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10-24-2014 | Metabolic syndrome | Review | Article

Pharmacological treatment and therapeutic perspectives of metabolic syndrome

Journal:
Reviews in Endocrine and Metabolic Disorders

Authors: Soo Lim, Robert H. Eckel

Publisher: Springer US

Abstract

Metabolic syndrome is a disorder based on insulin resistance. Metabolic syndrome is diagnosed by a co-occurrence of three out of five of the following medical conditions: abdominal obesity, elevated blood pressures, elevated glucose, high triglycerides, and low high-density lipoprotein-cholesterol (HDL-C) levels. Clinical implication of metabolic syndrome is that it increases the risk of developing type 2 diabetes and cardiovascular diseases. Prevalence of the metabolic syndrome has increased globally, particularly in the last decade, to the point of being regarded as an epidemic. The prevalence of metabolic syndrome in the USA is estimated to be 34 % of adult population. Moreover, increasing rate of metabolic syndrome in developing countries is dramatic. One can speculate that metabolic syndrome is going to induce huge impact on our lives. The metabolic syndrome cannot be treated with a single agent, since it is a multifaceted health problem. A healthy lifestyle including weight reduction is likely most effective in controlling metabolic syndrome. However, it is difficult to initiate and maintain healthy lifestyles, and in particular, with the recidivism of obesity in most patients who lose weight. Next, pharmacological agents that deal with obesity, diabetes, hypertension, and dyslipidemia can be used singly or in combination: anti-obesity drugs, thiazolidinediones, metformin, statins, fibrates, renin-angiotensin system blockers, glucagon like peptide-1 agonists, sodium glucose transporter-2 inhibitors, and some antiplatelet agents such as cilostazol. These drugs have not only their own pharmacologic targets on individual components of metabolic syndrome but some other properties may prove beneficial, i.e. anti-inflammatory and anti-oxidative. This review will describe pathophysiologic features of metabolic syndrome and pharmacologic agents for the treatment of metabolic syndrome, which are currently available.

1 Introduction

The metabolic syndrome is a constellation of cardiovascular and metabolic risk factors including abdominal obesity, hyperglycemia, dyslipidemia, and high blood pressure which predispose the subject to developing type 2 diabetes and cardiovascular disease (CVD) [ 1]. The prevalence of metabolic syndrome is increasing worldwide. According to data from the National Health and Nutrition Examination Survey (NHANES) III and NHANESs 1999–2006, the age-adjusted prevalence of metabolic syndrome increased from 29.2 to 34.2 % in the US [ 2]. More than 40 million US adults seem to be affected by the condition [ 3]. This increasing trend has been also observed in other regions such as Latin American and Asian countries [ 46], presenting a major challenge for public health professionals as well as becoming a social and economic problem in the near future.
Since World Health Organization (WHO) proposed a working definition for metabolic syndrome in 1998, several definitions have been proposed for clinical diagnosis of the metabolic syndrome (Table  1). Fundamentally, metabolic syndrome is associated with increased adipose tissue or adipose tissue distribution. In particular, abdominal visceral fat produces more pro-inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) [ 12, 13], which are linked to insulin resistance and additional biomarkers of systemic inflammation, i.e. hsCRP. Metabolic syndrome in cooperation with low grade inflammation contributes to increased risk of developing diabetes and CVD [ 14] and furthermore all-cause mortality [ 15].
Table 1
Criteria proposed for clinical diagnosis of the metabolic syndrome
 
