The Effect of Bariatric Surgery on Diabetic Retinopathy: Good, Bad, or Both?

Bariatric surgery, initially intended as a weight-loss procedure, is superior to standard lifestyle intervention and pharmacological therapy for type 2 diabetes in obese individuals. Intensive medical management of hyperglycemia is associated with improved microvascular outcomes. Whether or not the reduction in hyperglycemia observed after bariatric surgery translates to improved microvascular outcomes is yet to be determined. There is substantial heterogeneity in the data relating to the impact of bariatric surgery on diabetic retinopathy (DR), the most common microvascular complication of diabetes. This review aims to collate the recent data on retinal outcomes after bariatric surgery. This comprehensive evaluation revealed that the majority of DR cases remain stable after surgery. However, risk of progression of pre-existing DR and the development of new DR is not eliminated by surgery. Instances of regression of DR are also noted. Potential risk factors for deterioration include severity of DR at the time of surgery and the magnitude of glycated hemoglobin reduction. Concerns also exist over the detrimental effects of postprandial hypoglycemia after surgery. In vivo studies evaluating the chronology of DR development and the impact of bariatric surgery could provide clarity on the situation. For now, however, the effect of bariatric surgery on DR remains inconclusive

How do patients' clinical phenotype and the physiological mechanisms of the operations impact the choice of bariatric procedure?

Bariatric surgery is currently the most effective option for the treatment of morbid obesity and its associated comorbidities. Recent clinical and experimental findings have challenged the role of mechanical restriction and caloric malabsorption as the main mechanisms for weight loss and health benefits. Instead, other mechanisms including increased levels of satiety gut hormones, altered gut microbiota, changes in bile acid metabolism, and/or energy expenditure have been proposed as explanations for benefits of bariatric surgery. Beside the standard proximal Roux-en-Y gastric bypass and the biliopancreatic diversion with or without duodenal switch, where parts of the small intestine are excluded from contact with nutrients, resectional techniques like the sleeve gastrectomy (SG) have recently been added to the armory of bariatric surgeons. The variation of weight loss and glycemic control is vast between but also within different bariatric operations. We surveyed members of the Swiss Society for the Study of Morbid Obesity and Metabolic Disorders to assess the extent to which the phenotype of patients influences the choice of bariatric procedure. Swiss bariatric surgeons preferred Roux-en-Y gastric bypass and SG for patients with type 2 diabetes mellitus and patients with a body mass index >50 kg/m(2), which is consistent with the literature. An SG was preferred in patients with a high anesthetic risk or previous laparotomy. The surgeons' own experience was a major determinant as there is little evidence in the literature for this approach. Although trends will come and go, evidence-based medicine requires a rigorous examination of the proof to inform clinical practice

Mechanism Underlying the Weight Loss and Complications of Roux-en-Y Gastric Bypass. Review

Various bariatric surgical procedures are effective at improving health in patients with obesity associated co-morbidities, but the aim of this review is to specifically describe the mechanisms through which Roux-en-Y gastric bypass (RYGB) surgery enables weight loss for obese patients using observations from both human and animal studies. Perhaps most but not all clinicians would agree that the beneficial effects outweigh the harm of RYGB; however, the mechanisms for both the beneficial and deleterious (for example postprandial hypoglycaemia, vitamin deficiency and bone loss) effects are ill understood. The exaggerated release of the satiety gut hormones, such as GLP-1 and PYY, with their central and peripheral effects on food intake has given new insight into the physiological changes that happen after surgery. The initial enthusiasm after the discovery of the role of the gut hormones following RYGB may need to be tempered as the magnitude of the effects of these hormonal responses on weight loss may have been overestimated. The physiological changes after RYGB are unlikely to be due to a single hormone, or single mechanism, but most likely involve complex gut-brain signalling. Understanding the mechanisms involved with the beneficial and deleterious effects of RYGB will speed up the development of effective, cheaper and safer surgical and non-surgical treatments for obesity

