Hi, my name is Karla San André. I'm an endocrinologist and instructor of medicine at Houston Methodist Hospital in Houston, Texas. In the next slides, we're going to talk about diabetes, the relationship between diabetes and obesity, as well as we're going to discuss the evidence we have regarding treating obesity and the management of diabetes and its impact in cardiovascular risks. What is diabetes? So we've heard this term many times, probably, but it's actually a term that was coined since 1973 by Professor Ethan Simmons from Yale New Haven. He was very interested in studying the genetic and environmental factors that play a role in developing obesity and then obesity developing type 2 diabetes. So is this interaction, relationship between type 2 diabetes and obesity? Okay, so some statistics we have. Diabetes affects about 11.3% of the population in the United States and about 10.5% of the population in the world. Prediabetes affects about 40% of the US population and about 5.8% of the population worldwide. Obesity contributes to about 80-90% of cases of type 2 diabetes and patients with type 2 diabetes, about 90% of them have obesity. Globally, obesity is responsible for around 43% of type 2 diabetes cases and obesity is associated with a risk of developing type 2 diabetes 7-13 times higher than those who do not have obesity. So another important thing is 5-7 kilos of weight gain increases the risk of developing diabetes by 50% and 5 kilos, which is anywhere from 11-15 pounds, decreases the risk of developing diabetes also by 50%. In the next slides, we're going to be discussing the evidence for treating obesity to manage glucose and cardiovascular risk in people who have type 2 diabetes. So far, we know that weight loss has been associated with a wide range of positive health outcomes, including improved glycemic control, reduction in A1C levels, improved lipid profile, improved blood pressure, reduced risk of cardiovascular events, and positive impact on inflammatory markers. The American Diabetes Association, in its last Standards of Care in Diabetes publication in 2023, states that individuals with diabetes and overweight or obesity may benefit from modest or larger magnitudes of weight loss. Relatively small weight loss, which is anywhere from 3-7% of baseline weight, improves glycemia. Larger, sustained weight losses, which is considered more than 10% of their baseline weight, usually confers greater benefits, including remission of type 2 diabetes and improving long-term cardiovascular outcomes and mortality. One of the important studies is the Diabetes Prevention Program. So this program lasted about four years and involved about 3,000 participants with pre-diabetes. This was a multi-central randomized controlled child and it had three arms, placebo control, lifestyle interventions, and metformin. And it revealed that lifestyle interventions, including modest weight loss through dietary modifications and increased physical activity, actually reduced the risk of developing type 2 diabetes by almost 60% compared to the placebo group. And metformin was also important and demonstrated a decreased risk of type 2 diabetes of 31%. Another big study was LOOKAHEAD, Action for Health and Diabetes Study. It was a randomized controlled trial that lasted 9-11 years. It involved 5,000 participants with overweight or obesity and type 2 diabetes. And it wanted to assess the magnitude of weight loss and its association with improvements in glycemia, blood pressure, and lipid parameters. So compared with weight-stable participants, those who lost 5-10% of their weight had decreased levels of A1c by around 0.5%. They also had decreased levels of diastolic and systolic blood pressure, increased levels of HDL cholesterol, and decreased levels of triglycerides. And the odds of clinically significant improvement in most risk factors were even greater in those who lost about 10-15% of the body weight. So what do we know about GLP-1 receptor agonists? They are the most promising drugs for treatment of obesity. So apart from the weight loss and positive effect on glucose regulation, GLP-1s can also influence triglycerides and total cholesterol levels. So short and long-term treatment with GLP-1s reduce fasting and post-prandolipid levels in patients with type 2 diabetes, as well as in healthy populations with obesity data we currently have. There's also evidence that some GLP-1 receptor agonists can lower the concentration of atherogenic lipoproteins in plasma, such as like araclitide, which has shown to be able to reduce levels for small dense LDL. So GLP-1s has also anti-inflammatory