WHO (1998)
AACE (2003)
NCEP-ATPIII (2005)
IDF (2005)
IDF;NHLBI;AHA;WHF;IAS;IASO Harmonizing definition (2009)
Reference
[ 7]
[ 8]
[ 9]
[ 10]
[ 11]
Requirement
IGT, IFG, T2D, or lowered insulin sensitivity a plus any 2 of the following
IGT or IFG plus any of the following based on clinical judgment
Any 3 of the following 5 features
Increased WC plus any 2 of the following
Three out of 5 would qualify a person for the metabolic syndrome
Obesity
Men: WHR >0.90; Women: WHR >0.85 and/or BMI >30 kg/m 2
BMI ≥25 kg/m 2
WC ≥102 cm in men or ≥88 cm in women
Population-specific increased WC
Population- and country-specific WC cutoffs b
Triglycerides (TG)
TG ≥150 mg/dl
TG ≥150 mg/dl
TG ≥150 mg/dl or on TG lowering Rx
TG ≥150 mg/dl or on TG lowering Rx
TG ≥150 mg/dl c
HDL-cholesterol (HDL-C)
HDL-C <40 mg/dl in men or HDL-C <50 mg/dl in women
HDL-C <40 mg/dl in men or HDL-C <50 mg/dl in women
HDL-C <40 mg/dl in men or HDL-C <50 mg/dl in women on HDL-C increasing Rx
HDL-C <40 mg/dl in men or HDL-C <50 mg/dl in women on HDL-C increasing Rx
HDL-C <40 mg/dl in men or HDL-C <50 mg/dl in women b
Blood pressure
≥140/90 mmHg
≥130/85 mmHg
≥130/85 mmHg or on antihypertensive Rx
≥130/85 mmHg or on antihypertensive Rx
≥130/85 mmHg or on antihypertensive Rx
Glucose
IGT, IFG, or T2D
IGT or lFG (but not diabetes)
≥100 mg/dl (includes diabetes)
≥100 mg/dl (includes diabetes)
≥100 mg/dL d
WHO World Health Organization, NCEP-ATP III National Cholesterol Education Program-Adult Treatment Panel III, AACE American Association of Clinical Endocrinologists, IDF International Diabetes Federation, NHLBI National Heart, Lung, and Blood Institute, AHA American Heart Association, WHF World Heart Federation, IAS International Atherosclerosis Society, IASO International Association for the Study of Obesity, T2D type 2 diabetes, IGT impaired glucose tolerance, IFG impaired fasting glucose, WHR waist-to-hip ratio, WC waist circumference, BMI body mass index, TG triglycerides, HDL-C HDL-cholesterol, Rx therapy
aInsulin sensitivity measured under hyperinsulinemic-euglycemic conditions
bThe IDF cut points are recommended for non-Europeans and either the IDF or AHA/NHLBI cut points used for people of European origin until more data are available
cThe most commonly used drugs for elevated triglycerides and reduced HDL-C are fibrates and nicotinic acid. A patient taking 1 of these drugs can be presumed to have high triglycerides and low HDL-C. High-dose ω-3 fatty acids presumes high triglycerides
dMost patients with type 2 diabetes mellitus will have the metabolic syndrome by the proposed criteria
Since the impact of metabolic syndrome on health is enormous, much effort has been made to find optimal therapeutic agents. Currently, the best therapeutic approach for the metabolic syndrome is lifestyle modification including weight loss. However, pharmacological treatments are often needed in people with metabolic syndrome, due to the great difficulty for patients to take measures to change their lifestyle permanently. In people having diseases related to metabolic syndrome, a more broad-based pharmacological agent that modifies insulin resistance may be a good initial choice, i.e., thiazolidinedione (TZD) for diabetic patients with metabolic syndrome. Based on this concept, the treatment of the metabolic syndrome can be approached from very different angles, since each individual may have a different multifaceted health problem (Fig.  1).
In this review, we introduce pathophysiologic features of metabolic syndrome briefly and discuss the potential role of pharmacological agents that can be used focusing on specific component(s).

2 Pathophysiologic features of metabolic syndrome

2.1 Insulin resistance

The major underlying pathophysiology of the metabolic syndrome is insulin resistance. Insulin resistance reflects defects in insulin action in insulin sensitive organs, i.e. adipose tissue, skeletal/cardiac muscle and liver. In adipose tissue, this is a manifested initially as defects in the anti-lipolytic effects of insulin whereas in muscle the defect is insulin-mediated glucose uptake with subsequent reductions in glycogen biosynthesis. This results from inhibition of insulin-stimulated insulin-receptor substrate (IRS)-1 tyrosine phosphorylation and eventually reduced IRS-1–associated phosphatidyl inositol 3 kinase (PI3K) activity [ 16]. In liver, insulin resistance is manifested by defects in the ability of insulin to suppress glucose production, a defect that relates to maintenance of gluconeogenic enzymes and increased gluconeogenic substrate delivery.
Thus, insulin resistance indicates a pathophysiological condition in which a normal insulin concentration does not adequately produce a normal insulin response in the peripheral target tissues. In this metabolic setting, pancreatic β-cells secrete more insulin, in part to overcome the hyperglycemia and hyperinsulinaemia results. Although hyperinsulinaemia may in part compensate for some insulin resistance, it may contribute to others, i.e. salt retention, hypertension, and hepatic steatosis [ 17]. An inability of β-cells over time to produce sufficient insulin leads to impaired fasting glucose, impaired glucose tolerance and ultimately type 2 diabetes mellitus [ 16].
Insulin resistance commonly accompanies abdominal obesity. Although insulin-resistant individuals do not need to be obese, they almost always have preferential fat accumulation in the visceral depot. This is of particular interest in that ordinarily adipocytes obtained from visceral adipose tissue are much less insulin responsive than adipocytes obtained from subcutaneous depots, and additionally abdominally obese subjects also demonstrate more insulin resistance than subjects in whom excess body fat distribution is less central [ 18]. Some subjects who are not obese may also have insulin resistance associated with ectopic fat accumulation in metabolically active tissues such as liver and muscle [ 19].

