A new drug developed at Yale reduces a host of abnormalities associated with metabolic syndrome, an obesity-born condition that afflicts one of three adults in the United States, researchers report Oct. 2 in the journal Science Translational Medicine.
Metabolic syndrome is marked by insulin resistance leading to high blood sugar, excess body fat around the waist, abnormal blood cholesterol or triglyceride levels, and increased fat in the liver, a condition referred to as nonalcoholic fatty liver disease (NAFLD).
Metabolic syndrome is one of the biggest public health threats facing the developed world, and is linked to higher risk of heart disease, type 2 diabetes, and NAFLD, which can progress to liver fibrosis and liver cancer.
The Yale team reports that the drug administered to nonhuman primates safely reduces plasma triglycerides and LDL cholesterol (known as the “bad” cholesterol) and reverses NAFLD as well as liver insulin resistance – a key driver of heart disease and type 2 diabetes.
The drug spurs activity of the mitochondria, the cell’s energy-producing factory. An early version of the drug was used for weight-loss treatment in the 1930s but was banned because it produced dangerously high body temperatures.
However, Yale scientists created a time-released version of the drug that specifically targets cells in the liver, which are responsible for mediating many of the related metabolic abnormalities associated with metabolic syndrome and Type 2 diabetes.
This modification improved the safety and effectiveness of the drug by 100-fold, the researchers reported.
“Lifestyle changes such as diet and exercise are still the primary course of treatment for metabolic syndrome, NAFLD, and type 2 diabetes, but in most cases this approach is not effective in the long run so there is a great need for novel therapies,” said senior author Gerald I. Shulman, the George R. Cowgill Professor of Medicine (endocrinology) and professor of cellular and molecular physiology.
Metabolic syndrome is an accumulation of several disorders, which together raise the risk of an individual developing atherosclerotic cardiovascular disease, insulin resistance, and diabetes mellitus, and vascular and neurological complications such as a cerebrovascular accident. Metabolic disarrangement becomes a syndrome if the patient has any three of the following:
- Waist circumference more than 40 inches in men and 35 inches in women
- Elevated triglycerides 150 milligrams per deciliter of blood (mg/dL) or greater
- Reduced high-density lipoprotein cholesterol (HDL) less than 40 mg/dL in men or less than 50 mg/dL in women
- Elevated fasting glucose of l00 mg/dL or greater
- Blood pressure values of systolic 130 mmHg or higher and/or diastolic 85 mmHg or higher
Metabolic syndrome has serious implications on an individual’s health and healthcare costs. It is necessary to recognize the rising prevalence of metabolic syndrome in America as through intervention the progression of the syndrome can be halted and potentially reversed.[1][2][3]
Etiology
The underlying etiology of metabolic syndrome is extra weight, obesity, lack of physical activity, and genetic predisposition. The crux of the syndrome is a buildup of adipose tissue and tissue dysfunction that in turn leads to insulin resistance. Proinflammatory cytokines such as tumor necrosis factor, leptin, adiponectin, plasminogen activator inhibitor, and resistin, are released from the enlarged adipose tissue, which alters and impacts insulin handling adversely. Insulin resistance can be acquired or maybe due to genetic disposition. Impairment of the signaling pathway, insulin receptor defects, and defective insulin secretion can all contribute towards insulin resistance. Over time, the culmination of this cause development of metabolic syndrome that presents as vascular and autonomic damage.[4][5][6]
The distribution of body fat is also important, and it is known that upper body fat plays a strong role in developing insulin resistance. Fat accumulation can be intraperitoneal (visceral fat) or subcutaneous. Visceral fat may contribute to insulin resistance more strongly than subcutaneous fat. However, both are known to play a role in the development of metabolic syndrome. In upper body obesity, high levels of nonesterified fatty acids are released from the adipose tissue causing lipid to accumulate in other parts of the body such as liver and muscle, further perpetuating insulin resistance.
