CHEMICAL BIOLOGY

Metabolic Diseases, Biological Mechanisms of

 

Cynthia M. Arbeeny PhD, Endocrine and Metabolic Diseases, Genzyme Corporation, Framingham, Massachusetts

doi: 10.1002/9780470048672.wecb316

 

Obesity, type 2 diabetes (T2D), lipid disorders, and hypertension are chronic and disabling diseases that afflict hundreds of millions of individuals worldwide. In this article, they are collectively referred to as ''cardiometabolic diseases,'' because they have ''common ground:'' They increase the risk of cardiovascular disease (CVD) morbidity and mortality. Considerable research has been performed to understand the etiology of cardiometabolic diseases and to translate this research into effective treatment paradigms. However, it has been challenging to understand the initiation and progression of cardiometabolic diseases. This difficulty is attributed to the complexities involved in metabolic regulation, a resultant ''snowballing'' effect, and a downward spiral as disease progresses. The first line of therapy for treating obesity, T2D, and/or dyslipidemia is lifestyle intervention, which can impact significantly on disease and decrease CV risk, but is usually not effective because of lack of patient compliance. Patients are then given a plethora of drugs to treat the individual risk factors. However, new therapies are critically needed, because most patients require multiple drugs, some drugs may treat one CVD risk factor and exacerbate another, and most patients do not meet treatment goals.

A ''magic bullet'' that treats the underlying causes that contribute to cardiometabolic risk has been a longstanding goal but remains elusive. Ongoing research to uncover novel targets holds promise for future therapeutics that might treat multiple facets of cardiometabolic diseases. This introductory review focuses on the epidemiology and etiology of cardiometabolic diseases, current therapies, and future treatment strategies.

 

It is difficult to separate obesity, type 2 diabetes (T2D), dyslipidemia, and hypertension because they are a consequence of a dysregulation in metabolism, are interrelated, and each might drive disease progression of the other. These comorbidities are usually found as a cluster within patients, but each can occur in the absence of the others. Lifestyle (high caloric intake, low physical activity, and cigarette smoking) along with a genetic predisposition result in alterations in metabolism that lead to cardiometabolic diseases and increase the risk of CVD. The multiple factors that contribute to CVD are summarized in Fig. 1 (1). Recent studies have provided insight into the mechanisms by which metabolic abnormalities impair insulin-receptor signaling, trigger inflammation and endothelial dysfunction, and increase CVD risk. This finding might provide new opportunities to treat the multiple risk factors that result in insulin resistance and cardiovascular disease. (Author’s note: The author recognizes that numerous “landmark” studies have been published that have contributed to the understanding of cardiometabolic diseases, but she has chosen to reference newer publications and review articles in this introductory overview. Also, a list of abbreviations is provided at the end of this review.)

 

 

Figure 1. Risk factors that contribute to cardiometabolic risk. A model proposed by the ADA, where environmental and genetic factors lead to metabolic disorders that contribute to T2D and CVD. From Reference 1, with permission.

 

The Global Crisis in Obesity, Diabetes, and CV Risk

CVD is attributed to disorders of the heart and blood vessels, and it includes coronary heart disease (heart attacks), stroke, hypertension, peripheral artery disease, rheumatic heart disease, congenital heart disease, and heart failure. On a global perspective, 30% of all deaths are from CVD, which ranks it the number one cause of death (2). In 2005, an estimated 17.5 million people died from CVD; 43% of the deaths are attributed to heart attacks and 32% to stroke.

Current predictions suggest that the twin epidemics of obesity and diabetes worldwide will result in an increase in CVD rates, which have sharply declined over the past 30 years, after the introduction of effective lipid-lowering and antihypertensive therapies. The World Health Organization (WHO) reported that in 2002, deaths from CVD outnumbered deaths from the major communicable diseases (AIDS, tuberculosis, and malaria) by 3 to 1 (2). By 2015, an estimated 20 million people will die annually from CVD. Therefore, with the advent of the new millennium, there is a sense of urgency to address the burden of chronic cardiometabolic diseases worldwide. The information on the prevalence and etiology of cardiometabolic diseases, which is cited in this section was obtained from the WHO and Centers for Disease Control (CDC) websites (2-6).

 

Obesity

Overweight and obesity occurs when an energy imbalance exists within the body, in which energy intake exceeds energy used, resulting in an increase in body fat. The cause of an energy imbalance for each individual may be different, and it is the result of interplay between environmental and genetic factors, which makes it a complex disease to understand and treat. Although some societies might be more genetically prone to obesity, changes in environmental factors, particularly the quantity and quality of food consumed and a sedentary lifestyle, are the key drivers for the global obesity epidemic (3).

For adults, overweight and obesity are easily defined by the body mass index (BMI). This value is calculated from a person’s weight in kilograms divided by the square of the person’s height in meters (kg/m2); conversion tables are available for body weight in pounds and height in inches. An adult who has a BMI between 25 and 29.9 is considered overweight; an adult who has a BMI of 30 or higher is considered obese (4). Estimates of overweight and obesity for children and adolescents take age and gender into consideration.

Data obtained from the National Health and Nutrition Examination Survey for the 2003-2004 period indicated that 66% of adults in the United States were overweight (7). The prevalence of overweight and obesity had doubled for both adults and children, when compared with a previous survey for the 1976-1980 period. According to 2005 statistics from the WHO, approximately 1.6 billion adults were overweight, and at least 400 million adults were obese (3); that half of all diabetes cases would be eliminated if weight gain could be prevented. WHO projects that by 2015, approximately 2.3 billion adults will be overweight, and more than 700 million adults will be obese.