2.2 Pro-inflammatory state, oxidative stress, and renin-angiotensin system in metabolic syndrome

Metabolic syndrome is also considered to be a low-grade pro-inflammatory/pro-oxidative state [ 12, 20]. The multicenter Insulin Resistance Atherosclerosis Study had shown a linear relationship between the inflammatory marker high-sensitivity C-reactive protein (hsCRP) and the number of metabolic derangements [ 20]. The large amount of adipose tissue induces systemic inflammation due to an increase of secretory factors derived from adipocytes and macrophages embedded in this tissue [ 21]. In a population-based non-diabetic Swedish cohort, lipoprotein-associated phospholipase A2 was associated with metabolic syndrome, and each component was related to increased risk for incident CVD in a dose-dependent manner [ 22]. Thus, hsCRP is the most well-known biomarker for inflammation related to cardiovascular and metabolic risk [ 23, 24]. Other inflammatory markers such as fibrinogen [ 25], apolipoprotein-B [ 26], uric acid [ 27], and adhesion molecules [ 28] are also known to be associated with metabolic syndrome.
Atherogenic dyslipidemia manifested by high plasma triglycerides and low HDL-C levels, a strong marker for future cardiovascular events, is also associated with inflammation and oxidative stress in the metabolic syndrome [ 29]. HDL function is also affected by pro-inflammatory cytokines and oxidative stress [ 30]. The activation of the renin-angiotensin system (RAS) further promotes inflammation, lipogenesis and reactive oxygen species generation and impairs insulin signaling [ 31]. Consequently, the increase in circulating RAS, for which adipose tissue is partially responsible, represents a link between high blood pressure, insulin resistance, and inflammation.

3 Pharmacological treatment of metabolic syndrome

In addition to lifestyle including weight loss, a targeted approach for control of individual components of the metabolic syndrome is often necessary. Because there are drugs proven effective in reducing specific components of metabolic syndrome, optimal pharmacological management must be individualized.
First, because weight loss in patients with the metabolic syndrome increases insulin sensitivity [ 32], anti-obesity drugs should be considered. In the USA the list includes, phentermine, extended release phentermine/topiratmate, lorcaserin, orlistat, and now sustained release bupropion/naltrexone and the glucagon like peptide-1 (GLP-1) agonist liraglutide. Drugs such as TZD or metformin, which are insulin sensitizers, are recommended for insulin resistant patients. Metformin, rosiglitazone and pioglitazone are known to prevent type 2 diabetes in patients with and without the metabolic syndrome [ 3335] and pioglitazone also increases HDL-C and reduces triglycerides and hepatic steatosis [ 36]. Lipid-lowering agents such as statins are drugs of choice for atherogenic dyslipidemia [ 37]. Most but not all metabolic syndrome patients will be statin-eligible; moreover fibrates may reduce CVD events in patients who are hypertriglyceridemic and have reductions in HDL-C [ 38]. New antidiabetic agents such as GLP-1 agonists and sodium glucose transporter-2 (SGLT-2) inhibitors result in some weight loss and are candidate drugs particularly in metabolic syndrome patients with or at risk for diabetes [ 39, 40]. RAS blockers are effective in decreasing blood pressure and other cardiovascular risk [ 41]. Cilostazol, an antiplatelet agent, is also known to improve atherogenic dyslipidemia and increase nitric oxide levels [ 42]. The mechanism of action, targeted components of metabolic syndrome, additional benefits, and possible side effect of each drug are shown in Table  2.
Table 2
Metabolic syndrome drugs and therapeutic targets in metabolic syndrome, and their side effect
Medications
Mode of action
Main target of metabolic syndrome
Additional benefit
Side effect
Ref.
Lorcaserin
Selective 5-HT 2C agonist
(Abdominal) obesity
TG ↓
Attention deficit or memory problem
[ 43]
LDL-C ↓
Extended release phentermine + topiramate combination
Voltage-dependent sodium channels, glutamate receptors, and carbonic anhydrase, and augments the activity of γ-aminobutyrate
(Abdominal) obesity
Insulin sensitivity ↑
Pulse rate ↑
[ 44]
Sustained release bupropion and naltrexone
Alterations in the hypothalamic melanocortin system and brain reward systems that influence food craving and mood
(Abdominal) obesity
Insulin sensitivity ↑
Nausea
[ 45]
Pulse rate ↑
Blood pressure ↑
Thiazolidinedione
Peroxisome proliferator-activated receptor-γ agonist
High glucose
TG ↓
Fluid retention or weight gain
[ 46]
HDL-C ↑
Bone mineral density ↓
Inflammation ↓
 
