Cardiometabolic syndrome (CMS) is a combination of metabolic dysfunctions mainly characterized by insulin resistance, impaired glucose tolerance, dyslipidemia, hypertension, and central adiposity. CMS is now recognized as a disease entity by the World Health Organization and the American Society of Endocrinology.1
People with CMS are two times more likely to die from coronary heart disease and three times more likely to have a heart attack or stroke than those who do not have the syndrome. It is now known that central adiposity is a major contributor to increased cardiometabolic risk.1
There are many challenges to bringing CMS risk factors under control. However, cardiometabolic programs and therapeutic strategies exist that combine diet and exercise prescriptions and focus on behavioral change to maximize success in reducing cardiometabolic risk factors. These programs have specific recommendations for calorie intake, nutrition, and ongoing cognitive and psychological assessments of habits and unhealthy behaviors.2
This article briefly reviews the pathophysiology, challenges, and difficulties of CMS treatment and its economic burden. Currently, around 25% of the world’s adults are suffering from this syndrome.1
Pathophysiology
Various pathophysiological cardiometabolic factors have been reported to be associated with the risk of myocardial infarction.
Visceral fat is the result of an imbalance between energy intake and expenditure. It is metabolically active tissue that produces various proinflammatory and prothrombotic cytokines. Both fatty liver and abdominal visceral adipose tissue are correlated with CMS, but the association is stronger for visceral adipose tissue.3 It has been demonstrated that waist circumference is a more sensitive parameter than body mass index for prediction of cardiac risk.3
Various studies have shown that alterations in number or density of mitochondria and their oxidative mechanism are associated with development and progression of metabolic syndrome. It is also reported that defective oxidative metabolism seems to be involved in visceral fat gain and the development of insulin resistance.1
Similarly, insulin resistance seems to be associated with a decrease in the ratio of mitochondria to nuclear DNA in adolescents. Furthermore, for gestational-age newborns, conditions associated with metabolic syndrome in the mother result in a decreased ratio of mitochondria to nuclear DNA in the child’s adult life.4
Adiponectin is a fat protein from adipose tissue; it has been shown to have cardioprotective effects. Experimental models have confirmed that it has anti-inflammatory and antiatherogenic properties. Low levels of adiponectin have been found in patients with diabetes, dyslipidemia, and obesity; this finding has led to the proposed hypothesis that hypoadiponectinemia may explain the pathophysiology of metabolic syndrome.1
Excess secretion of free fatty acids from adipose tissue is also associated with insulin resistance through a reduction in glucose transport into the muscles. Reducing the free fatty acids in plasma may be a potential target in the treatment of CMS.1
Among all CMS risk factors, the relation between insulin resistance and hypertension is well established. Several different mechanisms are proposed. First, insulin is a vasodilator when given intravenously to people of normal weight, with secondary effects on sodium reabsorption in the kidney. In the setting of insulin resistance, the vasodilatory effect of insulin can be lost, while the renal effect on sodium reabsorption is preserved. Hyperinsulinemia may result in increased sympathetic nervous system activity and contribute to the development of hypertension, a risk factor for CMS.5
Treatment Challenges
The identification of the pathogenesis of CMS will help in developing a successful therapeutic strategy. There is ongoing research on controlling each individual component of this disease to reduce cardiovascular morbidity and mortality. The current approach to the treatment of CMS includes aggressive control of the classical risk factors, including dyslipidemia, hypertension, diabetes, and smoking. However, there is a major clinical need to address cluster risk factors, which include high plasma insulin, intra-abdominal obesity, and prothrombotic and proinflammatory cytokines.6
Impact of Exercise and Diet
Established and evolving treatment strategies, including moderate physical activity, weight reduction, rigorous blood pressure control, correction of dyslipidemia, and glycemic control, have proven beneficial in reversing cardiovascular risk.
Exercise experts agree that par-ticipating in a minimum of 30 minutes of moderate-intensity physical activity, such as fast walking, on a daily basis will reduce the incidence or intensity of CMS. Regular exercise as part of cardiorespiratory fitness programs in patients with CMS has been shown to trend toward a reduction in the risks associated with all-cause mortality.
Diet and regular exercise have shown more favorable effects on reducing the development of diabetes mellitus than have the oral anti-hyperglycemic agents. Treatment strategies should also focus initially on reducing LDL cholesterol and, once that is achieved, on bringing triglyceride levels to <150 mg/dL.6
Weight-Loss Surgery
The use of weight-loss surgery in the clinical management of type 2 diabetes in severely obese persons has been recommended by many influential organizations concerned with diabetes. However, the timing during the diabetic course in which the use of such surgery may have the better risk-benefit ratio remains to be determined.