 

Diabetes

Epidemiologic studies have established a strong relationship between obesity and the risk for T2D (8, 9). Therefore, because of the obesity epidemic, diabetes rates are soaring. WHO data indicate that over 240 million people have diabetes worldwide; the number is expected to reach 380 million by 2025 (5). The five countries with the largest numbers of people with diabetes are India, China, the United States, Russia, and Germany. For the U.S. population, 20.6 million people or 7% of the population have diabetes. Adults with diabetes have heart disease and risk of stroke about 2 to 4 times higher than adults without diabetes (10, 11). The CDC reports that diabetes is the sixth leading cause of death among adult Americans, and that two thirds of diabetics die from CVD and stroke (6). Diabetes is the major cause of renal disease, adult blindness, and lower-limb amputation. The economic burden of diabetes in the United States totals $174 billion annually; this figure has increased by 32% since 2002 (12).

Diabetes can manifest in several forms, and this review will focus on T2D, which afflicts 90-95% of all diabetics. (For an overview of diabetes diagnosis, classification, and standard of care, see References 12-15.) T2D is a metabolic disorder that is attributed to a defect in the secretion of insulin by the β-cells of the pancreas in response to metabolic signals, combined with the inability of cells to respond to insulin (i.e., insulin resistance), which results in impaired nutrient uptake and use and increased hepatic glucose output (Fig. 2). T2D is considered a “silent” disease, which progresses over decades, and it is usually diagnosed after a complication is evident or a cardiovascular event occurs.

Autopsy studies in humans have indicated that a curvilinear relationship is observed between β-cell mass and fasting blood glucose concentration, and a steep increase in blood glucose concentration is associated with β-cell deficiency (16). The data have provided research incentives focused on restoring β-cell mass to reverse diabetes or preventing diabetes by protection of β-cell mass. Abnormalities in β-cell function are therefore critical in defining the risk and development of T2D, particularly in obese subjects (17). The adipose tissue of obese individuals releases high levels of nonesterified fatty acids (NEFA), glycerol, hormones, proinflammatory cytokines, and other factors that increase insulin resistance (Fig. 2). When insulin resistance is accompanied by impaired insulin secretion by β-cells, blood glucose levels are not controlled, which results in overt diabetes.

Diabetes is diagnosed by a Fasting Plasma Glucose Test (FPG) or an Oral Glucose Tolerance Test (OGTT) (18). A FPG level of ≥ 126 mg/dL indicates diabetes. In the OGTT test, a blood glucose level 2 hours after drinking a glucose solution of ≥ 200 mg/dL indicates diabetes. A stable measure of long-term glucose status is to determine the percent of a glycated isoform of hemoglobin in blood (termed % HbA1c), which is a slowly turning over protein within the body that is modified by high blood glucose. Current treatment guidelines are to reduce HbA1c to <7% (13), because it reduces the patient’s risk of developing microvascular complications (nephropathy, retinopathy, and neuropathy) as well as macrovascular disease (cardiovascular disease and stroke) (19).

 

 

Figure 2. Model for the critical role of impaired insulin release in linking obesity with insulin resistance and T2D. Impaired insulin secretion results in decreased insulin levels and decreased signaling in the hypothalamus, which leads to increased food intake and weight gain, decreased inhibition of hepatic glucose production, reduced efficiency of glucose uptake in muscle, and increased lipolysis in the adipocyte. These results lead to increased plasma NEFA levels. The increase in body weight and NEFAs contribute to insulin resistance, and the increased NEFAs suppress the β-cell's adaptive response to insulin resistance. The increased glucose levels together with the elevated NEFA levels can synergize to affect β-cell health and insulin action adversely, which is often referred to as ''glucolipotoxicity.'' From Reference 17, with permission.

 

Dyslipidemia and hypertension

Abnormal circulating lipids [i.e., high LDL concentration (LDLc), low HDL concentration (HDLc), hypertriglyceridemia, Lp(a), and small dense LDL], and hypertension are strongly associated with CVD risk (2,20-22). These lipids are often found in obese and/or diabetic patients. Data from the Framingham Heart Study is used to estimate a person’s 10-year risk for “hard” CHD outcomes (myocardial infarction and coronary death), in which risk is calculated based on age, gender, total and HDL cholesterol, systolic blood pressure, and whether the individual is on blood-pressure-lowering medications or is a smoker. Numerous primary and secondary intervention studies have shown that improving lipid profile and lowering blood pressure significantly reduces disease morbidity and mortality (22, 23). Improved control of blood lipids in diabetics can reduce cardiovascular events by 20-50% (15, 24) In addition to lipids and blood pressure, inflammation and a procoagulant and prothrombotic state are additional CVD risk factors that need to be addressed, particularly in obese and insulin-resistant patients (25, 26). Results from a subgroup analysis of the Pravastatin or Atorvastatin Evaluation Trial (PROVE IT) (27) showed that intensive lipid-lowering intervention significantly reduced acute coronary events in diabetics, but most patients did not reach the dual goal of LDLc < 70 mg/dL and high sensitivity C-reactive protein < 2 mg/L (CRP is an inflammatory marker associated with CV risk). The data highlight the need for additional strategies in this high-risk group, particularly those that target inflammation.

