Rev Endocr Metab Disord DOI 10.1007/s11154-014-9298-4
Pharmacological treatment and therapeutic perspectives of metabolic syndrome Soo Lim & Robert H. Eckel
# Springer Science+Business Media New York 2014
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 highdensity 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, S. Lim Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-city 463-707, South Korea e-mail: [email protected] R. H. Eckel (*) Division of Endocrinology, Diabetes and Metabolism and Division or Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, 12801 East 17th Ave., RC1 South, Room 7107, Aurora, CO 80045, USA e-mail: [email protected]
thiazolidinediones, metformin, statins, fibrates, reninangiotensin 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. Keywords Metabolic syndrome . Therapeutic implication . Pharmacologic agent 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
Rev Endocr Metab Disord
MAPK eNOS NO
mitogen-activated protein kinase endothelial nitric oxide synthase nitric oxide
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 [4–6], 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]. 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 proinflammatory/pro-oxidative state [12, 20]. The multicenter Insulin Resistance Atherosclerosis Study had shown a linear relationship between the inflammatory marker highsensitivity C-reactive protein (hsCRP) and the number of metabolic derangements [20]. The large amount of adipose
IGT, IFG, or T2D
Glucose
WC ≥102 cm in men or ≥88 cm in women TG ≥150 mg/dl or on TG lowering Rx HDL-C
Pharmacological treatment and therapeutic perspectives of metabolic syndrome Soo Lim & Robert H. Eckel
# Springer Science+Business Media New York 2014
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 highdensity 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, S. Lim Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-city 463-707, South Korea e-mail: [email protected] R. H. Eckel (*) Division of Endocrinology, Diabetes and Metabolism and Division or Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, 12801 East 17th Ave., RC1 South, Room 7107, Aurora, CO 80045, USA e-mail: [email protected]
thiazolidinediones, metformin, statins, fibrates, reninangiotensin 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. Keywords Metabolic syndrome . Therapeutic implication . Pharmacologic agent 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
Rev Endocr Metab Disord
MAPK eNOS NO
mitogen-activated protein kinase endothelial nitric oxide synthase nitric oxide
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 [4–6], 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]. 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 proinflammatory/pro-oxidative state [12, 20]. The multicenter Insulin Resistance Atherosclerosis Study had shown a linear relationship between the inflammatory marker highsensitivity C-reactive protein (hsCRP) and the number of metabolic derangements [20]. The large amount of adipose
IGT, IFG, or T2D
Glucose
WC ≥102 cm in men or ≥88 cm in women TG ≥150 mg/dl or on TG lowering Rx HDL-C