Metformin
Increase in AMPK activity
High glucose
Inflammation ↓
Gastrointestinal trouble
 
Lactic acidosis
Statins
HMG-CoA reductase inhibitor
High TG
LDL-C ↓
Glucose ↑
[ 37]
Inflammation ↓
Muscle weakness
Fibrates
Peroxisome proliferator-activated receptor-α agonist
High TG
Inflammation ↓
Muscle side effect combined with statin
[ 47]
Low HDL-C
ACE inhibitors/ARBs
Renin-angiotensin system blockers
High blood pressure
Inflammation ↓
Cough with ACE inhibitor
[ 48]
Insulin sensitivity ↑
GLP-1 agonists
Stimulation of GLP-1 receptor
High glucose
Body weight ↓
Gastrointestinal trouble
[ 49]
Blood pressure ↓
SGLT-2 inhibitors
Inhibition of glucose reabsorption in sodium glucose transporter-2
High glucose
Body weight ↓
Urinary tract and genital infection
[ 50]
Blood pressure ↓
Cilostazol
PDE3 inhibitor
TG ↓
Bleeding tendency
[ 42]
HDL-C ↑
Inflammation ↓
AMPK AMP-activated protein kinase, HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A, ACE angiotensin converting enzyme, ARB angiotensin receptor blocker, GLP-1 glucagon-like peptide-1, SGLT-2 sodium glucose transporter-2, PDE3 phosphodiesterase 3, Ref. reference

3.1 Anti-obesity drugs

Previously, anti-obesity drugs such as sibutramine and orlistat had shown that they reduced body weight and central obesity, resulting in improvement of the components of metabolic syndrome [ 51]. Rimonabant improved glycemic homeostasis and lipid components of metabolic syndrome: increase in HDL-C levels by 23 % and decrease in triglyceride levels by 15 % [ 52, 53]. However, due to adverse effects, many anti-obesity drugs, i.e. sibutramine and rimonabant were withdrawn from the market [ 54]. Phentermine and orlistat remain available; however, several new drugs are now available in the USA and increasingly around the world to consider.

3.1.1 Lorcaserin

Lorcaserin (Belviq®) is approved for its use in obese adults who have high blood pressure, high cholesterol, or type 2 diabetes. In therapeutic doses, lorcaserin acts as a selective 5-HT 2C agonist on pro-opiomelanocortin neurons, which in turn causes release of α-melanocyte-stimulating hormone (α-MSH). Further α-MSH acts on melanocortin 4 receptors in the paraventricular nucleus in the hypothalamus, leading to a decrease in appetite [ 55]. A multicenter, double-blinded study showed 47.5 % in lorcaserin group and 20.3 % in placebo group lost 5 % or more of body weight after 1 year treatment [ 43]. At the end of the second year weight loss was maintained by 67.9 % patients who continued to receive lorcaserin, whereas 50.3 % could maintain weight loss who received placebo [ 43]. Plasma triglycerides and LDL-C levels were significantly lower in the lorcaserin group. These data support that lorcaserin might be beneficial in obese metabolic syndrome subjects with atherogenic dyslipidemia. However, it has been reported that lorcaserin may cause attention deficits and cognitive impairment [ 43, 55]. Other common side effects include headache, dizziness, fatigue, nausea, dry mouth, and constipation [ 55].

3.1.2 Extended release phentermine and topiramate combination

A combination of extended release phentermine and topiramate (Qysmia®) has also been recently approved by the US FDA. Phentermine works by reducing appetite and topiramate by unclear mechanism(s) [ 56]. Topiramate blocks voltage-dependent sodium channels, glutamate receptors, and carbonic anhydrase, and augments the activity of γ-aminobutyrate [ 57]. The combination of extended release phentermine and topiramate is well tolerated and can result in impressive weight reduction despite low doses of each drug that would have minimal effects alone. Target subjects for the drug are obese or overweight people who suffer from conditions such as diabetes, hypertension and/or hypercholesterolemia. Thus, patients with metabolic syndrome would be good candidates. However, there is still a safety concern with this combination such as elevation in blood pressure and pulse rate for phentermine and peripheral neuropathy and possible teratogenic effects for topiramate [ 58].