 

Metabolic syndrome versus additive cardiometabolic risk factors

Cardiometabolic diseases may present as separate diseases but more often cluster within patients. Because of this clustering, the concept of “The Metabolic Syndrome” (also termed insulin resistance syndrome or syndrome X) has been put forth. Several definitions of the Metabolic Syndrome are available, with the overall viewpoint that multiple interrelated risk factors increase the risk for atherosclerotic cardiovascular disease and increase the risk for T2D. Guidelines to define the metabolic syndrome have been developed by the WHO, National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP), and International Diabetes Federation (IDF), which are reviewed in Reference 28. Each definition includes traditional risk factors: obesity and an abdominal fat distribution, insulin resistance, diabetes, dyslipidemia (high TG, low HDL) and hypertension. Shown in Table 1 are the new IDF definition (29) and the revised National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) definition (30), which are the most widely used. Each definition has its strengths and weaknesses, and both groups are working toward harmonizing criteria (31).

According to CDC statistics that use the NCEP criteria (32), the metabolic syndrome is found in 20% of the U.S. adult population. Its prevalence increases with aging, and it is highest in Hispanic women with 35% prevalence. According to the WHO, 25% of the world’s population and at least two thirds of diabetics have the metabolic syndrome. Considerable evidence suggests that the metabolic syndrome is a significant predictor of CVD and T2D, and risk increases with increasing number of risk factors (33). However, a recent assessment (34) states that “the Metabolic Syndrome is a stronger predictor of T2D than CHD and it does not predict CHD as well as the Framingham Risk Score, but it serves as a simple clinical tool for identifying high-risk subjects predisposed to CVD and T2D”.

The clinical significance of the metabolic syndrome came into question in 2005, after “A Critical Appraisal of the Metabolic Syndrome” that was jointly written by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (35). These organizations questioned the clinical value of diagnosing the metabolic syndrome, stating that CV risk is not greater than the sum of the individual risk factors, and treatment of the syndrome is no different than the treatment for each of its components. Their recommendation was to continue efforts to understand the relationships of risk factors that contribute to CVD. Numerous rebuttals to the ADA/EASD statement have been given, particularly by the American Heart Association (AHA) (36). In 2007, the AHA and ADA jointly issued a publication that attempted to harmonize the recommendations of both organizations where possible, and recognized areas where they differ (24). Overall, it is feasible that common ground will be reached in the near future.

 

Table 1. The IDF and NCEP definitions of the metabolic syndrome

 

International Diabetes Federation

National Cholesterol Education Program-ATPIII

Central obesity: waist circumference-ethnicity specific plus any two of the following:

Any three of the five criteria: Elevated waist circumference

For US population: >102 cm (40 in) in men, >88 cm (> 35 in) in women lower cut points for insulin resistant individuals or ethnic groups

High TG: >150 mg/dL (1.7 mmol/L)

High TG: >150 mg/dL (1.7 mmol/L)

Low HDL cholesterol: <40 mg/dL (1.03 mmol/L) in men, <50 mg/dL (1.3 mmol/L) in women

Low HDL cholesterol: <40 mg/dL (1.03 mmol/L) in men, <50 mg/dL (1.3 mmol/L) in women

High blood pressure: >130 mmHg systolic, > 85 mmHg diastolic

High blood pressure: >130 mmHg systolic, > 85 mmHg diastolic

Elevated plasma glucose: Fasting plasma glucose >100 mg/dL (5.6 mmol/L) or previously diagnosed T2D. If above 5.6 mmol/L an oral glucose tolerance test is strongly recommended but not necessary to define the presence of the syndrome.

Elevated fasting glucose: >100 mg/dL (5.6 mmol/L)

Limitations: Central obesity is required, criteria and cutoff values might need to be further defined

Limitations: Cutoff values do not consider ethnicity differences and age, criteria and cutoff values might need to be further defined

Information was obtained from References 29 and 30.

* Central obesity not necessary if three of the other risk factors are present

 

Underlying Mechanisms that Lead to Insulin Resistance and CVD

Chronic excessive nutrient intake leads to the deposition of fat, in not only its normal storage site, which is the adipose tissue, but also in liver and skeletal muscle. Nutrient excess also triggers an inflammatory response, with the release of inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and CRP]. These inflammatory mediators, along with the intracellular accumulation of lipid metabolites, lead to impaired insulin receptor signaling and defective metabolism in skeletal muscle and liver (37, 38). Nutrient excess also damages cells by generating reactive oxygen species, which results in protein modifications and in the depletion of nitric oxide that maintains vascular tone. These changes lead to cell dysfunction, alterations in blood lipids, elevated blood pressure, coagulation, fibrinolysis, and additional inflammation, which drives the downward spiral of insulin resistance, endothelial dysfunction, and atherosclerosis (39).