effects, cardio-protective effects in ischemia, decreased platelet aggregation, reducing macrophage inflammation, among other benefits. A meta-analysis showed subcutaneous semaglutide is the most potent GLP-1 receptor agonist in reducing blood pressure, followed by oral semaglutide, exenatide, and laryngotide in patients with type 2 diabetes. The importance of cardiovascular reduction is best illustrated by the fact that decreases in systolic blood pressure by about 10 millimeters of mercury reduces cardiovascular risk by 11 percent, as well as decreases in LDL cholesterol of about one millimeter per liter, also decreases the risk for cardiovascular disease by 30 percent in diverse groups of patients. A review of head-to-head trials from 2018 of six GLP-1 receptor agonists showed that the greatest statistical difference in blood pressure was about 2.7 millimeters of mercury. Laryngotide resulted in a significant greater decrease from baseline systolic blood pressure compared to the laryngotide, as well semaglutide, 1.0 milligrams once weekly, also showed significantly decreased systolic blood pressure compared to exenatide, with a difference of 2.4 millimeters of mercury. And other benefits, prosporondial hypertriglyceridemia is also a potent risk predictor of atheroscleric cardiovascular disease, even in the presence of normal fasting triglycerol levels, recalling prosporondial. Reduction in triglycerol levels by laryngotide, for example, was the main contributor of the reduction in clinical atherosclerosis, highlighting the importance of this triglyceride-lowering agent. Another important topic is bariatric surgery and its association with reduced incidence of diabetes in people with obesity. So this is a core study of adult patients from a UK-wide database of family practices. This is about 2,000 patients who had obesity BMIs of about 30 kg per meter square and did not have diabetes. These patients had underwent bariatric surgery from 2002 to 2014. You can see here the years, you know, for about seven years. The procedures include laparoscopic gastric banding, about 50% of patients, gastric bypass, about almost 40% of patients, and gastrectomy, about 15% of the patients. So by the end of seven years of follow-up, the comparison was like 4.3% of patients who underwent bariatric surgery developed diabetes, compared to 16.2% of match controls. A lot of these studies impede surgical therapy and medications potentially eradicate diabetes efficiently. This was published in New England Journal of Medicine 2017, and it was evaluating the outcomes of five years after 150 participants who had type 2 diabetes and BMI levels above 27 were randomly assigned to receive either intensive medical therapy alone or intensive medical therapy plus rheumatoid gastric bypass or gastrectomy. The primary outcome was to achieve levels of A1c of 6% or less, diabetes, you know, remission. So the results show that only 5% of those patients who received medical therapy alone achieved A1c levels of 6% or less, versus 29% of patients who underwent gastric bypass and versus 23% of patients who underwent gastrectomy. Secondary outcomes was also the change in body weight. For example, patients with gastric bypass were able to lose about minus 23% of excess body weight compared to minus 19% gastrectomy and closer to 5% only medical therapy groups. Thirdly, survivals also were changed. Minus 40% in patients with gastric bypass compared to 29% gastrectomy and minus 8% in medical therapy alone. HDL levels of cholesterol also increased. About 32% of patients who underwent gastric bypass, 30% gastrectomy, and 7% medical therapy alone. The use of insulin, about 35% of patients with rheumatoid gastric bypass were off insulin compared to 34% gastrectomy and about 13% intensive medical therapy. The quality of life also improved much better in patients who underwent bariatric surgery compared to intensive medical therapy alone. A recent study published in New England Medicine 2021 compared the effect of trisepatide and somatotide in glycated hemoglobin levels in patients with diabetes from baseline to 40 weeks. It was a phase 3 trial involving 1800 patients and they were randomized to 1 to 1 to 1 to 1 ratio, trisepatide 5, 10, 15 milligram or somatotide 1 milligram. The primary endpoint was changes in A1c level from baseline which was around 8.2% to 40 weeks. The mean reductions in A1c with trisepatide max dose 15 milligram was around minus 3.2% versus minus 2.6% with somatotide 1 milligram. Also a total of 65 to 80% of patients who received trisepatide were able to lose at least 5% of excess body weight