Once the diagnosis of MetS is made, aggressive interventions should be adopted that in the form of lifestyle changes, pharmacology, or procedures.
In early MetS, when the severity of component risks are mild, lifestyle interventions should be implemented that minimize refined carbohydrates, avoid processed foods; favor meats that are lean; and contain large amounts of fruits, vegetables, and fish. Debate continues over the ideal diet, but beneficial dietary pattern examples include the Mediterranean diet, the New Nordic diet, the Dietary Approaches to Stop Hypertension (DASH) diet, and the Ornish diet. The use of very low carbohydrate diets, such as the Atkins diet, can also be considered. The most important consideration for dietary intervention is the ability of the individual to maintain this new lifestyle over the long term.89
The relatively low prevalence of atherosclerotic disease in the Mediterranean region prompted interest in the metabolic health benefits of the local diet.90 There are many types of Mediterranean diets with varying degrees of pork, meat, and wine consumption, depending on the region and specific culture. The key features of this general lifestyle are subject to debate but likely to include a high polyphenol content, a diversity of fruits and vegetables, and healthy protein sources.91
Numerous observational studies demonstrate reduced rates of obesity, T2D, and CVD in people consuming a Mediterranean diet.91 In a large randomized controlled trial, subjects assigned to the Mediterranean diet had the greatest weight loss, as well as significant reduction in LDL, triglycerides, fasting serum glucose, and fasting plasma insulin levels, compared to subjects assigned to a very low carbohydrate diet or a low-fat diet.92 In another randomized trial, individuals on the Mediterranean diet demonstrated a 30% reduction in cardiovascular events and cardiovascular mortality over 6 years, compared to subjects assigned a low-fat diet.93 Additionally, there was a 30% reduction in the incidence of T2D among subjects on the Mediterranean diet in this trial.94
The content of the Mediterranean diet provides a nutritional basis that addresses many of the molecular mechanisms of MetS. Approximately 30% of calories are derived from carbohydrates in the form of whole grains and fruits, which are high in fiber and in polyphenols. At least three to four fruits are consumed daily. Additionally, three to four servings of vegetables are consumed daily. These are comparable to the recommended fruit and vegetable intake given by the Institute of Medicine, which suggests six to eight total servings daily.95
Another 35% to 40% of the total calories of the Mediterranean diet are in the form of fats and oils. Sources include high amounts of olive oil, nuts, cheese, poultry, and fish. These foods are generally rich in n-3 fatty acid content and low in saturated fats. There is a low content of red meat and minimal amounts of refined grains and simple sugars.
A moderate amount of wine consumption is included in most of the Mediterranean diets, which may provide metabolic benefits. A recent randomized trial demonstrated improved fasting blood glucose, reduced fasting insulin, and increased HDL levels in subjects already on the Mediterranean diet that were provided red wine with dinner.96 These benefits, possibly related to the higher polyphenol content in red wine, were not observed in individuals provided white wine or water. Many other small trials corroborate these results that moderate red wine consumption, defined as zero to one servings of wine daily for women and one to two servings daily for men, may confer clinical benefits in obesity and MetS.95,97
The Ornish and New Nordic diets are similar to the Mediterranean diet in that they contain high amounts of fruits, vegetables, legumes, and nuts, with minor differences in animal and fish protein sources. A recent large randomized study demonstrates that after 6 months of follow-up, subjects with obesity assigned the New Nordic diet had greater weight loss, reduced fasting serum glucose by 5 mg/dL, reduced fasting insulin, and reduced fasting triglyceride levels by 18 mg/dL, compared to those assigned a western diet.98 Studies of the Ornish diet are limited in that they are observational in nature. Still, cohort studies of subjects on the Ornish diet demonstrate reduced fasting glucose and hemoglobin A1c levels, as well as reduced total LDL content and shifts to larger LDL particle size.99,100
Although they are not approved by the US Food and Drug Administration, several agents that improve glucose metabolism and potentially reduce insulin resistance are effective treatments for people with MetS. In the Diabetes Prevention Program, the use of metformin reduced the incidence of T2D by 27% in subjects with insulin resistance and increased BMI.31 In comparison studies focusing specifically on people with MetS, the use of metformin is similar in efficacy to intensive lifestyle interventions and has been shown to reduce weight, fasting serum glucose, triglyceride, and LDL levels.101 In people taking antipsychotic medication, metformin has been shown to protect against obesity and MetS, with greater efficacy than lifestyle changes alone.102 Through effects on glucose and lipid metabolism within the liver, metformin can improve hepatosteatosis that is commonly present in people with MetS.103 Metformin use is also associated with reduced TNFα and increased adiponectin levels when administered to adolescents with obesity, and it raises endothelial NO production, which mitigates MetS development.104,105 Because of the relative low cost, long history of use, and favorable safety profile, metformin is a first-line agent in the treatment of MetS.