3.1.3 Sustained release bupropion and naltrexone

The US FDA recently approved sustained release bupropion and naltrexone (Contrave®) in September, 2014. In part this decision was based on the results of CONTRAVE Obesity Research-II (COR-II), a double-blind, placebo-controlled study of 1,496 obese (BMI 30–45 kg/m 2) or overweight (27–45 kg/m 2) patients with dyslipidemia and/or hypertension [ 45]. Treatment of combined naltrexone sustained-release (SR) (32 mg/day) plus bupropion SR (360 mg/day) (NB32) for up to 56 weeks resulted in a greater weight loss than placebo at week 28 (−6.5 % vs. −1.9 %) and week 56 (−6.4 % vs. −1.2 %) (both p < 0.001). In addition, the combination produced greater improvements in various cardiometabolic risk markers. The most common adverse event was nausea, which was generally mild and transient. Although the mechanism of action of the combination of sustained release bupropion and naltrexone for weight reduction has not been fully revealed, the combination may induce alterations in the hypothalamic melanocortin system as well as brain reward systems that influence food craving and mood [ 59].

3.2 Insulin sensitizers

3.2.1 Thiazolidinedione (TZD)

TZD is a synthetic ligand of peroxisome proliferator-activated receptor-γ (PPARγ), which is a member of the nuclear hormone receptor family and contributes to many biological processes such as glucose regulation and lipid metabolism [ 46]. PPARγ is known to regulate expression of the gene encoding prodifferentiation transcription-factor pancreas duodenum homeobox-1 (PDX-1) in pancreatic β-cells [ 60], which regulates glucose-responsive insulin gene transcription as well as the transcription of glucose transporter-2 and glucokinase [ 61, 62]. Many studies demonstrate that TZDs reduce insulin resistance, a core defect in metabolic syndrome, via several mechanisms [ 63]. First, TZDs reduces the intracellular levels of toxic lipid metabolites, resulting in less lipotoxicity [ 64]. TZDs also protect against the cytostatic effect of free fatty acids and restores glucose-mediated insulin release [ 65]. TZDs also increase insulin sensitivity in the liver and muscle tissue [ 66].
In the Actos Now for Prevention of Diabetes (ACT NOW) study, pioglitazone decreased the rate of conversion of subjects with impaired glucose tolerance to type 2 diabetes by 72 % and significantly improved the disposition index [ 35]. In the A Diabetes Outcome Progression Trial (ADOPT) study, rosiglitazone treatment improved insulin sensitivity and prevented decline of β-cell function more than either metformin or sulfonylurea [ 67]. Since TZDs, pioglitazone more than rosiglitazone, improve various features of metabolic syndrome such as hyperglycemia, elevated blood pressure, hypertriglyceridemia, and low HDL-C, TZDs are an useful agent for the treatment of the metabolic syndrome [ 36, 68].
TZDs also decrease inflammatory factors such as hsCRP and promote adipose tissue differentiation in subcutaneous adipose tissue regions, which increases the synthesis of adiponectin, thereby further reducing insulin resistance. TZDs are also known to reduce circulating levels of free fatty acids, resistin, IL-6, TNF-α, and ICAM-1 [ 69, 70]. However, side effects of the TZDs such as fluid retention and weight gain are important to consider. In addition, adverse effects of TZDs on bone health and perhaps bladder cancer, although not yet confirmed, prevent its wide use in clinical practice [ 7173].

3.2.2 Metformin

Metformin increases AMP-activated protein kinase (AMPK) activity, a pharmacological target for the treatment of insulin resistance. Metformin is a biguanide and is recommended as a first line drug for type 2 diabetes by the American Diabetes Association and European Association for the Study of Diabetes guidelines [ 74]. Recent evidence indicates that metformin can also have antidiabetic activity through mediation of a family of proteins known as sirtuins, a type of histone deacetylases controlling cellular metabolism through regulation of the expression of several genes [ 75]. Metformin also has modest anti-inflammatory properties [ 76]. Because metformin like TZDs reduces the incidence of new onset diabetes in individuals with metabolic syndrome, it should be seriously considered in metabolic syndrome subjects with impaired fasting glucose or impaired glucose tolerance (prediabetes).

3.3 Lipid lowering agents

Statin, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and fibrate, a PPARα agonist, are good candidates for pharmacologic agents for metabolic syndrome with dyslipidemia. A combination of statins and fibrates can be recommended to control atherogenic dyslipidemia in metabolic syndrome.