Some clinicians believe it is better to use surgery very early in the course of the disease in order to anticipate clinical deterioration; others suggest a delayed approach to surgery only in patients not adequately controlled pharmacologically. Reserving surgery for more advanced and complicated stages of type 2 diabetes seems to confer fewer benefits for the clinical course of the disease and risks exposing these more frail patients to the possible detrimental effects of a rapid weight loss.7
Obesity management strategy can be challenging, and it is now generally believed that behavioral modification, dietary macronutrient composition, and physical activity are key components that affect CMS management.6
Costs of CMS
A meta-analysis of 383,420 individuals with one or more components of CMS (hypertension, diabetes, lipid abnormalities, and adiposity) revealed that the adjusted total annual healthcare cost per individual patient with one component of CMS was $5,564 while the cost of care for those with four components came to $12,287.8
The Chicago Heart Association Detection Project in Industry, initiated in 1967-1973, followed a prospective cohort of 6,582 adult participants (40% women) aged 33 to 64 years until the end of life (at ages ranging from 66 to 99 years); the study revealed a significant cost difference during the lifetime of patients with and without CMS.8 In patients at low risk for CMS, the annual cost of CVD care was $10,367 less than in those with four or more components of CMS, and the annual cost of total charges was $15,318 less. The proportion of patients in society who are >65 years is expected to increase from 12% in 2000 to 20% in 2050. Individuals at high risk for CVD are expected to significantly escalate the cost of care to new and unprecedented levels.8,9
Patients at high risk for CMS who were participating in diabetes prevention and lifestyle modification programs had a reduction from 72% to 61% in the 30-year chance of diabetes, and a reduction in diabetes-complications–related death from 13.5% to 11.2%, compared to outcomes in nonparticipants.8
In addition, obesity has increased the annual cost of care for the treatment of subarachnoid hemorrhage from $3,911 to $6,197; for diabetes, from $6,006 to $7,986; and for dyslipidemia treatment from $4,760 to $7,636. Furthermore, diabetes, dyslipidemia, and hypertension resulted in a greater number of missed workdays and reduced overall productivity per affected patient, costing $1,217, $763, and $622 respectively.8
The direct medical cost of treating obese individuals in the United States, based on a 1996 and 1997 National Health Interview Survey, was estimated to have been $51.5 billion and to have risen to $74.3 billion in 2007. Obese individuals were estimated to have missed 39.3 million days of work collectively, at a cost of $4 billion in 1994 dollars.8
In the U.S., patients with CMS risk factors were 40% to 45% less likely to be employed, and they missed 179% more workdays, creating $18.7 billion in lost productivity in 2007. In 2002 dollars, obesity and smoking each had a national medically related price tag in excess of $90 billion.8
In 2014, national medical expenditures attributable to cardiometabolic risk factor clusters (CMRFC) in the U.S. totaled $80 billion, of which $27 billion was spent on prescription drugs. On average, individuals with CMRFC spent $1,668 out-of-pocket, of which $830 was for prescription drugs. Smokers had 16% higher Medicare costs than nonsmokers. Systolic blood pressure of 160 mmHg is associated with 11% higher Medicare costs compared with a systolic blood pressure of 140 mmHg, and a total blood cholesterol level of 260 mg/dL is associated with 6% higher Medicare costs compared with a total blood cholesterol of 180 mg/dL. If CMS is not controlled or treated properly, the total annual health cost for patients who have it may escalate to an unexpected and unimaginable level.8
Conclusion
CMS involves a group of interrelated abnormalities (obesity, dyslipidemia, hyperglycemia, and hypertension) that increase the risk for cardiovascular disease and type 2 diabetes. This is a common metabolic disorder that increases in prevalence as the population becomes more obese. CMS was introduced as a diagnostic category to identify individuals who may respond to lifestyle changes as well as drug treatment when needed, with the goal of decreasing the risk of cardiovascular disease and type 2 diabetes mellitus.
Cardiometabolic syndrome is a major medical problem. Scientific research must focus on addressing the diverse constellation of risk factors and identifying a new care model that takes an integrated approach to treating these risk factors across diverse populations.
REFERENCES
1. Srivastava AK. Challenges in the treatment of cardiometabolic syndrome, Indian J Pharmacol. 2012;44(2):155-156.
2. Mayo Clinic. Cardiometabolic program. Overview. http://www.mayoclinic.org/departments-centers/cardiovascular-diseases/overview/specialty-groups/cardiometabolic-program/overview. Accessed January 18, 2017.
3. Castro JP, El-Atat FA, MacFarlane SI, et al. Cardiometabolic syndrome: pathophysiology and treatment. Curr Hypertens Rep. 2003;5:393-401.
4. Gemma C, Sookoian S, Alvarinas J, et al. Mitochondrial DNA depletion in small- and large-for-gestational age newborns. Obesity. 2006;14:2193-2199.
5. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548-2556.
6. Gill H, Mugo M, Whaley-Connell A, et al. The key role of insulin resistance in the cardiometabolic syndrome. Am J Med Sci. 2005;330:290-294.
7. Busetto L. Timing of bariatric surgery in people with obesity and diabetes. Ann Transl Med. 2015;3(7):94.
8. Kelli HM, Kassas I, Lattouf OM. Cardiometabolic syndrome: a global epidemic. J Diabetes Metab. 2015(6):1-14.
9. Sonnenberg GE, Krakower GR, Kissebah AH. A novel pathway to the manifestations of metabolic syndrome. Obes Rev. 2004;12:180-186.
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