 

Metabolic stress and impaired cellular function

Nutrient excess leads to the intracellular accumulation of long chain acyl CoA and diacylglycerol, and in the activation of several serine/threonine kinases, which include protein kinase C isoforms, inhibitor of kappa B kinase (IKK), and c-jun N-terminal kinase (JNK) (37). A key step in insulin receptor signaling is the tyrosine phosphorylation of IRS1 and 2, which regulates carbohydrate, lipid, and protein metabolism. The activation of several serine/threonine kinases results in serine phosphorylation of IRS1 and 2, which inhibits insulin receptor signaling. The activation of the two principal inflammatory pathways, IKKp/NFkappa B and JNK, by nutrient excess and inflammatory cytokines, also impairs insulin receptor signaling and propagates the stress response (37). In skeletal muscle, it results in impaired insulin action on cell metabolism, which includes decreased insulin-stimulated glucose transport and decreased glycogen synthesis, leading to impaired glucose use and hyperglycemia. In the liver, glycogen synthesis is decreased, and gluconeogenesis is stimulated, which results in an increase in hepatic glucose production and hyperglycemia (38, 40).

Recently, the sphingolipid ceramide, which is a product of fatty acyl CoA, has been identified as the link between excess nutrients (i.e., saturated fatty acids) and inflammatory cytokines (i.e., TNFα), to the induction of insulin resistance. Moreover, ceramide has been shown to be toxic to pancreatic β-cells, cardiomyocytes, and endothelial cells, which contributes to diabetes, hypertension, cardiac failure, and atherosclerosis (41). However, the role of ceramide in mediating insulin-resistance humans is still unclear (42).

The endoplasmic reticulum (ER) is a network of membranes in which secreted and membrane proteins are assembled into their secondary and tertiary structures. The ER seems to be the site for sensing metabolic stress and to translate this stress into inflammatory signals (43). Under certain stress conditions, such as energy excess, lipids, and pathogens, the ER activates a complex response system known as the unfolded protein response to slow down protein synthetic pathways and to restore functional integrity to the organelle. Data from experimental models have shown that obesity leads to ER stress, which activates both JNK and IKK, and initiates pathways that trigger inflammation and insulin resistance. In the pancreatic β-cell, ER stress impairs insulin secretion and contributes to progression of T2D.

 

Inflammation

Obesity, and particularly the accumulation of abdominal fat, creates an inflammatory milieu that is the key driver of insulin resistance and CVD (44-46). In the normal state, adipose tissue coordinately regulates the synthesis and secretion of peptides that regulate numerous processes in the body (47, 48), which include fat mass, nutrient homeostasis and energy expenditure, the immune response, blood pressure control, hemostasis, bone mass, and reproductive function. In obesity, adipose tissue inflammation results in the secretion of proinflammatory peptides and reduction of anti-inflammatory peptides, which lead to deleterious effect on the liver, muscle, and the vasculature (Fig. 3). A reduction in abdominal fat improves the atherogenic lipid profile, reduces inflammation, and decreases blood pressure, which thereby decreases CV risk (44, 49). Current strategies are focused on identifying additional inflammatory markers that put the patient at cardiometabolic risk.

Chronic hyperglycemia induces numerous alterations in the vasculature that accelerate the atherosclerotic process. Several major mechanisms contribute to the pathological alterations in blood vessels in diabetes, including: 1) the nonenzymatic glycosylation of proteins and lipids, which form advanced glycation endproducts (AGEs) that can interfere with their normal function; and 2) the induction of oxidative and nitrosative stress, as well as exacerbation of proinflammatory responses (50). These abnormalities lead to impaired endogenous platelet inhibition and platelet activation, which could result in arterial thrombosis, and consequently myocardial infarction and stroke (51).

 

 

Figure 3. Adipokine expression and secretion by adipose tissue in insulin-resistant, obese subjects. Obesity results in adipose tissue inflammation with macrophage infiltration. This result leads to 1) a decrease in adiponectin, which si an anti-inflammatory adipokine, that is positively correlated with insulin sensitivity and plays a protective role on the vasculature; and 2) an increase in inflammatory cytokines (TNFα, IL-6, and resistin) which causes insulin resistance, inflammation, and atherosclerosis. From Reference 47 with permission.

 

Impaired endothelial function

Because of metabolic stress, the endothelium loses its ability to balance vasodilating and vasoconstricting factors to maintain hemostasis. Nitric oxide (NO) is the most important mediator of vasodilation, and loss of NO bioavailibility contributes to the loss of vessel tone and damage to the endothelium. This damage is particularly evident in the insulin-resistant state, in which insulin plays a key role in maintaining endothelial function and stimulating NO production. In diabetes, defective insulin signaling in the endothelial cell results in an imbalance between the vasodilating agent NO and the vasoconstricting agent endothelin-1, which results in additional endothelial dysfunction and hypertension (52). Furthermore, markers of an activated endotheium appear prior to the presentation of overt diabetes, which suggests that the endothelium plays a primary role in the disease process.

A dysfunctional endothelium makes it susceptible to damage by adhesion molecules, inflammatory cytokines, activated platelets, and lipids, which culminates in atherosclerosis (46, 53). In the kidney, endothelial dysfunction impairs glomerular filtration and leads to the progressive loss in renal function. Endothelial dysfunction can be addressed by treating the patient with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs), which block the deleterious effects of an activated renin-angiotensin-aldosterone system (RAAS) on the endothelium (54). Reviews of endothelial damage and current treatment strategies can be found in References 53 and 55. Novel therapies are needed to prevent progressive endothelial damage, whereas early intervention might improve endothelial function, offering an opportunity to protect against both CVD and organ damage. The consequences of metabolic dysregulation on endothelial damage and end organ injury that culminate in CVD are summarized in Fig. 4.