3.3.1 Statins

Statins are competitive inhibitors of HMG-CoA reductase, blocking the rate-limiting step in cholesterol biosynthesis [ 77]. Hence, statins are effective in reducing circulating total and LDL-C levels. Of interest, however, is that the lowering of LDL-C is not via a reduction in LDL-C synthesis that occurs via lipoprotein lipase-mediated hydrolysis of VLDL, but by reducing the intrahepatic cholesterol pool size and increasing LDL receptors [ 78, 79].
Much evidence has proven that statin therapy significantly and substantially reduces cardiovascular risk [ 79]. Many prospective, randomized trials such as the COmparative study with rosuvastatin in subjects with METabolic Syndrome (COMETS) and the Measuring Effective Reductions in Cholesterol Using Rosuvastatin TherapY I (MERCURY I) trial showed that statins improved atherogenic dyslipidemia in people with metabolic syndrome [ 8082]. In a meta-analysis from 27 randomised trials, statin therapy in people at low risk of vascular disease was also effective in reducing CVD [ 83]. Although the use of statins for the primary prevention in subjects with a low CVD risk remains suspensive in its cost-effectiveness [ 84], statin treatment has demonstrated consistently a significant reduction in cardiovascular and all-cause mortality in people at high risk of CVD [ 37, 85, 86].
Independently of their action upon cholesterol; statins diminish oxidative stress and improve endothelial function [ 87]. Statins also have anti-inflammatory properties by inhibition of isoprenoid (farnesyl or geranyl) formation and blockage of the activation of the Rho and Rac pathways which are involved in the activation of Nuclear Factor(NF)-κB as well as direct inhibition of the NF-κB activation [ 88]. With these beneficial effects on other cardiovascular risk as well as lipid-lowering property, statins are recommended as the cornerstone of treatment of dyslipidemia in most patients with metabolic syndrome. The risk estimator developed by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines can be utilized to estimate risk in patients with the metabolic syndrome without known CVD [ 89].
Recently, several meta-analyses of randomized controlled trials have suggested more insulin resistance following statin treatment [ 90, 91]. The mechanisms by which statins aggravate insulin resistance have not been fully elucidated. However, statins may decrease the production of metabolites of HMG-CoA, such as isoprenoids, which thereupon down regulate insulin-responsive glucose transporter (GLUT)-4, thereby decreasing glucose uptake [ 92]. This pharmacological effect has been documented for simvastatin and atorvastatin [ 92, 93]. In patients with prediabetes, this mechanism could be important in the transition from prediabetes to diabetes [ 94]. Another mechanism could be the recently described weight gain seen in statin-treated patients [ 95]. It would be prudent that the risk of deteriorating insulin sensitivity and weight gain in statin-treated patients be balanced with the more substantial benefits in reducing cardiovascular risks [ 96].

3.3.2 Fibrates

Fibrates are PPARα activators and useful for the treatment of dyslipidemia, particularly for patients with hypertriglyceridemia and low levels of HDL-C [ 47]. Fibrates also diminish circulating levels of fibrinogen, IL-1, IL-6, and hsCRP, leading to reduction of NF-κB and improvement of vascular function [ 47]. In the FEILD study, fenofibrate treatment reduced cardiovascular outcomes by 27 % in subjects with hypertriglyceridemia and low HDL-cholesterol, although it did not significantly reduce the risk of the primary outcome of coronary events [ 97]. Most studies have shown that fibrates reduce triglycerides levels by 30–45 % [ 98, 99] and increase HDL-C by up to 25 % but most often by <10 % [ 100]. Fenofibrate also decreased fibrinolysis inhibitor concentrations and improved endothelial function in metabolic syndrome patients, suggesting another potential mechanism for protection against CVD [ 101].
In some patients, the treatment for atherogenic dyslipidemia requires two drugs with different targets. Statin and fibrate combination is a good combination for treatment of lipid components and CVD risk in metabolic syndrome patients [ 102].

