Welcome to the ATTD 2023 Interactive Program
IS015 - GLP-1 Analogs for the treatment of obesity (ID 230)
Abstract
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The classic approach to obesity treatment is a “treat to failure” model. If patients fail to lose weight or regain lost weight, they progressively escalate in a stepwise fashion to more intensive therapies, from lifestyle/behavioural therapy to pharmacotherapy and bariatric surgery.Weight loss that is associated with clinically impactful outcomes for most adiposity based chronic disease (ABCD) is 10 to 20%. The marked increment in efficacy of modern anti-obesity medications (AOMs) permits the weight loss within this range of magnitude as a new treatment target. The first AOM that fully enables such “treat to target” approach is GLP-1 receptor agonist (RA) semaglutide 2.4 mg.
The safety and efficacy of semaglutide was evaluated in The Semaglutide Treatment Effect in People with Obesity (STEP) Phase 3a clinical development program. STEP 2 enrolled patients with overweight or obesity with type 2 diabetes (T2D), while the remaining STEP studies (STEP 1, 3 and 4) enrolled patients with overweight and at least one weight-related comorbidity or obesity without T2D. Semaglutide safely produces ≥10% placebo subtracted weight loss in 69.1-75.3% of patients without T2D and in 45.6% of patients with T2D. The estimated treatment differences for semaglutide versus placebo were 10.3 to 17.4%. More than half of patients lost ≥15%, up to 35% of patients were able to achieve ≥ 20% weight loss as an adjunct to lifestyle. In STEP 5 semaglutide led to clinically impactful and sustained weight loss of 15.2% at week 104 in adults with obesity without T2D, along with improvements in weight related cardiometabolic risk factors. The ongoing study SELECT was designed to see if semaglutide may reduce the risk of having cardiovascular events in patients with prior cardiovascular disease and will be completed in 2023.
Significantly more females than males in STEP 1, 3 and 4, while in STEP 2, a distribution between females and males was more even. Understanding some inter-sex related difference in efficacy and some sex-specific effects of GLP-1 RAs is important to further improve therapeutic approaches in obesity care. GLP-1 RAs is being studied in women with obesity and polycystic ovary syndrome (PCOS). The ovulation rate and menstrual frequency improved with GLP-1 RAs exenatide and liraglutide. Short-term preconception intervention with exenatide resulted in an increase of natural pregnancy rates in overweight and obese women with PCOS. A pilot study showed that preconception treatment with liraglutide increased pregnancy rates for patients with PCOS undergoing in vitro fertilization who responded poorly to first line reproductive treatment. In another pilot study liraglutide was superior to testosterone replacement therapy in improving an overall health benefit in men with obesity-associated functional hypogonadism after lifestyle intervention failed.
The great advances are being seen in the use of GLP-1 receptor agonists in combination with multi-agonist unimolecular peptides, such as glucose dependent insulinotropic polypeptide (GIP), gastrin, amylin analogue, and others. GLP-1 RAs and other developing therapeutic tools will change the way clinicians approach obesity and the prognosis of many ABCDs.