 

 

 

Figure 4. The contribution of impaired metabolism to cardiovascular risk. A dysregulation in nutrient metabolism contributes to cardiovascular risk by the following mechanisms: 1) impaired β-cell function, tissue damage, and insulin resistance; 2) an atherogenic lipid profile that is characterized by high TG, low HDL, and abnormal lipoproteins; 3) hypertension and vascular dysfunction; and 4) alterations in cytokines and adipokines that lead to a proinflammatory and procoagulant state.

 

Current and Next Generation Therapeutics

Numerous drugs are marketed to treat metabolic diseases, which include weight reducing agents, antidiabetics, lipid-lowering treatments, and antihypertensives. The pharmacology, positive attributes, efficacy, and limitations for each drug class are summarized in Tables (2-5) (56, 57).

 

Weight-loss agents

The three currently marketed weight-loss drugs are listed in Table 2. Orlistat is a pancreatic lipase inhibitor that acts at the level of the gastrointestinal (GI) tract to inhibit the absorption of dietary fat. Sibutramine and rimonabant act at different transporters or receptors to modulate central and peripheral metabolism. The paucity of weight loss agents that are available is attributed to the hurdles in developing weight-loss drugs. Large placebo-controlled trials are required; the placebo group is given a low-calorie diet and exhibits weight loss. A variation is observed in response and a significant number of nonresponders, and safety considerations often emerge. Most weight-loss treatments are associated with improvement in insulin sensitivity and lipids, but the drugs have side effects that generally limit use.

 

Table 2. Currently prescribed weight-loss agents

 

Treatment

Pharmacology and positive attributes

Efficacy (clinical trials)

Limitations

Orlistat

(oral)

Inhibits pancreatic lipase, blocks the digestion and absorption of dietary triglycerides.

Causes weight loss, improves lipid profile and insulin sensitivity.

At 1 year of treatment, 57% of the orlistat-treated patients and 31% of the placebo-treated patients lost ≥5% of their body weight; weight loss was maintained at 2 years of treatment.

Oily spotting, abdominal pain, fecal urgency

Sibutramine

(oral)

Inhibits the reuptake of norepinepherine, serotonin and dopamine; suppresses appetite and increase energy expenditure.

Causes weight loss, improves lipid profile and insulin sensitivity.

At 2 years of treatment, 67% of sibutramine-treated patients and 49% of placebo-treated patients lost ≥5% of their body weight.

May increase blood pressure and heart rate

 

Rimonabant

(oral)

 

An inverse agonist for the cannabinoid receptor CB1, reduces appetite and improves metabolism.

Causes weight loss, improves lipid profile, blood pressure and insulin sensitivity.

 

At 1 year of treatment, 75% of rimonabant-treated patients and 28% of placebo-treated patients lost ≥5% of their body weight.

 

Nausea, dizziness, may cause severe depression. Not approved for use in the U.S.

Information was obtained from References 49 and 56.

 

Antidiabetic agents

Current marketed antidiabetic treatments are shown in Table 3. These drugs may act to: improve insulin sensitivity, decrease hepatic glucose output, decrease the absorption of glucose in the GI tract, or stimulate the secretion of insulin. Numerous studies have shown that antidiabetic and weight-loss interventions, either by lifestyle or by drug treatment, prevent the development of diabetes in patients at risk for developing that disease (58). However, antidiabetic and weight-loss drugs are not prescribed as preventative agents. Because diabetes is a complicated disease, a treatment paradigm has been developed, and multiple treatments are generally required (57). However, a patient’s diabetes still progresses even when given several antidiabetic drugs in combination. This progression seems to be caused by the progressive loss of β-cell function despite multiple treatments (59).

Oral antidiabetic agents consist of several classes: biguinides, sulfonylureas (SUs), non-SU secretagogues, α-glucosidase inhibitors (AGI), thiazolidinediones (TZDs), and dipeptidyl peptidase IV (DPP-IV) inhibitors, which are used as monotherapy or in combination. Metformin is the only available biguinide in the United States, and its exact mechanisms are not clearly understood. However, it has been shown to increase insulin sensitivity by inhibiting hepatic glucose production. SU and non-SU secretagogues increase the release of insulin from pancreatic β-cells and potentiate insulin action, but hypoglycemia may result. The non-SU secretagogues differ from SUs in that they are absorbed more rapidly and are eliminated. They can minimize postprandial glucose (PPG) excursions and lower postprandial insulin levels, with reduced risk of hypoglycemia. AGIs act at the level of the GI tract to delay carbohydrate digestion and absorption, which thereby limits PPG excursions. TZDs are peroxisome-proliferator-activated receptor-γ (PPAR-γ) receptor agonists that enhance adipocyte differentiation and decrease lipolysis, increase insulin-stimulated glucose uptake in muscle, and decrease hepatic glucose production. In early 2007, a prospective review of clinical data for the TZD rosiglitazone has raised cardiovascular concerns. The issues are discussed in Reference 57, and a revision of the treatment paradigm for diabetic patients has resulted.