3.4 RAS blockers

There is an important relationship of RAS with insulin resistance and endothelial dysfunction, which are found in people with metabolic syndrome and obesity-related hypertension [ 103, 104]. Angiotensin II inhibits insulin signaling and produces oxidative stress that accelerates hyperglycemia and atherosclerosis [ 105]. Therefore, blockers of the RAS are an important component of therapeutic agents for metabolic syndrome. There are two types of RAS blockers: angiotensin converting enzyme (ACE) inhibitor and angiotensin-II receptor blocker (ARB).
Enalapril, an ACE inhibitor, is hydrolyzed to the active form enalaprilat, which reduces the plasma levels of angiotensin-II, leading to a decrease in blood pressure by peripheral vasodilatation [ 48]. Ramipril, another ACE inhibitor, proved cardiovascular benefit in a large clinical trial [ 106]. A fixed-dose combination of perindopril with indapamide showed substantial protection against cardiovascular morbidity and mortality [ 107]. ARBs are also known to exert blood pressure lowering by reducing the secretion of vasopressin and aldosterone [ 108].
Angiotensin-II also has a central role in glucose metabolism that includes activation of insulin-stimulated mitogenic pathways that promote vascular smooth muscle proliferation via mitogen-activated protein kinase (MAPK), but suppression of pathways involved in glucose transport such as PI-3 K [ 109]. The beneficial effect of ACE inhibitors on glucose metabolism is demonstrated by clinical trials such as the HOPE (Heart Outcomes Prevention Evaluation) Study, which showed a reduced rate of new onset diabetes mellitus in patients taking the ACE inhibitor ramipril [ 110] although this effect has been variable [ 111]. ARBs also have insulin sensitizing and antidiabetic effects, induce PPARγ activity and reduce serum uric acid levels [ 112].
ACE inhibitors also have anti-inflammatory effects, pleiotropic actions of the drugs that are not related with ACE itself. ACE inhibitors increase the synthesis of adiponectin [ 113]. Furthermore, ACE inhibitors reduce oxidative stress and endothelial dysfunction particularly in subjects with depressed cardiac function [ 114]. ARBs also have anti-inflammatory effects: reduction of circulating levels of IL-6 and TNF-α [ 115] and decrease in hsCRP and ICAM-1 levels [ 116]. ARBs have good tolerability and safety profile, which have been reported to be similar to placebo [ 117]. A recent analysis with Cardiovascular Health Study showed that RAS blocking agents reduced cardiovascular events in patients with metabolic syndrome [ 118]. Thus, RAS blockers are indicated for the treatment of elevated blood pressure in people with metabolic syndrome.

3.5 Novel antidiabetic agents

3.5.1 Glucagon like peptide-1 (GLP-1) agonists

GLP-1 agonists are an incretin-based therapy, which is derived from the concept that ingested glucose results in a greater increase in insulin secretion compared with intravenous glucose administration. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), two intestinal-derived hormones, stimulate insulin secretion in pancreatic β-cells [ 49]. In addition, GLP-1 infusion has been shown to inhibit glucagon secretion, slow gastric emptying, and reduce food intake [ 119, 120]. Endogenous GLP-1 is rapidly inactivated by dipeptidyl peptidase-4 enzyme. To overcome this rapid inactivation of native GLP-1, synthetic GLP-1 receptor agonists with prolonged action profiles have been developed for treatment of patients with type 2 diabetes [ 121].
GLP-1 agonists improve hyperglycemia by enhancing glucose-stimulated insulin secretion through activation of cyclic adenosine monophosphate (cAMP). Increased cAMP upregulates protein kinase A (PKA) and exchange protein activated by cAMP, which leads to rapid increases in intracellular calcium and insulin exocytosis in a glucose-dependent manner [ 122, 123]. Moreover, GLP-1 agonists have the potential to reduce insulin resistance which helps reverse insulin resistance-associated defects in the failing β-cells. GLP-1 is also known to attenuate endoplasmic reticulum stress via activation of PKA [ 124].
Specifically, among GLP-1 agonists, liraglutide 3 mg (Saxenda®) has been approved by the US FDA as an antiobesity drug. In addition to stimulation of insulin release and decrease of glucagon secretion in response to hyperglycemia, liraglutide at higher doses, i.e. 3 mg, has resulted in more weight loss presumably by greater reductions in appetite and energy intake. In a large scale, randomized clinical trial, treatment with liraglutide 3 mg induced sustained weight loss by 7.2 kg over 20 weeks, reduced blood pressure, and improved glycemic control [ 125]. Despite the higher dose, liraglutide was reasonably well tolerated with gastrointestinal side effects being most commonly encountered. Thus, liraglutide 3 mg provides a sustainable weight loss and improvement of several metabolic syndrome-related comorbidities. In summary, GLP-1 agonists seem to be a good candidate drug class for metabolic syndrome subjects with hyperglycemia and overweight/obesity since it enhances insulin sensitivity and reduces body weight as well as increases insulin secretory function.

