In treating obesity as a chronic disease, the essential goal of weight loss therapy is not the quantity of weight loss as an end unto itself but rather the prevention and treatment of complications ...to enhance health and mitigate morbidity and mortality. This perspective on obesity care is consistent with the complications-centric American Association of Clinical Endocrinology (AACE) obesity guidelines and the diagnostic term of adiposity-based chronic disease (ABCD). Many complications require 10% to 20% weight loss to achieve therapeutic goals; however, existing obesity medications fail to produce ≥10% weight loss in the majority of patients. In June, 2021, semaglutide 2.4 mg/week was approved for chronic weight management. Phase 3 clinical trials demonstrated that this medication produced > 10% placebo-subtracted weight loss, more than half of patents lost ≥15%, and over one third lost ≥20% of baseline weight. This essentially doubles effectiveness over existing obesity medications, provides sufficient weight loss to ameliorate a broad range of complications, and qualifies as the first member of a second-generation class of obesity medications. The advent of second-generation medications fully enables a treat-to-target approach for management of ABCD as a chronic disease. Specifically, with this degree of efficacy, second-generation medications permit active management of body weight as a biomarker to targets associated with effective treatment and prevention of specific complications. ABCD can now be managed similar to other chronic diseases such as type 2 diabetes, hypertension, and atherosclerosis, which are treated to biomarker targets that can be modified based on the clinical status of individual patients ie, hemoglobin A1c (HbA1c), blood pressure, and low-density lipoprotein cholesterol (LDL-c) to prevent the respective complications of these diseases.
Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie ...metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma concentrations of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis to identify 158 metabolite components that strongly correlated with fasting HbA1c over a broad range of the latter (r = −0.631; p<0.0001). In addition to many unidentified small molecules, specific metabolites that were increased significantly in T2DM subjects included certain amino acids and their derivatives (i.e., leucine, 2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate, long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations rose with increasing HbA1c, and significantly correlated with plasma acetylcarnitine concentrations. It is hypothesized that this reflects a close link between abnormalities in glucose homeostasis, amino acid catabolism, and efficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. It is speculated that a mechanism for potential TCA cycle inefficiency concurrent with insulin resistance is “anaplerotic stress” emanating from reduced amino acid-derived carbon flux to TCA cycle intermediates, which if coupled to perturbation in cataplerosis would lead to net reduction in TCA cycle capacity relative to fuel delivery.
Type 2 diabetes (T2D) is a public health threat. Prediabetes represents a window of opportunity for intervention to prevent T2D. Men with T2D and prediabetes often have low testosterone. Since ...testosterone improves glycemic control in T2D, we investigated whether testosterone therapy (TTh) in men with hypogonadism and prediabetes prevents progression to T2D.
Three hundred and sixteen men with prediabetes (defined as HbA
5.7-6.4%) and total testosterone levels ≤12.1 nmol/L combined with symptoms of hypogonadism were analyzed. Two hundred and twenty-nine men received parenteral testosterone undecanoate (T-group), and 87 men with hypogonadism served as untreated control subjects. Metabolic and anthropometric parameters were measured twice yearly for 8 years.
HbA
decreased by 0.39 ± 0.03% (
< 0.0001) in the T-group and increased by 0.63 ± 0.1% (
< 0.0001) in the untreated group. In the T-group, 90% achieved normal glucose regulation (HbA
<5.7%). In the untreated group, 40.2% progressed to T2D (HbA
>6.5%). TTh was also associated with significant improvements in fasting glucose, triglyceride:HDL ratio, triglyceride-glucose index, lipid accumulation product, total cholesterol, LDL, HDL, non-HDL, triglycerides, and Aging Males' Symptoms (AMS) scale. Significant deterioration in all these parameters was seen in the untreated group. Mortality was 7.4% in the T-group and 16.1% in the untreated group (
< 0.05). The incidence of nonfatal myocardial infarction was 0.4% in the T-group and 5.7% in the untreated group (
< 0.005).
Long-term TTh completely prevents prediabetes progression to T2D in men with hypogonadism and improves glycemia, lipids, and AMS score. TTh holds tremendous potential for the large and growing population of men with prediabetes and hypogonadism.
Adiposity-based chronic disease (ABCD) requires life-long treatment and follow up. Obesity protects obesity through altered regulation of caloric intake and set point mechanisms, which help maintain ...a high equilibrium body weight. Lifestyle interventions and obesity medications do not permanently alter the set point, which often makes weight loss achieved using lifestyle changes short-lived and operates to drive weight regain once medications are discontinued. Bariatric surgery procedures can alter appetite and lower the “set point” for the equilibrium body weight via unknown mechanisms. However, few patients attain an ideal body weight following surgery, many regain weight, and all require long-term follow up for the disease. The excess adiposity associated with ABCD gives rise to complications that impair health and confer morbidity and mortality; however, the genetic risks and potential interactions between genes and the environment that give rise to complications cannot be eliminated. The equilibrium body weight around which set point mechanisms operate can be modified by the environment, which underscores the importance of a less obesogenic environment for the prevention and treatment of ABCD on a population basis.
Whether ABCD will eventually be curable will depend on a clear understanding of the molecular mechanisms that determine the set point regulation of body weight and the ability to permanently modulate the set point to oscillate around a lean body mass. However, the conceptualization of ABCD as a chronic disease does present us with opportunities for primary, secondary, and tertiary prevention to avert disease progression. For tertiary care, the advent of new, more effective second-generation obesity medications will allow clinicians to treat to target via active management of body weight into a target range that will ameliorate specific complications.