Newer targets include potentiating the effects of glucagon-like peptide-1 (GLP-1) and amylin, which are reviewed in Reference 60. GLP-1 is a key regulatory hormone that is secreted by the L-cells of the intestine. This hormone stimulates insulin secretion by the pancreatic β-cells in response to glucose, inhibits gastric emptying and glucagon secretion, and has a central effect to inhibit food intake. Two approved pharmacological treatments to promote GLP-1 action are as follows: 1) to inject a GLP-1 protein mimetic (i.e., exenatide) or 2) to potentiate endogenous GLP-1 action by inhibiting its degradation via sitaglipin, which is an oral DPP-IV inhibitor. Amylin is another regulatory hormone involved in glucose homeostasis. It is cosecreted with insulin by β-cells and decreases PPG excursions by slowing gastric emptying and decreasing glucagon secretion. Pramlintide, which is an injectable analog of amylin, is approved to treat both T1 and T2D patients.

 

Table 3. Currently prescribed anti-diabetic agents

 

Treatment

Pharmacology and positive attributes

Expected efficacy

Limitations

Insulin (injectable or inhaled protein, multiple products)

Metformin (oral)

 

Sulfonylureas and non-SU secretagogues (oral, multiple agents)

α-Glucosidase inhibitors (oral, multiple agents)

Thiazolidine-diones (oral, rosiglitazone, pioglitazone)

 

Exenatide (injectable protein)

 

Sitaglipin (oral)

 

Pramlintide (injectable protein)

Increases insulin levels, improves glucose tolerance, improves lipid profile.

Decreases hepatic glucose output plus additional mechanisms, improves glycemic control, ↓TG and LDLc, ↑HDLc

Increases insulin secretion by pancreatic beta cells, improves glycemic control

 

Delays GI absorption of carbohydrates, improves glycemic control

 

PPARy agonist, increases insulin sensitivity and improves glycemic control, ↓TG (rosiglitazone may ↑TG), ↑LDLc and ↑HDLc; pioglitazone has greater beneficial effects on blood lipids)

Long acting GLP-1 analog, improves glycemic control, decreases TG and increases HDLc, causes weight loss.

Inhibits DPP-IV thereby potentiating the action of GLP-1; improves glycemic control, weight neutral.

Amylin analog, improves glycemic control, causes weight loss.

HbA1c reductions of 1.5-3.5% (less reduction for inhaled vs injectable)

HbA1c reductions of 1.0-2.0%

 

HbA1c reductions of 1.0-2.0% for ulfonylureas 1.0-1.5 % for non-SU secretagogues

HbA1c reductions of 0.5-0.8%

 

HbA1c reductions of 0.5-1.4%

 

 

HbA1c reductions of 0.5-1.0%

 

HbA1c reductions of 0.5-0.8%

 

HbA1c reductions of 0.6%

May cause hypoglycemia, weight gain

 

May cause GI problems, lactic acidosis (rare)

May cause hypoglycemia, weight gain

 

 

May cause GI problems

 

Associated with weight gain, edema; not recommended for patients with CHF

Associated with GI problems

 

Recently approved, little experience

 

Associated with GI problems

Information was obtained from References 56 and 57.

 

Lipid-lowering agents

Many lipid-lowering agents are used alone or in combination to achieve lipid goals (Table 4). Although numerous lipid-lowering agents are available, which are used alone and in combination, additional therapies are required to decrease other atherogenic components and to enhance reverse cholesterol transport.

The “statins” inhibit HMGCoA reductase, which results in an inhibition of cholesterol synthesis and upregulation of LDL clearance. This result leads to a marked reduction in LDLc, with additional positive effects to decrease TG modestly and to increase HDL. Bile acid sequestrants are also used alone or in combination to lower LDLc. Bile acid sequestrants also upregulate LDL clearance and decrease LDLc, but the effect is generally less than with a statin. In addition to lowering cholesterol, bile acid sequestrants may elicit an antidiabetic effect (61); a newer seqeustrant colesevelam HCl received approval to treat both T2D and high LDL cholesterol.

Ezetimibe is a newer drug that inhibits cholesterol absorption by the GI tract; it reduces LDLc modestly as monotherapy and is used in combination therapy with simvastatin (marketed as Vytorin) to achieve good cholesterol lowering and minimizing the “statin” dose to reduce side effects. However, the “Enhance” clinical trial results (62) have raised concerns about the lack of vascular benefit with ezetimide, and additional outcome trials are ongoing.

The fibrates act at the level of the liver to decrease VLDL-TG substantially and to increase HDLc secretion. Nicotinic acid also decreases TG and is considered to the most potent agent to increase HDL. The effects of fibrates and nicotinic acid on TG and HDL are generally greater than those observed with “statins,” which are generally the most effective LDLc-lowering agents.

 

Table 4. Currently prescribed lipid-lowering agents

 

Treatment

Pharmacology and positive attributes

Efficacy

Limitations

HMGCoA reductase inhibitors “Statins” (oral, multiple agents)

Bile acid sequestrants (oral, multiple agents)

Ezetimibe (oral)

 

Fibrates (oral, multiple agents)

 

 

Niacin and nicotinic acid (oral, multiple agents)

Oral agent, inhibits HMGCoA reductase and upregulates the LDL receptor, decreases LDLc and TG, increases HDLc

Binds bile acids in the GI tract, resulting in the upregulation of the hepatic LDL receptor and a decrease in LDLc

Inhibits the intestinal absorption of cholesterol, decreases LDLc

Decreases TG synthesis and VLDL secretion and increases LPL, decreases TG, increases HDL, decreases fibrinogen and Lp(a), may cause weight loss

