Effects of exercise and statins on lipid profile and glycemic control

Resumen

Background. Metabolic syndrome (MetS) is a cluster of related risk factors that include abdominal obesity, hypertension, fasting hyperglycemia, and dyslipidemia (high blood triglycerides and low HDL-cholesterol). The MetS increase the risk for cardiovascular diseases (CVD) and all-cause mortality and have become a major public health problem worldwide which prevalence has reached almost 31% of adults in Spain. The alteration in lipid profile is an independent risk factor for CVD. Among the 5 components of MetS, atherogenic dyslipidemia (i.e., high fasting blood triglycerides [TG] and low-density lipoprotein-cholesterol [LDL] with low high-density lipoprotein-cholesterol [HDL]) is a major risk factor for the development of CVD. Statins (3-hydroxy-methylglutaryl-coenzyme A reductase inhibitors) are the first-choice treatment for hypercholesterolemia. This group of drugs acts by blocking the pathway of endogenous synthesis of cholesterol in the liver. In addition, it can act by improving other components of the lipid profile such as triglycerides. Statins are highly effective, and generally well tolerated, except for rare cases of myalgia. In recent years, other adverse effects of statins have been studied, such as the impairment of glycemic control or the limitation of fat oxidation. However, knowledge of these pleiotropic and side effects is limited. The first-line defense against MetS, and other cardiometabolic diseases is lifestyle modifications, which most often co-exist with pharmacological treatment. Healthy lifestyle modifications, including weight management, regular physical activity, a balanced diet, and stress relief play a crucial role in preventing cardiovascular risk. Within lifestyle modifications, increased physical activity and undergoing an aerobic exercise training program are effective means of improving the blood lipid profile in subjects with MetS. There are several modes of aerobic exercise training (i.e., continuous, interval), which vary in intensity and duration, factors that can markedly affect the mobilization and oxidations of lipids and carbohydrates as fuels. Purpose. This dissertation encompasses eight studies, to address the possible synergies between two therapies, pharmacological (i.e., statin) and non-pharmacological (i.e., exercise), on promoting metabolic health of dyslipidemic, abdominally obese individuals with MetS and high CVD risk. First, we addressed the long-term statin effects on lipid profile and glycemic control in a fasting and postprandial situation by reviewing the literature. We intervened these individuals with a bout of aerobic exercise (different modalities) or discontinue their statin therapy, to study the metabolic interactions between exercise and statins. Finally, we also studied if aerobic exercise training (4-month program) adaptations are influenced by statin therapy. Main findings. The high level of triglycerides in the postprandial state is an independent predictor for the development of coronary artery disease. Treatment with statins or with a bout of prior exercise are both effective in lowering postprandial triglyceride levels. In study 1 using the available literature (i.e., metanalysis) we compared the effects of statins to the effects of aerobic exercise on fasting and postprandial triglyceride levels in individuals with CVD risk. The results suggest that both statins and exercise induce a reduction in plasma triglyceride concentrations. The effects were observed in fasting as well as in postprandial levels. However, the effects of exercise were of less magnitude than the effect of statins, and thus, expecting exercise to reduce blood triglyceride to the desired levels in patients with severe hyperlipidemia may be unrealistic. Nevertheless, exercise may be a useful coadjutant therapy. After reviewing the literature in study 1, it became apparent that statins and exercise could have additive effects on lowering postprandial triglyceridemia. In study 2, we aimed to determine if the combination of exercise and statin could normalize postprandial hypertriglyceridemia in MetS individuals. MetS participants were resistant to the exercise effects. We observed that statins were effective in lowering postprandial triglyceridemia, apparently by reducing intestinal chylomicron formation as suggested by a reduction in blood apolipoprotein B48 levels. However, we could not detect a measurable effect of a bout of increasing intensity exercise on lowering postprandial hypertriglyceridemia in MetS individuals. In the third study, we turned our view to the effects of statins on glycemic control. The most recent meta-analysis on the effects of