3.5.2 Sodium glucose transporter-2 (SGLT-2) inhibitors

The kidney plays an important role in glucose homeostasis by mediating reabsorption of glucose from the glomerular filtrate, which happens through SGLT-2 and SGLT-1 [ 50]. SGLT-2 inhibitors block 90 % of reabsorption of filtered glucose in the proximal tubules, leading to increased urinary glucose excretion, which eventually reduces hyperglycemia [ 126]. In 2013–2014, the US FDA approved three drugs in this class: canagliflozin, empagliflozin, and dapagliflozin as antidiabetic medications. In addition to glucose lowering efficacy [ 127, 128], SGLT-2 inhibitors result in loss of calories and weight loss [ 129]. In fact, treatment with dapagliflozin and metformin reduced body weight by 5 % after 24 weeks [ 40]. Initial weight loss may come from fluid loss, as urinary glucose excretion results in mild osmotic diuresis. But dapagliflozin treatment reduced body weight, predominantly by reducing fat mass [ 40]. This finding suggests that caloric loss from glycosuria, not fluid loss, by SGLT-2 inhibition is mainly responsible for the decrease in body weight and fat mass. SGLT-2 inhibitors also reduced blood pressures by 3–9 mmHg in clinical studies [ 130, 131], which is likely mediated by osmotic diuresis.
SGLT-2 inhibitors have additional benefits in management of metabolic syndrome. Treatment with empagliflozin, another SGLT-2 inhibitor, showed anti-inflammatory effect with a reduction of IL-6, TNF-α, and monocyte chemotactic protein-1 levels in an animal study [ 132]. SGLT-2 inhibitors also affect lipid metabolism. Dapagliflozin treatment increased HDL-C and reduced triglycerides [ 133, 134]. In contrast, canagliflozin treatment increased HDL-C and LDL-C, and resulted in inconsistent changes in triglycerides [ 135]. SGLT-2 inhibitors also reduced serum uric acid levels by approximately 1 mg/dL [ 127, 131]. Hyperuricemia is related to insulin resistance and some consider this a component of metabolic syndrome.
Based on these data, SGLT-2 inhibitors may have the potential to reduce cardiovascular risk not only via glucose lowering effect but via beneficial effects on body weight, blood pressure and serum uric acid in patients with metabolic syndrome [ 136].

3.6 Cilostazol

Among several antiplatelet agents, cilostazol has properties that would be helpful for metabolic syndrome subjects. Cilostazol, a selective phosphodiesterase-3 (PDE-3) inhibitor, is an antithrombotic agent with vasodilating properties. Cilostazol activates AMPK and causes phosphorylation of endothelial nitric oxide synthase (eNOS), leading to increased production of nitric oxide (NO), while it inhibits cytokine-induced NF-kB activation and suppresses VCAM-1 gene expression [ 137]. Cilostazol attenuates cytokine-induced expression of the iNOS gene by inhibiting NF-kB following AMPK activation in vascular smooth muscle cell [ 138]. Cilostazol also appears to exert a beneficial effect against hepatic steatosis by suppressing mitogen-activated protein kinase (MAPK) activation induced by oxidative stress [ 139]. In a clinical trial, cilostazol reduced triglycerides by 15.8 % and increased HDL-C by 12.8 % [ 42]. Increases in lipoprotein lipase activity by cilostazol treatment seems to be responsible for these lipid changes [ 140]. Thus, cilostazol may be a candidate drug for metabolic syndrome subjects at high risk of atherosclerosis.

4 Conclusion

Metabolic syndrome is a pleiotropic pathophysiology related to increasing body fat and/or distribution and insulin resistance. Metabolic syndrome is also a public health problem predicting higher rates of type 2 diabetes and CVD. Metabolic syndrome is also a pro-inflammatory condition that involves vascular endothelium and adipose tissue. Adipose tissue secretes many bioactive substances (known as adipocytokines) and inflamed fat contributes to development and complications of metabolic syndrome [ 141, 142].
Recently approved anti-obesity drugs can be prescribed to reduce body weight, particularly abdominal visceral fat. Other medications such as TZDs, metformin, lipid-lowering medications, RAS blockers, and cilostazol exert many metabolic effects including anti-inflammation.
In this review, we have discussed potential therapeutic agents that can help reduce insulin resistance fundamentally and others that target specific components of metabolic syndrome (Table  2).

Conflicts of Interest

None.
Abbreviations
CVD
cardiovascular disease
HDL-C
high-density lipoprotein cholesterol
α-MSH
S-melanocyte-stimulating hormone
GLP-1
glucagon like peptide-1
SGLT-2
sodium glucose transporter-2
hsCRP
high sensitivity C-reactive protein
IL-6
interleukin 6
TNF-α
tumor necrosis factor-α
IRS
insulin-receptor substrate
FDA
Food and Drug Association
TZD
Thiazolidinedione
PPARγ
peroxisome proliferator-activated receptor-γ
PDX-1
pancreas duodenum homeobox-1
HMG-CoA
3-hydroxy-3- methylglutaryl- coenzyme A
ACE
angiotensin-converting enzyme
ARBs
angiotensin II receptor blockers
ICAM
intracellular adhesion molecule
VCAM
vascular cell adhesion molecule
cAMP
cyclic adenosine monophosphate
PKA
protein kinase A
MAPK
mitogen-activated protein kinase
eNOS
endothelial nitric oxide synthase
NO
nitric oxide
Literature

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