compared to 54% of those who received somatotide. You can see the patients who were on trisepatide were able to lose more weight, 10 or even 15% of excess body weight compared to somatotide. Total changes in total cholesterol and LDL levels did not differ. Now we're going to review the ACE, American Association of Clinical Endocrinology Clinical Practice Guidelines for Patients with Diabetes and Obesity. So the Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity published in 2016. The topic is therapeutic benefits of whalers in patients with overweight or obesity. Question 5 is whalers effective to treat diabetes risk, for example prediabetes metabolic syndrome, and prevent progression to type 2 diabetes and how much whalers should be required. The states that patients with overweight obesity and with either metabolic syndrome or prediabetes or patients identify a high risk of type 2 diabetes should be treated with lifestyle therapy including reduced calorie healthy meal plan and physical activity. And the whalers goal should be 10%. Medication-assisted whalers employing phentermin topiramidexin-released laryngotide or Olistat should also be considering patients at risk for future type 2 diabetes and should be used when needed to achieve 10% whalers. Diabetes medications such as metformin, acarose, and TCDs can be considered in selected high risk patients with prediabetes who are not successfully treated with lifestyle and weight loss medications and who remain glucose intolerant. Continuing, the next question is, is weight loss effective to treat type 2 diabetes and how much weight loss would be required? So patients with overweight or obesity and type 2 diabetes should be treated with lifestyle therapy to achieve 5 to 15% weight loss or more as needed to achieve target lowering A1c. Weight loss medications should be considered as an adjunct to lifestyle therapy in all patients with type 2 diabetes as needed for weight loss sufficient to improve glycemic control, lipids, and blood pressure. Patients with obesity, BMI above 30, and diabetes who have failed to achieve target clinical outcomes following treatment with lifestyle therapy and weight loss medications may be considered for bariatric surgery, preferable room-wide gastric bypass, celiac gastrectomy, or biliopentagrotic diversion. Diabetes medications that are associated with modest weight loss or are weight neutral are preferable in patients with obesity and type 2 diabetes. Next question, is weight loss effective to treat or prevent cardiovascular disease and how much weight loss would be required? Remember this is from July 2016. Does weight loss prevent cardiovascular disease events from mortality? Weight loss therapy is not recommended based on available data at the time, however, evidence suggests that the degree of weight loss achieved by bariatric surgery can reduce mortality. We do have data on that, right? Does weight loss prevent cardiovascular disease events from mortality and diabetes and at that time it was not recommended based on available data. When should bariatric surgery be used to treat obesity and weight-related complications? And at that time it was required to have a BMI of 30 to 34.9 kg per meter square with diabetes or metabolic syndrome for you to be considered for bariatric surgery. In 2022, we had an update in the clinical practice guideline developing a diabetes mellitus comprehensive care plan. The diagnosis and evaluation of AVCD adiposity-based chronic disease in persons with pre-diabetes type 1 diabetes or type 2 diabetes should include both anthropometric and clinical components. The anthropometric evaluation should include a BMI conferred by either physical exam that excludes excess mass muscle edema or sarcopenia. Also waist circumference should be measured as a marker of cardiometabolic disease risk. The clinical evaluation of persons with both pre-diabetes type 1 diabetes or type 2 diabetes and AVCD should assess the presence and severity of weight-related complications including cardiometabolic complications such as dyslipidemia, hypertension, NAFLD, cardiovascular disease, heart failure, CKD, biomechanical complications such as OSA, osteotritis, GERD, urinary incontinence, abnormalities involving sex steroids such as infertility, PCOS, hypergonadism, and as well as impact physiological disorders and quality of life. Continuation persons with type 2 diabetes and obesity AVCD with BMIs above 27 should be treated with diabetes medications associated with weight loss including GLP-1 receptor agonist and SGLT2 inhibitors. In addition for people with pre-diabetes type 1 diabetes