens' work where carbohydrate was restricted to just 40% of calories! Numerous other studies - from Gannon, Nutall, Westman, Volek, Noakes, Phinney, Yancy, Stern, Brehm and others resulted in similar findings. Yet, these studies continue to be omitted from reviews and analysis of effective lifestyle interventions! This is not only neglectful, it's shameful.

In the United States, we have a real crisis today - 25% of all adults are estimated to already have Metabolic Syndrome; another 20-30% are at risk for developing Metabolic Syndrome; and some 4% of all adolescents and 30% of overweight adolescents meet the criteria for Metabolic Syndrome. If we do not do something now to educate those already affected or at risk for the disorder - and do it quickly - these numbers will continue to grow with pre-mature death the end result of our failure to act from an evidence-based approach.

When compared side-by-side - carbohydrate-rich, low-fat diets and carbohydrate restricted diets - we see dramatically different results. The low-fat diets often raise LDL and triglycerides, lower HDL, have little impact on glycemic control, and minimal effect on blood pressure. These effects are negative impacts that increase the risk of progression of Metabolic Syndrome. While the low-fat diet can and often will result in weight loss, the long-term the benefit of weight loss is negated as weight is re-gained and completely offset by the negative effect on the risk markers for Metabolic Syndrome.

On the other hand, a carbohydrate restricted diet - whether fat or protein or a combination of both is substituted for calorie requirements - has a profound effect on triglycerides, significantly lowering them, raising HDL, improving TC/HDL ratios, increasing insulin sensitivity and glycemic control, reducing blood pressure and reducing weight. Again, in the long-term, it is not certain if the weight loss can be sustained as we have few studies to date that meet the standard of level one evidence. However, the positive impacts on the risk markers of Metabolic Syndrome are promising, especially given the fact that recent data suggests that even without weight loss, such improvements to the various risk factors are seen when carbohydrate restriction is followed.

The bottom line is that a large number of researchers have invested years of time studying diet and nutrition to learn how different macronutrient ratios affect the risk markers associated with Metabolic Syndrome. We have level one evidence that points clearly to carbohydrate restriction as an effective lifestyle intervention.

We have millions of people in the United States today who are being denied this evidence each time a review is published and the author omits the data from these gold standard studies because they counter the established dogma.

I've said it before and I'll say it again - DOGMA IS NOT EVIDENCE!

I implore you to take the time to read the paper published by Dr. Jeff Volek and Dr. Richard Feinman - Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction - and review the 112 references included in their extensive review of the literature.

If you do that - take the time - I think you'll find yourself asking the same question I do - When will the leading medical organizations and experts finally take an evidence-based approach to making recommendations for those at risk for or already presenting features of Metabolic Syndrome?