In addition, agents that more directly influence insulin sensitivity can be considered. The GLP-1 receptor analog liraglutide is presently approved for the treatment of obesity and T2D. The class of drugs achieves supraphysiologic plasma GLP-1 activity; serves to supplement the relatively low GLP-1 activity in MetS; and exerts a plurality of beneficial effects, such as improved insulin sensitivity, improved pancreatic β-cell function, activation of central controls of satiety, and reduced hepatic glucose release.106 Together, these effects lead to weight loss and reduced insulin resistance, which can lead to improved outcomes, although direct confirmatory data are lacking.106
Acarbose, an α-glucosidase inhibitor, acts to slow the hydrolysis and absorption of dietary carbohydrates. The use of acarbose in T2D is limited by a relatively low efficacy on serum glucose reduction. However, the preventive use of acarbose in people with obesity and insulin resistance reduces the incidence of T2D by approximately 20%.107 A post-hoc analysis of subjects with MetS included in this study demonstrated a reduction in the incidence of T2D by 38%.107
Pioglitazone and rosiglitazone (thiazolidinediones) activate peroxisome proliferator-activated receptor (PPAR)-γ, which enhances insulin signaling, especially in adipose and muscle tissues. Although these agents have the potential to improve both insulin resistance and lipid profiles in individuals with MetS,108 concerns about their safety and potential for weight gain may limit their utility in MetS.
Inhibitors of sodium glucose cotransporter type 2 have been approved for treatment of T2D. Mechanistically, these agents prevent reuptake of glucose in the proximal collecting tubules, lowering the renal glucose threshold and promoting glucose excretion within urine.109 In addition to minimizing hyperglycemia, these agents induce weight loss, increase GLP-1 levels and may preserve normal pancreatic β-cell function.110 All of these effects would be beneficial in MetS, although studies addressing this specific use have not been conducted. An observed reduction of cardiovascular events with the use of empagliflozin in T2D demonstrates the therapeutic potential for this class of agents.111
Weight Loss Pharmacotherapy
Drugs that are directed specifically for weight loss may also be beneficial in the treatment of MetS. In general, currently available weight-loss agents induce a modest weight reduction of 3% to 5% that is maintained over 1 to 2 years of follow-up.112,113 Lorcaserin reduces appetite through modulation of serotonin receptors within the hypothalamus.112 The combination of phentermine and topiramate also reduces appetite, although there are concerns for use in patients with underlying CVD resulting from tachycardia induced by phentermine.113 The combination of Wellbutrin and naltrexone affects both appetite regulation and reward pathways. These agents demonstrate similar degrees of modest weight reduction, although to date, improvements in cardiovascular events and other outcomes have not been demonstrated.