different statin types on promoting insulin resistance was published more than a decade ago. Since then, some papers have reported no effects of statin on insulin resistance, and one study using pravastatin reports a lowering of insulin resistance. In study 3 we compiled all the current information about the diabetogenic effect of statins and analyze it using metanalysis. We segregated studies by statins type, the index used to assess diabetes (i.e., HOMA-IR or HbA1c), and by subject’s glycemic profile (i.e., diabetic vs normoglycemic subjects). Statin treatment increased insulin resistance and worsens glycemic control, regardless of the glycemic profile of the individual at the beginning of the intervention. In general, the statin type or dosage prescribed did not seem to modify this effect. The association between the use of statins and incident diabetes is still puzzling and may prevent the prescription of this anti-atherogenic medicine to patients at risk of developing diabetes (i.e., MetS). It is then crucial to establish if this side-effect of statins is relevant in a MetS sample of individuals at risk of developing diabetes. In study 4 we evaluated whether withdrawal of statin therapy reduces insulin resistance in MetS individuals. We hypothesized that if statins are promoting insulin resistance its withdrawal would delete those effects. Statin withdrawal had no effect on our insulin resistance index (ISIMATSUDA; OGTT). Our data suggested that the pre-diabetes that accompanies the MetS does not seem to be induced by taking statins. More importantly by combining statins with a bout of exercise, we found that statin prescription does not interfere with exercise improvements in the glycemic response to a meal. Statins and exercise are effective in reducing postprandial hypertriglyceridemia after a high-fat meal, but their coordinated actions are not clear. On the other hand, statins could reduce insulin sensitivity, while an exercise bout could compensate for this side effect. In study 5, we used stable isotopic tracer to assess the interaction between statins and a single bout of continuous exercise on postprandial plasma glucose turnover and fat oxidation in individuals with MetS. We found that statins effectively reduce triglyceride levels after a mixed meal without affecting plasma glucose turnover. On the other hand, exercise improves postprandial lipolysis and fat oxidation compensating the inhibition of lipolysis by statins. The combination of both interventions efficiently improves postprandial fat metabolism in this population. Low and moderate exercise intensity is mainly fuelled by fat oxidation while carbohydrates became the main fuel during moderately high and high exercise intensities. Individuals with MetS may have blunted exercise stimulation to mobilize and oxidize fat during low-intensity exercise or to mobilize and oxidize carbohydrates during high intensity exercise. Those metabolic limitations may explain their resistance to lower blood glucose and triglycerides with exercise training. In study 6 we assessed the effects of MetS on exercise fuel utilization using in wide range of exercise intensities (25-85% V̇O2MAX). The main finding was that despite all metabolic dysregulations of the MetS at rest, during low-intensity aerobic exercise, lipolysis, endogenous glucose production, and the oxidation of fat and carbohydrates were comparable to healthy-young individuals. The ability to oxidize fat during submaximal exercise inversely correlates with CVD risk. However, the literature is not abundant regarding the role of statins in substrate utilization during moderate-intensity continuous exercise. In study 7 we aimed to stablish if statins affect the capacity to mobilize and oxidize fat during continuous aerobic exercise in MetS individuals. Our results showed that chronic statin treatment did not affect whole-body fat oxidation or circulating substrates during 75 minutes of low-intensity continuous exercise (equivalent to brisk walking). Statin treatment seems to blunt the effects of aerobic exercise training on promoting cardiorespiratory fitness and skeletal muscle mitochondrial content. However, it is unclear if statin limits the higher reliance on fat oxidation as fuel after training that permits individuals to use exercise to efficiently lose body fat. The purpose of study 8 was to determine if long-term statin use in dyslipidemic individuals limits the increases in exercise rates of fat oxidation, typically observed after an aerobic exercise-training program. We found that before training, exercise fat oxidation is blunted by statin treatment. However, exercise training drives fat oxidation rates to improve similarly to individuals not taking statins.