Epidemiology
In the United States, the prevalence of metabolic syndrome in adults 18 years and older is continuing to be significant. Data shows that the prevalence of this disease process increased from the 1980s to 2012 by 35%. In the 1980s, the incidence was noted to be 25.3% and increased to 34.2% in 2012. However, the most recent data from National Health and Nutrition Examination Survey (NHANES) shows the prevalence is on a decline with 24% in men and 22% in women.[7][8]
Pathophysiology
Metabolic syndrome adversely influences several body systems. Insulin resistance causes microvascular damage, which predisposes a patient to endothelial dysfunction, vascular resistance, hypertension, and vessel wall inflammation. Endothelial damage can impact the homeostasis of the body causing atherosclerotic disease and development of hypertension. Furthermore, hypertension adversely affects several body functions including increased vascular resistance and stiffness causing peripheral vascular disease, structural heart disease comprising of left ventricular hypertrophy and cardiomyopathy, and leading to renal impairment.
Accumulated effects of endothelial dysfunction and hypertension due to metabolic syndrome can further result in ischemic heart disease. Endothelial dysfunction due to increased levels of plasminogen activator type 1 and adipokine levels can cause thrombogenicity of the blood and hypertension causes vascular resistance through which coronary artery disease can develop. Also, dyslipidemia associated with metabolic syndrome can drive the atherosclerotic process leading to symptomatic ischemic heart disease.[9][10]
Histopathology
The proinflammatory cytokines released from the adipose tissue are responsible for the development of atherosclerosis and coronary artery disease. Specifically, at low levels, adiponectin is associated with the formation of coronary artery disease in addition to causing insulin resistance and inflammation.
Metabolic syndrome can also trigger a spectrum of liver damage by causing steatosis that can progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Histologically, non-alcoholic steatohepatitis presents as steatosis, hepatocyte ballooning, lobular inflammation, Mallory bodies, and pericellular fibrosis. The exact mechanism of developing non-alcoholic steatohepatitis is unknown however it has been linked to metabolic syndrome and specifically insulin resistance and proinflammatory state.
History and Physical
History and physical exam are vital for disease recognition, treatment, and prevention. The patient encounter starts with vitals and general appearance, which can clue a clinician into potential diseases such as hypertension, dyslipidemia, and metabolic syndrome.
Although no identified genetic group which is predisposed to metabolic syndrome, there are genetic disorders which may predispose individuals to the development of metabolic syndrome and insulin resistance. a Therefore, a patient should be questioned about any such potential genetic disorders.
Social and lifestyle history should also be obtained, as there are modifiable factors that can significantly impact the development of metabolic syndrome. A physical exam is crucial for the diagnosis of metabolic syndrome as one of the criteria involves the waist circumference.
Furthermore, if suspected, the patient should be screened for physical manifestations of insulin resistance such as peripheral neuropathy, retinopathy, acanthosis nigricans. A clinician should listen for arterial bruits that could be due to atherosclerotic disease. Patients with dyslipidemia may present with xanthomas. Thus, a thorough physical examination is vital to the diagnosis of metabolic syndrome.
Evaluation
After a thorough history and physical, the evaluation needs to be complemented with laboratory analysis. The blood work should include hemoglobin A1C to screen for insulin resistance and diabetes mellitus type 2.
A lipid panel should also be drawn to assess for abnormally elevated triglyceride level, low HDL level, and elevated low-density lipoprotein level. The initial evaluation should also include a basic metabolic panel to evaluate for renal dysfunction and examine glucose level. Further studies such as C-reactive protein, liver panel, thyroid study, and uric acid can be drawn to investigate the existence of further and support the diagnosis of metabolic syndrome.