IS016 - Unimolecular multiagonists (dual and triple) for the management of obesity and cardiorenal risk – An update (ID 231)
Abstract
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The selective glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, dulaglutide) have gained an ever-increasing prominence in the management of type 2 diabetes (T2D) and obesity, and several agents in the class have proven cardiovascular (CV) benefits. We are now moving into an era of incretin-based multiagonists. These so-called unimolecular multiagonists are single molecules that bind to and agonize 2 or more receptors. Recently, tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors was approved by regulatory agencies in the U.S. and Europe. In the T2D phase 3 SURPASS clinical development program, tirzepatide at 5, 10 and 15 mg once weekly demonstrated unprecedented glycemic and weight control across the spectrum of the disease, exceeding that seen with once-weekly semaglutide 1.0 mg (SURPASS-2) and titrated insulin degludec (SURPASS-3). In these studies, tirzepatide-treated patients exhibited a dose-dependent reduction in body weight exceeding a mean reduction of 10% in each trial, with up to approximately 60% of patients achieving ≥10% weight loss. In the recently published SURMOUNT-1 study, assessing tirzepatide for weight management in persons with overweight or obesity (without T2D), participants lost an average of over 20% body weight at 72 weeks, with approximately 40% achieving greater than 25% weight reduction. The tirzepatide CV outcomes trial (SURPASS-CVOT) is underway and scheduled to complete in 2024. A prespecified meta-analysis of 7 randomized-controlled trials assessing tirzepatide CV safety was recently published, demonstrating a 20% reduction in 4-point MACE for tirzepatide versus comparators thereby indicating its cardiovascular safety. Other GIP/GLP-1 receptor dual agonists as well as GLP-1/glucagon receptor agonists are currently in clinical development for T2D, obesity and/or non-alcoholic fatty liver disease. Additionally, a triple agonist (GIP/GLP-1/glucagon receptor) recently reported encouraging 12-week data in patients with T2D, with significant improvement in glycemic control and a mean reduction in body weight of approximately 10% at 12 weeks. It will be entering late stages of clinical development. As we look into the future, these important agents that address obesity and its many complications (including dysglycemia) should gain increasing prominence in our management of metabolic diseases. We await further weight loss data as well as data demonstrating potential cardiorenal benefits.
Challenging treatment guidelines: Reversing type 2 DM from Day One (ID 232)
IS017 - Bariatric surgery: An update (ID 233)
Abstract
Abstract Body
Background: The classic description, I.e., that Type 2 Diabetes (T2D)is an incurable, unique and progressive disease due to insulin resistance, no longer holds true.Methods: Basic and clinical studies as well as literature review
Results: The world-wide epidemic of obesity, T2D and hypertension and the dramatic effects of bariatric surgery and the newer medications call for a reassessment of our traditional beliefs about these diseases. The first challenge came from geriatric surgery. How could the two most commonly performed bariatric surgical operations, i.e. the gastric sleeve and bypass
(Fig. 1), lead to full normalization of glucose, insulin and lactate levels in less than a week, before there is any significant loss of adiposity? If insulin resistance is directly related to T2D, why, as shown in Fig 2,
did it remain unchanged for three months in our studies? Further, how does the traditional dogma explain the broad response to the surgery with the rapid and durable remission of T2D (83%), other expressions of metabolic disease also show long-term correction: hypertension (52%), dyslipidemia (63%), non-alcoholic steatotic hepatitis (NASH) 37%,, polycystic ovary syndrome (79%), migraine (57%), obstructive sleep apnea (74%), asthma 82%, cardiovascular disease (82%). stress urinary incontinence (44%), degenerative joint disease (41%), venous stasis disease (95%), gout (77%), improvement in cognition, reduction in the prevalence of cancer within five years and an 89% reduction in all-cause mortality? The durability of these effects is also remarkable. We have two patients, operated on 32 and 33 years ago, still free of T2D.
Conclusions: The key to understanding these effects, lies in the high lactate levels, reflecting only partial utilization of glucose by mitochondria, in patients with the metabolic syndrome. Because all of these effects follow a highly specific and limited intervention, i.e., decreasing contact between food and the stomach with rapid correction of glucose, insulin and lactate, a likely explanation is that this portion of the foregut sends a dysmetabolic signal to mitochondria that limits the utilization of glucose and fatty acids in most if not all organ systems as shown in Fig. 3.
Instead of full utilization of glucose to produce 32 ATP, the signal limits energy production to 4 ATP with conversion of the remainder to lactate, glucose and fat.
While this mechanism that limits the conversion of glucose to ATP by mitochondria may be injurious today at a time of ready access to food, it could be an ancient adaptation that facilitated storage of fat in times of plenty. It could also be an underlying process in hibernation.
Based on these observations, our approach to T2D, obesity and the other expressions of the metabolic syndrome deserve review. Insulin resistance is not the cause of T2D.
Q&A (ID 752)