Decreases TG synthesis and VLDL secretion, inhibits FFA release from adipose tissue, decreases TG, raises HDL, decreases fibrinogen and Lp(a)

LDLc ↓18-55% HDLc ↑5-15% TG↑7-30%

LDLc ↓15-30% HDLc ↑3-5% TG no change or ↑

LDLc ↓18% HDLc ↑1% TG ↓8%

 

LDLc ↓5-20% (may increase in patients with high TG) HDLc↑10-20% TG ↓20-50%

LDLc ↓5-25% HDLc ↑15-35% TG↓20-50%

Potential for elevating liver enzymes and causing myopathy

May cause GI problems, decreased absorption of other drugs

Hypersensitivity reactions, myalgia, increase in liver enzymes

May cause dyspepsia, gallstones, myopathy

 

 

May cause stomach upset, flushing, headache, may decrease glucose tolerance

Information was obtained from References 23 and 56.

 

Blood pressure agents

Several classes of blood-pressure-lowering agents are available and are often used in combination to achieve goals (Table 5). Results of large clinical trials have indicated that the benefits of antihypertensive treatment is caused by the lowering in blood pressure and largely independent of the drugs employed (22). A challenge has been to understand why differential responses to a specific class or combination are observed.

Three antihypertensives (ACEi, ARB, and renin blockers) block different steps the RAAS pathway, which results in a downstream blockade of AT1 receptors that resulting vasodilation, decreased secretion of vasopressin, and decreased secretion of aldosterone, contributing to a blood pressure lowering effect. The decrease in aldosterone decreases sodium and water resorption in the kidney and decreases potassium excretion, which leads to a lowering in blood pressure. These drugs are often used to treat hypertension, diabetic nephropathy, and congestive heart failure (63). ACEi also blocks the bradykinin pathway, which induces nitric oxide and vasodilation, but it is often associated with the persistent dry cough and/or angioedema that may limit ACEi therapy. This side effect is rarely observed with ARBs. Although ACEi and renin antagonism decrease circulating angiotensin II, ARBs block its activity at the AT1 receptor. ARBs increase angiotensin II levels by uncoupling the negative-feedback loop, and increase its stimulation of AT2 receptors, which is associated with beneficial and negative effects. A direct renin inhibitor has recently entered the market, which may result in more complete inhibition of the RAAS system inhibition than with ACEi or ARBs, but more clinical experience and outcome trial results are necessary to assess its potential adequately (64).

Beta adrenergic receptor antagonists reduce cardiac output (caused by negative chronotropic and inotropic effects), decrease renin release from the kidneys, and cause smooth muscle relaxation. However, blockage may also decrease secretion of insulin from pancreatic β-cells, which limits its use in T2D. Calcium channel antagonists act on L-type voltage gated channels in the heart and blood vessels to reduce vascular resistance and arterial pressure. Diuretics are also widely used to decrease blood pressure, particularly in the elderly and hypertensive black populations.

 

Table 5. Currently prescribed blood pressure-lowering agents

 

Treatment

Pharmacology and positive attributes

Conditions favoring use

Limitations

ACEi (oral, multiple agents)

Prevents conversion of Ang I to Ang II, which prevents action of Ang II at its receptor to cause vasoconstriction and cardiac stimulation

HF, post-MI, nephropathy, LV hypertrophy, carotid atherosclerosis, trial fibrillation, MetS

May cause cough, elevated potassium levels, low blood pressure, dizziness, headache

ARBs (oral multiple agents)

Blocks the action of Ang II at its receptor

HF, post MI, nephropathy, LV hypertrophy, atrial fibrillation, MetS

May cause cough, elevated potassium levels, low blood pressure, dizziness, headache

Aliskiren (oral)

Direct renin inhibitor, inhibits the RAAS pathway.

HF, post MI, diabetic nephropathies, hypertension, kidney disorders

Side effects include angioderma, hyperkalemia, hypotension, GI symptoms

Beta blockers (oral, multiple agents)

Blocks the PAR, decreases the chronotropic, inotropic and vasodilator responses to PAR stimulation

HF, post MI, angina pectoris, tachyarrhythmias, glaucoma, pregnancy

May cause weight gain, decrease insulin sensitivity and adversely affect plasma lipids

Thiazide diuretics (oral, multiple agents)

Inhibits Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na+-Cl- symporter

Isolated systolic hypertension (elderly), HF, hypertension in blacks

May cause hypokalemia and increased serum cholesterol; long-term use may increase homocysteine (associated with atherosclerosis)

Calcium antagonists: dihyropyridines (oral, multiple agents)

Block L-type voltage-gated calcium channels in muscle cells of the heart and blood vessels; often used to reduce systemic vascular resistance and arterial pressure

Isolated systolic hypertension, angina pectoris, LV hypertrophy, carotid/coronary atherosclerosis, pregnancy, hypertension in blacks

Side effects include peripheral edema, dizziness, not used to treat angina (with the exception of amlodipine); contra-indicated in certain patient populations.

Calcium antagonists: (oral, verapamil diltiazem)

L-type calcium channel blocker, decreases impulse conduction through the AV node, protects ventricles from atrial tachyarrhythmias; causes smooth muscle relaxation and vasodilation.

Angina pectoris, carotid atherosclerosis, supraventricular tachycardia

Side effects include headache, constipation, Side effects include dizziness, flushing, peripheral edema.(Diltiazem is contra-indicated in certain patient populations.)