Objective
The development of these updated clinical practice guidelines (CPGs) was commissioned by the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), American ...Society for Metabolic and Bariatric Surgery (ASMBS), Obesity Medicine Association (OMA), and American Society of Anesthesiologists (ASA) Boards of Directors in adherence with the AACE 2017 protocol for standardized production of CPGs, algorithms, and checklists.
Methods
Each recommendation was evaluated and updated based on new evidence from 2013 to the present and subjective factors provided by experts.
Results
New or updated topics in this CPG include: contextualization in an adiposity‐based chronic disease complications‐centric model, nuance‐based and algorithm/checklist‐assisted clinical decision‐making about procedure selection, novel bariatric procedures, enhanced recovery after bariatric surgery protocols, and logistical concerns (including cost factors) in the current health care arena. There are 85 numbered recommendations that have updated supporting evidence, of which 61 are revised and 12 are new. Noting that there can be multiple recommendation statements within a single numbered recommendation, there are 31 (13%) Grade A, 42 (17%) Grade B, 72 (29%) Grade C, and 101 (41%) Grade D recommendations. There are 858 citations, of which 81 (9.4%) are evidence level (EL) 1 (highest), 562 (65.5%) are EL 2, 72 (8.4%) are EL 3, and 143 (16.7%) are EL 4 (lowest).
Conclusions
Bariatric procedures remain a safe and effective intervention for higher‐risk patients with obesity. Clinical decision‐making should be evidence based within the context of a chronic disease. A team approach to perioperative care is mandatory, with special attention to nutritional and metabolic issues.
...ILI participants were found to have greater fitness and gait speed persisting over the course of the trial, which argues against any adverse effects on muscle function. An important aspect of the ...Look AHEAD data is that there was progressive weight loss in both subgroups occurring 6 to 12 years after randomization in contrast with an expected increase in body weight that occurs over time in many cohorts. ...this phenomenon is explained, the degree to which ILI may have an independent effect on frailty fractures will remain uncertain. Regarding CVD events and mortality, data from Look AHEAD, a meta-analyses of data from phase III trials of weight loss medications (4), and nested case-control studies in bariatric surgery (5) all suggest that benefits can be expected only with weight loss of 10% or greater. ...the evidence base calls for weight loss of at least 7% to 10% or more in patients with T2D and obesity, which can be achieved using the tools of obesity medicine, including ILI.
Obesity is closely related to the development of insulin resistance and type 2 diabetes (T2D). The prevention of T2D has become imperative to stem the rising rates of this disease. Weight loss is ...highly effective in preventing T2D; however, the at-risk pool is large, and a clinically meaningful metric for risk stratification to guide interventions remains a challenge. The objective of this study is to predict T2D risk using full-information continuous analysis of nationally sampled data from white and black American adults age ≥45 years.
A sample of 12,043 black (33%) and white individuals from a population-based cohort, REasons for Geographic And Racial Differences in Stroke (REGARDS) (enrolled 2003-2007), was observed through 2013-2016. The mean participant age was 63.12 ± 8.62 years, and 43.7% were male. Mean BMI was 28.55 ± 5.61 kg/m2. Risk factors for T2D regularly recorded in the primary care setting were used to evaluate future T2D risk using Bayesian logistic regression. External validation was performed using 9,710 participants (19% black) from Atherosclerotic Risk in Communities (ARIC) (enrolled 1987-1989), observed through 1996-1998. The mean participant age in this cohort was 53.86 ± 5.65 years, and 44.6% were male. Mean BMI was 27.15 ± 4.92 kg/m2. Predictive performance was assessed using the receiver operating characteristic (ROC) curves and area under the curve (AUC) statistics. The primary outcome was incident T2D. By 2016 in REGARDS, there were 1,602 incident cases of T2D. Risk factors used to predict T2D progression included age, sex, race, BMI, triglycerides, high-density lipoprotein, blood pressure, and blood glucose. The Bayesian logistic model (AUC = 0.79) outperformed the Framingham risk score (AUC = 0.76), the American Diabetes Association risk score (AUC = 0.64), and a cardiometabolic disease system (using Adult Treatment Panel III criteria) (AUC = 0.75). Validation in ARIC was robust (AUC = 0.85). Main limitations include the limited generalizability of the REGARDS sample to black and white, older Americans, and no time to diagnosis for T2D.
Our results show that a Bayesian logistic model using full-information continuous predictors has high predictive discrimination, and can be used to quantify race- and sex-specific T2D risk, providing a new, powerful predictive tool. This tool can be used for T2D prevention efforts including weight loss therapy by allowing clinicians to target high-risk individuals in a manner that could be used to optimize outcomes.
The development of these updated guidelines was commissioned by the AACE, TOS, and ASMBS Board of Directors and adheres to the AACE 2010 protocol for standardized production of clinical practice ...guidelines (CPG). Each recommendation was re-evaluated and updated based on the evidence and subjective factors per protocol. Examples of expanded topics in this update include: the roles of sleeve gastrectomy, bariatric surgery in patients with type-2 diabetes, bariatric surgery for patients with mild obesity, copper deficiency, informed consent, and behavioral issues. There are 74 recommendations (of which 56 are revised and 2 are new) in this 2013 update, compared with 164 original recommendations in 2008. There are 403 citations, of which 33 (8.2%) are EL 1, 131 (32.5%) are EL 2, 170 (42.2%) are EL 3, and 69 (17.1%) are EL 4. There is a relatively high proportion (40.4%) of strong (EL 1 and 2) studies, compared with only 16.5% in the 2008 AACE-TOS-ASMBS CPG. These updated guidelines reflect recent additions to the evidence base. Bariatric surgery remains a safe and effective intervention for select patients with obesity. A team approach to perioperative care is mandatory with special attention to nutritional and metabolic issues.
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