Combined GLP-1 Receptor Agonist and Amylin Analogue Pharmacotherapy to Treat Obesity Comorbid With Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) with obesity is increasingly common, prompting effective clinical interventions to induce weight loss in this population. We present 3 patients with T1DM and obesity prescribed a glucagon-like peptide 1 receptor agonist (GLP-1RA) and pramlintide. Case 1: A 32-year-old male with obstructive sleep apnea (OSA) who lost -20.9 kg (-16.1% of total body weight [TBW]) over 10 months on semaglutide and pramlintide. Case 2: A 68-year-old female with diabetic retinopathy, coronary artery disease, hypertension, hypothyroidism, and depression/anxiety initially treated with topiramate, losing -8.4 kg, but experiencing weight plateau. After adding dulaglutide and pramlintide, she lost an additional -12.8 kg (-14.0% TBW) over 7 months, with total weight loss of -21.2 kg (-23.1% TBW). Case 3: A 49-year-old female with hypertension, hypothyroidism, and depression who lost -14.6 kg (-17.9% TBW) over 6 months on semaglutide and pramlintide. No significant side effects were experienced. All patients reported decreased insulin requirements on pramlintide, and hemoglobin A1c levels remained constant or decreased throughout the treatment period. Pramlintide and GLP-1RA resulted in excellent weight loss in our patients with obesity and T1DM. This combination may have a synergistic effect on the gut-brain axis. More research is required to substantiate these findings.

Combination anti-obesity medications to effectively treat bariatric surgery weight regain at an academic obesity center.

Background: Combination anti-obesity medications (AOMs) to treat postoperative bariatric surgery weight regain have limited data on their use in the clinical setting. Understanding the optimal treatment protocol in this cohort will maximize weight loss outcomes. Methods: A retrospective review of bariatric surgery patients (N = 44) presenting with weight regain at a single academic multidisciplinary obesity center who were prescribed AOM(s) plus intensive lifestyle modification for 12 months. Results: Age: 28-76 years old, 93% female, mean weight 110.2 ± 20.3 kg, BMI 39.7 ± 7.4 kg/m2, presenting 5.2 ± 1.6 years post-bariatric surgery [27 (61.4%), 14 (31.8%), and 3 (6.8%) laparoscopic Roux-en-Y gastric bypass (RYGB), laparoscopic vertical sleeve gastrectomy (VSG), and open RYGB, respectively], with 15.1 ± 11.1 kg mean weight gain from nadir. Mean weight loss after medical intervention at 3-, 6-, and 12-month time points was 4.4 ± 4.6 kg, 7.3 ± 7.0 kg, and 10.7 ± 9.2 kg, respectively. At 12 months, individuals prescribed 3 or more AOMs lost more weight than those prescribed one (-14.5 ± 9.0 kg vs. -4.9 ± 5.7 kg, p < 0.05) irrespective of age, gender, number of comorbidities, initial weight or BMI, type of surgery, or GLP1 use. RYGB patients lost less weight overall (7.4% vs. 14.8% VSG respectively; p < 0.05). Conclusions: Combination AOMs may be needed to achieve optimal weight loss results to treat post-operative weight regain.

Comparative effects of weight loss and incretin-based therapies on vascular endothelial function, fibrinolysis and inflammation in individuals with obesity and prediabetes: A randomized controlled trial.

AIM: To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms. MATERIALS AND METHODS: Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1) and urine albumin-to-creatinine ratio (UACR). RESULTS: Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1). CONCLUSION: Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.

DPP4 (Dipeptidyl Peptidase-4) Inhibition Increases Catecholamines Without Increasing Blood Pressure During Sustained ACE (Angiotensin-Converting Enzyme) Inhibitor Treatment.

BACKGROUND: DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study. METHODS: We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout. RESULTS: We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan. CONCLUSIONS: Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.