Information was obtained from References 22 and 56.

 

Future treatment strategies

Future treatments are focused on correcting the metabolic dysregulation, which contributes to cell damage and tissue dysfunction. A list of selected novel targets for treating cardiometabolic diseases is shown in Table 6. The focus for new antiobesity approaches has been to target the gut-brain axis to regulate feeding behavior and energy expenditure, as well as modulating peripheral metabolism (65). These targets should also be effective in treating obese T2D. However, it has been difficult to target feeding behavior, because considerable redundancies exist in the regulation of food intake. Another focus to treat the metabolic dysregulation in insulin-resistant and diabetic patients is to augment insulin receptor signaling and also to treat P-cell impairment. Future approaches to treating vessel wall damage include activating reverse cholesterol transport and novel antihypertensive targets.

Several challenges are faced in developing novel therapeutics to treat cardiometabolic disorders. These challenges include identifying and validating novel targets, using predictive animal model of human efficacy, identifying responsive patient populations, obtaining an acceptable safety and tolerability profile for chronic treatment, and positioning a product in a huge, competitive marketplace. However, there is a high unmet medical need and room for new, differentiated products. Recent advances hold promise for novel therapies for treating multiple risk factors for T2D and CVD.

 

Table 6. Future treatments for metabolic diseases

 

 

 

Predicted Positive Effect

 

Novel pharmacological targets

Bwt Loss

Anti-Diab

Lipid Impr.

BP Redn

Vasc Impr.

Improve Energy Homeostasis

Central regulation: ↓NPY, ↑MSH-R Gut regulation: ↓Ghrelin, ↑CCK, ↑PYY Peripheral regulation: ↓ACC, ↓SCD-1, ↑AMPK, ↑Sirt1, ↓11-βHSD, GH analogs, TH analogs Adipokine and cytokine regulation: ↑adiponectin, ↓inflammation

Improve Glucose Homeostasis

Insulin signaling stimulation: ↓PTEN, Glycogen regulation: ↓GSK3, ↑GS Gluconeogenesis inhibitors, β-cell restoration

Improve Lipid Profile

Reverse cholesterol transport stimulation: ↑HDL, ↑apo AI, ↑ABC transporter, ↓CETP LDL reduction: Anti-Apo B, ↓MTP, ↓PCSK9

Lower Blood Pressure

Neutral endopeptidase inhibitors, Nitric oxide donors, Endothelin receptor antagonists

√/?

 

√/?

 

 

 

 

 

√/?

 

 

 

 

 

 

 

 

√/?

 

 

 

 

 

Summary of predicted positive effects on body weight reduction, improvement in diabetes control, improvement in lipid profile, blood pressure decrease, and improvement in the vasculature.

 

Appendix: List of Abbreviations

ACC, acetyl CoA carboxylase

ACEi, angiotensin converting enzyme inhibitor

AGE, advanced glycation endproducts

AGI, alpha glucosidase inhibitor

AMPK, AMP-activated protein kinase

ARB, angiotensin receptor blockers

βAR, beta adrenergic receptor

CCK, cholecystokinin

CETP, cholesteryl ester transfer protein

CHD, coronary heart disease

CVD, cardiovascular disease

CRP, C-reactive protein

FFA, free fatty acid

GH, growth hormone

GLP-1, glucagon-like protein 1

GS, glycogen synthase

GSK3, glycogen synthase kinase 3

HDL, high density lipoprotein

HF, heart failure

IKK, inhibitor of kappa B kinase

JNK, c-jun N-terminal kinase

LDL, low density lipoprotein

Lp(a), lipoprotein “little” a

LV, left ventricular

MetS, metabolic syndrome

MI, myocardial infarction

MSH-R, melanocyte stimulating hormone receptor

MTP, microsomal triglyceride transfer protein

NEFA, non-esterified fatty acids

NO, nitric oxide

NPY, neuropeptide Y

PCSK9, proprotein convertase subtilisin/kexin type 9

PPAR-γ, peroxisome-proliferator-activated receptor-γ receptor agonists PPG, post-prandial

PTEN, phosphatase and tensin homolog

PTPase, phosphotyrosine phosphatase

PYY, peptide YY

RAAS, renin, angiotensin, aldosterone system

SCD-1, stearoyl-CoA desaturase 1

Sirt1, silent information regulator 1

TG, triglyceride

TH, thyroid hormone

TZD, thiazolidinedione

VLDL, very low density lipoprotein

11-βHSD1, 11 beta-hydroxysteroid dehydrogenase type 1

 

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Further Reading

Bamba V, Rader DJ. Obesity and atherogenic dyslipidemia. Gastroenterology 2007; 132:2181-2190.

Lebovitz, HE. Insulin resistance - a common link between type 2 diabetes and cardiovascular disease. Diabetes Obes. Metab. 2006; 8:237- 249.

Woods SC, Benoit S and Clegg DJ. The brain-gut-islet connection. Diabetes 2006; 55:S114-S121.

Yach D, Stuckler D and Brownwell KD. Commentary: epidemiological and economic consequences of the global epidemic of obesity and diabetes. Nat. Med. 2006; 12:62-66.

 

See Also

LDL and HDL Receptors

Lipid Homeostasis

Lipoproteins, Chemistry of

Metabolic Diseases, Chemical Biology of