New strategies against obesity comorbidities
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Worldwide obesity prevalence has nearly doubled since 1980.1 As obesity continues to increase at a dramatic rate, the risk for its associated comorbidities is skyrocketing as well. Obese adults are at risk for many serious health conditions, including diabetes, coronary heart disease, hypertension, stroke, obstructive sleep apnea (OSA), depression and liver disease.
Lifestyle modification — to include dietary adjustment, exercise and behavioral change — has been proven to help treat obesity and its related diseases. As every clinician knows, however, behavioral changes are difficult to implement and have varying levels of success, depending on a patient's motivation. What follows is a review the latest treatment strategies — intended for use in collaboration with lifestyle modification — for the comorbidities of obesity.
Diabesity is a term used to describe obese individuals who have type 2 diabetes. Such conventional diabetic treatments as sulfonylureas, thiazolidinediones (TZDs), and insulin promote weight gain, which can exacerbate further insulin resistance, worsen obesity-related comorbidities and reduce patient compliance.
Bariatric surgery is currently the most successful treatment for diabesity, resulting in significant weight loss and a sustained remission of diabetes in most patients.2,3 Many of the weight-loss effects of bariatric surgery have been shown to be mediated via postoperative increases in appetite-inhibitory gut hormones. Research is currently aimed at finding the pharmaceutical equivalent to bariatric surgery — a drug or combination therapy with anorexigenic gut hormones that can mimic the effects of surgery and restore a patient's metabolism to a healthy, nondiabetic state.
Glucagon like peptide (GLP)-1 receptor agonist therapy is a major breakthrough in diabetes treatment. GLP-1 is a gut incretin hormone that stimulates the release of insulin in response to elevated levels of blood sugar, inhibits the release of glucagon following meals and slows the rate of absorption of foods from the gut into the bloodstream.
In the active form, GLP-1 has a short half-life of only one or two minutes, due to rapid destruction by the dipeptidyl peptidase (DPP)-4 enzyme, making it seemingly impractical as a diabetes treatment. However, the GLP-1 receptor agonists were designed to have a prolonged half-life attributable to reduced degradation by the DPP-4 enzyme. After many years of development, GLP-1 receptor agonists are now well established in the management of type 2 diabetes.
In addition exenatide (Byetta) and liraglutide (Victoza), several new GLP-1 receptor agonists are in development. Lixisenatide, a once-daily preparation currently in phase III clinical trials, has limited experience with only one clinical study to date. This 13-week study showed a 0.7% reduction in hemoglobin A1c with the use of lixisenatide 20 µg daily from a baseline of 7.5% in patients with type 2 diabetes.4 The National Institute of Health registry lists several ongoing clinical trials studying lixisenatide.
Bydureon is an investigational, long-acting form of exenatide that has been shown to have better glycemic effect than conventional exenatide.5 In October 2010, the FDA declined to approve Bydureon, requesting further testing to measure cardiovascular risk in patients taking the drug; Amylin plans to resubmit to the FDA in the second half of 2011.6 Bydureon was approved in the European Union in June 2011.7
All of the GLP-1 receptor agonists currently require parenteral administration, which can interfere with patient compliance. Oral versions of GLP-1 are being developed and are currently in phase I clinical trials.
Cardiovascular disease (CVD) remains the leading cause of death throughout the world.8 The World Health Organization predicts deaths from CVD and stroke will exceed 20 million within the next decade. Risk factors include hypertension (HTN), diabetes, obesity and tobacco use. The leading risk factor for mortality, HTN is responsible for nearly 13% of deaths worldwide.9
Percutaneous renal denervation is a new and evolving HTN treatment. The procedure involves insertion of a percutaneous catheter into the common femoral artery and threaded to the renal arteries; six radiofrequency ablation treatments are then delivered distally and proximally from the bifurcation to the ostium. Each ablation involves delivery of eight watts of energy lasting two minutes.10
Patients with resistant essential HTN who have undergone this procedure have shown a reduction in systolic BP of 27 mm Hg at 12 months.10 Decreased arterial pressure after renal denervation is a result of reduced peripheral sympathetic nervous system activity.10
Based on animal research, it is assumed that denervation of the efferent nerves will result in reduced renin release, reduced sodium retention, and an increase in renal blood flow, producing a normalization of arterial pressure.10 Data also support the idea that afferent sensory nerve denervation will attenuate the kidneys' effect on centrally mediated sympathetic nervous system activity. Over time, the cause of an individual's HTN may change due to altering variables. Therefore, denervation of efferent and afferent renal nerves is expected to produce a long-term treatment effect.New hypertension guidelines are expected within the year from the Kidney Disease: Improved Global Outcomes (KDIGO) foundation and The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8).
Coronary artery disease and peripheral
Atherosclerosis presenting as coronary artery disease (CAD) and/or peripheral artery disease (PAD) is a significant and costly result of obesity. Medical treatments for this systemic disease remain relatively unchanged. However, there is renewed focus on prevention and early detection as evidenced by the new guidelines for women and heart disease from the American Heart Association.11
Risk factors for PAD include HTN, diabetes, hyperlipidemia and tobacco use. Because PAD can be asymptomatic, a comprehensive vascular exam is essential. Persons who are at highest risk are aged 70 years or older, smokers (current or past) and/or diabetic. The ankle-brachial pressure index (Table 1) should be measured in the office.
This calculates the ratio of the ankle to brachial systolic pressure and is determined using a sphygmomanometer and a handheld Doppler device. If detected early, treatment goals can be directed at risk reduction and limiting further disease progression.
Improved morbidity and mortality outcomes and improving walking distance are the two primary objectives in treatment of PAD. A supervised exercise treatment (walking program) is essential. This treatment can be costly and is often not reimbursed but is proven to provide significant improvements in functional outcomes. Maximal walking ability can be increased by 150%, greater than any pharmacologic approach.