The use of orlistat, a pancreatic lipase inhibitor, may also be beneficial in MetS because of effects of modest weight loss and decreased lipid absorption. Clinical trials of orlistat demonstrate reduced fasting glucose levels, triglycerides, and blood pressure, as well as improvements in hepatosteatosis.114 These benefits should be weighed against the potential adverse effect of loose bowel movements and malabsorption of fat-soluble vitamins.115
Rapid development of novel therapeutic agents for the treatment of obesity continues. Potential targets include ghrelin inhibition, peptide YY analogs, and inhibition of the Dyrk family of proteins involved in the nutrient-sensing cascade.116
The treatment target for hypertension with MetS should be a systolic blood pressure of 120 mm Hg or less.117 Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers demonstrate the greatest protection from atherosclerotic and renal disease and may be protective against the development of T2D.87 Agents from either of these classes should be considered as first-line therapy for hypertension in the setting of MetS.118
Treatment targets for hyperlipidemia with MetS should involve lowering LDL cholesterol (< 100 mg/dL)1,4 while also addressing severe hypertriglyceridemia. The LDL reduction achieved by statin therapy significantly reduces cardiovascular risk in MetS. PCSK-9 inhibitors are presently approved for individuals with familial hypercholesterolemia or those with atherosclerotic disease unable to achieve therapeutic targets with statins. Ezetimibe can be considered as an adjunct to statin therapy, although its LDL-lowering effect is only modest in comparison.
Colesevelam deserves special attention in the case of MetS. This bile acid sequestrant lowers LDL cholesterol by approximately 18% and slows dietary carbohydrate absorption, which lowers serum glucose levels and insulin requirements.119 Several randomized trials demonstrate reduced incidence of T2D with the use of colesevelam.120,121 In a trial of men with MetS already taking statins, colesevelam treatment increased insulin sensitivity and reduced fasting serum glucose by 6 mg/dL, postprandial serum glucose by 17 mg/dL, and LDL cholesterol by 22 mg/dL.119
Treatment of hypertriglyceridemia is also beneficial. Several large trials suggest pharmacologic intervention in individuals with triglyceride levels greater than approximately 200 mg/dL and HDL levels less than approximately 35 mg/dL can reduce the risk of cardiovascular events.122,123,124 Fibrate medications reduce circulating triglycerides through activation of PPAR-α, which increases lipoprotein lipase activity and reduces hepatic triglyceride synthesis. Administration of concentrated long-chain n-3 fatty acids can also reduce hypertriglyceridemia. However, preventive cardiovascular effects of long-chain n-3 supplementation are not consistently demonstrated in clinical trials.125,126,127
Several surgical and nonsurgical procedures have been developed and approved for the treatment of obesity, but they also mitigate the severity of MetS components. Approved bariatric surgical procedures include the Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), biliopancreatic diversion with or without duodenal switch (BPD), and laparoscopic gastric banding (LGB). Approved nonsurgical procedures include the insertion of a gastric balloon or a duodenal sleeve (endoluminal barrier).128 Other nonsurgical procedures are being tested and hold promise, including vagal nerve stimulation.129
Surgically induced changes in the gastrointestinal tract affect energy physiology, insulin resistance, hypertension, hyperlipidemia, and other weight-related complications.130 Additionally, many of the factors contributing to MetS improve and the risk of cardiovascular events and mortality is reduced.131 In people undergoing RYGB, SG, or BPD, insulin resistance improves in the immediate postoperative period, signifying the predominance of improved energy regulatory hormone signaling well before weight loss occurs.132 Following LGB, insulin resistance declines in association with weight loss.132 The significant improvement and possible resolution of T2D is also substantially higher following RYGB, SG, and BPD, when compared to LGB.133,134,135 These observations suggest that the metabolic benefits of RYGB, SG, and BPD may confer additional improvement to people with MetS.
At present, bariatric surgery is approved for people with BMI of (1) at least 40 kg/m2 or (2) at least 35 kg/m2 in the presence of T2D, CVD, or other weight-related complications. Special consideration should be given to people with obesity and MetS, in whom bariatric surgical procedures can drastically alter their risk of atherosclerotic disease and T2D.136 In the case of people with MetS and mild obesity, defined as a BMI ranging from 30 to 35 kg/m2 (or just over the BMI cutoff for Asians), clinical evidence is mounting for reduction in the incidence of T2D following bariatric surgery.137
Evidence for the reduction in atherosclerotic risk or improvement in components of MetS would be expected at the levels of weight loss associated with nonsurgical procedures for obesity. Specifically, results from current published trials demonstrate reductions in hemoglobin A1C (0.4%–1.6%), LDL, triglycerides, and blood pressure following endoscopic bariatric procedures or gastric electrical stimulation.128,129