Using the lowering of LDL-C as a surrogate marker, accomplished through either diet or medicines, has proven to be, at best, inconsistent and, at worst, misguided. Furthermore, using weight or body mass index (BMI) as a surrogate marker has been uniformly ineffective. While some people lose weight acutely through self-imposed dieting, they routinely gain it back, often with worsening of their metabolic state.
Rather, we should examine other risk factors, which more clearly drive the aberrant pathophysiology. The risk factor that has been most consistently associated with CVD, type 2 diabetes and obesity is ‘insulin resistance’ — defined as an impaired biological response to insulin. In fact, insulin resistance plays a primary and causative role in the pathogenesis of hypertension, dyslipidaemia, fatty liver disease, and type 2 diabetes, collectively termed ‘metabolic syndrome[30]’.
We propose that insulin resistance is the most important predictor of CVD and type 2 diabetes, a view that is strongly borne out of the work of Gerald Reaven and colleagues[31]. In a seminal natural history study, these researchers took a group of healthy people who were insulin sensitive and free from heart disease. After five years they found that none of the people who remained insulin sensitive developed heart disease whereas 14% of people in the highest tertile of insulin resistance developed heart disease in the same period[31].
In another study, up to 69% of patients who were admitted to hospital with acute heart attacks were found to have metabolic syndrome[32], which was associated with increased risk of death or readmission over the following 12 months.
Mathematical modelling has demonstrated that correcting insulin resistance in young adults could prevent 42% of episodes of myocardial infarction[33]. The study reported the next most important determinant of CVD is systolic hypertension, prevention of which would reduce myocardial infarctions by 36%, followed by low HDL-C (31%), high BMI (21%) and LDL-C (16%). Of note, insulin resistance belies each of these phenomena[33].
Metformin and thiazolidinediones are two drugs that mildly improve insulin sensitivity. While metformin has been shown to reduce CVD in type 2 diabetics, no data on primary prevention has yet been elaborated. Furthermore, rosiglitazone increased mortality in those with type 2 diabetes[34]. This may be one reason why using insulin resistance as a surrogate marker has received little attention over the decades. Another reason may be that since fasting insulin correlates poorly with obesity (i.e. the calorie hypothesis), the American Diabetes Association eschews its use. In contrast, good old-fashioned lifestyle interventions can significantly reduce insulin resistance, CVD, and mortality.
Excessive consumption of refined carbohydrates (especially sugar) and the resultant glycaemic load can overwhelm hepatic mechanisms that regulate the body’s blood glucose levels[35]. Evidence surrounding the use of low carbohydrate, high fat diets for the prevention and treatment of CVD, type 2 diabetes, and obesity is accumulating[36]. Unfortunately, other than Brazil, there has been little change to any nation’s dietary guidelines, which continue to recommend a low fat diet, which often results in diets high in refined carbohydrates (especially sugar).
Furthermore, dietary guidelines (as well as a recent presidential advisory by the American Heart Association) recommend replacing saturated fat with unsaturated fat in order to reduce LDL-C[37]. In practice, this translates to recommending vegetable oils and margarines rich in omega-6 polyunsaturated fatty acids (PUFA). Hence, the consumption of omega-6 PUFA has skyrocketed in recent decades and dwarfed the intake of omega-3 PUFA.
In traditional societies, the ratio of omega-6 to omega-3 polyunsaturated fatty acids was 1:1[38]. This came about due to diets rich in fish, plant foods and free-grazing animals, and eggs from chickens that ate plants high in omega-3 fats. But now in industrialised countries, the dietary ratio is closer to 20:1. This is a more ‘pro-inflammatory’ mix of PUFAs and may contribute to worsening of inflammatory atherosclerotic plaques. The benefits of the Mediterranean diet have been attributed to its high alpha-linolenic acid (omega-3) and polyphenol content present in nuts, extra virgin olive oil, vegetables and oily fish, which act to dampen the inflammatory response. What little carbohydrate there is exists along with its inherent fibre, thus reducing glycaemic load, liver fat, and insulin response.
Furthermore, even minimal exercise can help to reverse insulin resistance. A recent article stated that regular brisk walking, just 30 minutes per day more than three times per week, can reverse insulin resistance[39], while another study suggested that just 15 minutes of moderate-intensity exercise per day can increase lifespan by 3 years[40].
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