or type 2 diabetes who have obesity AVCD we should consider FDA approved weight loss medications as an adjunct to lifestyle intervention to achieve lowering A1C levels, reduction of cardiovascular risk factors, treatment or prevention of other complications. Persons with BMI above 35 and one or more severe obesity-related complications remediable by weight loss including type 2 diabetes, poorly controlled hypertension, osteotritis, etc. should be considered for bariatric procedures. In persons with BMIs of 30 to 34.9 kg per meter square and type 2 diabetes with inadequate glycemic control despite optimal lifestyle should be considered for bariatric procedure. So if you can actually see the BMI threshold decreased. This is a nice graph that is summarizing comprehensive type 2 diabetes management from ACE. So for nutrition people who have overweight or obesity is recommended to add a caloric deprevention of 500 to 1000 kcal per day. For adults 18 years or older it's also important to have about six to eight hours of sleep per night. It's also important for formal counseling tools which include the WHO well-being index, the PHQ-9 for depression, referral for cognitive behavioral therapy or medical intervention should be considered when depression is present. Medications, weight loss medications or anti-obesity medications should be considered in combination with a reduced calorie diet to achieve and sustain weight loss goals in patients with BMIs 27 to 29.9 with type 2 diabetes or other ABCD complications and all persons with BMI above 30. And interventions metabolic procedures such as bariatric surgery should be considering patients with BMIs of 30 to 34.9 with uncontrolled diabetes in spite of a lifestyle medical therapy and BMIs above 35 and one or more ABCD complications including pre-diabetes which can be remedied with weight loss. So this is the ABCD algorithm from ACE. I find it very useful okay so you first see that you have to assess BMI anthropometric measures right after it then you assess for any comorbidities after you have BMI comorbidities you can stage them stage one stage two stage three depending on the stage is where you're going to go and look at the recommendations for nutrition physical activities sleep medications or interventions it's very very useful. The next slides we're going to review the data for the use of increasing therapies with GLP-1, GLP-2 in people with type 2 diabetes and who are at risk of cardiovascular events. So this slide I really like it because it's summarizing you look to your right all the current available clinical trials that we have with GLP-1 or separate agonists and the prevention of major adverse cardiovascular events compared to placebo and the only one that we don't see any benefit is lexinsenatide so we'll talk more about it in the next slide. So summarizing the past graphs we show that with the exception of lexinsenatide all other GLP-1s or at least showed a trend of reduced incidence of major adverse cardiovascular events which is usually cardiovascular death non-fatal MI or non-fatal stroke. So lexinsenatide and alveglutide are not in the market anymore. Levaglutide in the later trial was unique not only significantly reduced MACE events but also decreased cardiovascular and all-cause mortality in people with type 2 diabetes. Dualvaglutide in rewind trial reduced the risk of MACE by 12% in patients without established cardiovascular disease who had multiple cardiovascular risk. Somaglutide in a subcutaneous trial sustained 6 an oral trial which primary 6 showed impressive results especially you know considering the the sample sizes. Across all trials significant reductions by 9 to 16% in the incidence of acute MI, stroke, cardiovascular and even all-cause mortality could be achieved by the GLP-1 receptor agonist class. Select which is somaglutide 2.4 milligram reduces risk of MACE in adults with type 2 diabetes or obesity and has about 20% risk reduction. This is the newest data we have. So this is the last slide and we don't have a lot of information on tercepatide or dual GIP GLP-1 receptor agonist. However what we found from this study showing that tercepatide decreases to pro-inflammatory markers like CRP, YKL-40, ICAM-1, leptin levels after treatment. So and these substances are usually associated with increased risk of MACE. So this pattern suggests an early direct effect of tercepatide suppressing inflammation and improving endothelium function independent of weight loss. So all of this is very promising.

diabetes

obesity

weight loss

GLP-1 receptor agonists

bariatric surgery

cardiovascular risk factors