Imaging studies can be ordered when appropriate. For instance, anyone suspected to have atherosclerotic coronary artery disease should have an electrocardiogram to evaluate for signs of cardiac ischemia, infarct, arrhythmias, as well as evaluate for hypertension with structural heart disease. If warranted, patients should be evaluated further with cardiac stress testing including electrocardiogram stress test, stress echocardiography, stress single-photon emission computed tomography or myocardial perfusion imaging.[11][12]
Treatment / Management
Management should be targeted at treating the conditions contributing to metabolic syndrome and possibly reverting the risk factors. Thus, modifiable factors such as diet and exercise should be emphasized in patients with metabolic syndrome.[13][14][15]
As per the most recent Joint National Committee (JNC) guidelines, the target blood pressure in general population should be 140/90 mmHg, and in patients with diabetes mellitus, the goal is less than 130/80 mmHg. The most recent Joint National Committee-8 guidelines have further specified that in patients aged 60 or older the goal should less than 150/90 mmHg.
Patients with hypertriglyceridemia defined as triglycerides more than 150 mg/dL should be evaluated and further workup should include checking full lipid analysis, thyroid stimulating hormone level, urinalysis, and liver function tests. After a comprehensive analysis, patients should first be counseled for lifestyle changes including abstinence from smoking, weight loss, and diet and exercise modification.
Physicians will start treating hypertriglyceridemia once the level is above 500 mg/dL, and usually, patients have mixed dyslipidemia disorder by that point. Patients are usually on a moderate to high-intensity statin therapy first; however, fibrates, niacin, and omega acids are also available for treating hypertriglyceridemia.
Elevated LDL should also be aggressively managed in these patients especially if the atherosclerotic cardiovascular disease (ASCVD) risk score if more than 7.5%, which establishes a patient’s 10-year ASCVD risk. These patients should be placed on a high-intensity statin therapy with a goal of dropping the LDL by 50%.
Pearls and Other Issues
Sleep health and hygiene should also be discussed with patients who have metabolic syndrome because sleep apnea and sleep deprivation can lead to the development of metabolic syndrome. Studies have shown that in patients with moderate to severe sleep apnea, 3 months of continuous positive airway pressure can reduce blood pressure and potentially reverse some metabolic syndrome abnormalities.
To recognize the development of metabolic syndrome is crucial to treatment, prevention, and reversal of the disease process. Through history and physical exam, patient education, and workup of the contributing factors appropriately, physicians can not only treat the metabolic syndrome but also potentially alter the trajectory of disease development.
Enhancing Healthcare Team Outcomes
The management of metabolic syndrome is best done with an interprofessional team that includes a dietitian, physical therapist, pharmacist, cardiologist, internist, neurologist, bariatric surgeon, nurse practitioner, an endocrinologist, and a social worker. The key to this disorder is the prevention and education of the patient.
The patient must be told of the importance of changes in lifestyle and weight loss. The dietitian should educate the patient on a Mediterranean-style diet and the importance of exercise. The patient should be urged to stop smoking and abstaining from alcohol.
The pharmacist must ensure that the patient is compliant with the medications. Probably the most important intervention is an exercise because it can lower body weight, cholesterol, blood pressure, and blood glucose at the same time. Finally, patients with metabolic syndrome should be educated on good sleep hygiene. [16][17](Level V)
Outcomes
Patients with metabolic complications can develop a wide range of complications including heart disease, aortic stenosis, atrial fibrillation, stroke, and even thromboembolic disease. Today evidence seems to indicate that the risk of an ischemic stroke is much higher in patients with metabolic syndrome than previously thought. In addition, other problems associated with metabolic syndrome include a risk for malignancies of the kidney, gallbladder, colon and even the prostate gland.
Further, the metabolic syndrome may also increase the risk of eclampsia and affect cognitive performance. Finally, patients with metabolic syndrome also face higher medical bills, are more likely to be poor and may find access to good quality healthcare difficult. [18][19](Level V)
More information: Leigh Goedeke et al. Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates, Science Translational Medicine (2019). DOI: 10.1126/scitranslmed.aay0284
Journal information: Science Translational Medicine
Provided by Yale University