The Neurobiological Impact of Ghrelin Suppression after Oesophagectomy

Ghrelin, discovered in 1999, is a 28-amino-acid hormone, best recognized as a stimulator of growth hormone secretion, but with pleiotropic functions in the area of energy homeostasis, such as appetite stimulation and energy expenditure regulation. As the intrinsic ligand of the growth hormone secretagogue receptor (GHS-R), ghrelin appears to have a broad array of effects, but its primary role is still an area of debate. Produced mainly from oxyntic glands in the stomach, but with a multitude of extra-metabolic roles, ghrelin is implicated in complex neurobiological processes. Comprehensive studies within the areas of obesity and metabolic surgery have clarified the mechanism of these operations. As a stimulator of growth hormone (GH), and an apparent inducer of positive energy balance, other areas of interest include its impact on carcinogenesis and tumour proliferation and its role in the cancer cachexia syndrome. This has led several authors to study the hormone in the cancer setting. Ghrelin levels are acutely reduced following an oesophagectomy, a primary treatment modality for oesophageal cancer. We sought to investigate the nature of this postoperative ghrelin suppression, and its neurobiological implications

Inhibition of food intake in obese subjects by peptide YY3-36

Background: The gut hormone fragment peptide YY3-36 (PYY) reduces appetite and food intake when infused into subjects of normal weight. In common with the adipocyte hormone leptin, PYY reduces food intake by modulating appetite circuits in the hypothalamus. However, in obesity there is a marked resistance to the action of leptin, which greatly limits its therapeutic effectiveness. We investigated whether obese subjects were also resistant to the anorectic effects of PYY.Methods: We compared the effects of PYY infusion on appetite and food intake in 12 obese and 12 lean subjects in a double-blind, placebo-controlled, crossover study. The plasma levels of PYY, ghrelin, leptin, and insulin were also determined.Results: Caloric intake during a buffet lunch offered two hours after the infusion of PYY was decreased by 30 percent in the obese subjects (P<0.001) and 31 percent in the lean subjects (P<0.001). PYY infusion also caused a significant decrease in the cumulative 24-hour caloric intake in both obese and lean subjects. PYY infusion reduced plasma levels of the appetite-stimulatory hormone ghrelin. Endogenous fasting and postprandial levels of PYY were significantly lower in obese subjects (the mean [+/-SE] fasting PYY levels were 10.2+/-0.7 pmol per liter in the obese group and 16.9+/-0.8 pmol per liter in the lean group, P<0.001). Furthermore, the fasting PYY levels correlated negatively with the body-mass index (r=-0.84, P<0.001).Conclusions: We found that obese subjects were not resistant to the anorectic effects of PYY. Endogenous PYY levels were low in the obese subjects, suggesting that PYY deficiency may contribute to the pathogenesis of obesity

Pharmacological profile of once-weekly injectable semaglutide for chronic weight management

Introduction: The recent approval in the USA (Food and Drug Administration), Canada (Health Canada), UK (Medicines and Healthcare products Regulatory Agency), and EU (European Medicines Agency) of once-weekly injectable semaglutide 2.4 mg, as an adjunct to a calorie-controlled diet and increased physical activity, for chronic weight management provides health-care practitioners with an additional option when prescribing weight-loss medication. Areas covered: We describe the chemistry, mechanism of action, and pharmacological properties of semaglutide (a glucagon-like peptide 1 receptor agonist [GLP-1 RA]) and discuss clinical data and considerations for using once-weekly subcutaneous semaglutide 2.4 mg as treatment for overweight and obesity among patients with and without type 2 diabetes (T2D). Expert opinion: Once-weekly subcutaneous semaglutide 2.4 mg is the most efficacious medication approved for chronic weight management among patients with overweight and obesity, with and without T2D, and is the first drug to induce sustained double-digit reductions in percentage body weight over 1- to 2-year treatment periods. It demonstrates a similar safety and tolerability profile to other GLP-1 RAs. Semaglutide 2.4 mg treatment could dramatically improve clinical approaches to weight management, but the relatively high cost might prevent patients accessing treatment. Further research exploring the cost-effectiveness of subcutaneous semaglutide 2.4 mg is required

Measurement of hepatic insulin sensitivity early after the bypass of the proximal small bowel in humans

Objective: Unlike gastric banding or sleeve gastrectomy procedures, intestinal bypass procedures, and the Roux-en-Y gastric bypass (RYGB) in particular, lead to rapid improvements in glycaemia early after surgery. The bypass of the proximal small bowel may have weight loss and even caloric restriction independent glucose-lowering properties on hepatic insulin sensitivity. In this first in humans mechanistic study, we examined this hypothesis by investigating the early effects of the duodeno-jejunal bypass liner (DJBL; GI Dynamics, USA) on the hepatic insulin sensitivity using the gold standard euglycaemic hyperinsulinaemic clamp methodology. Method: Seven patients with obesity underwent measurement of hepatic insulin sensitivity at baseline, one week after a low-calorie liquid diet and after a further one week following insertion of the DJBL whilst on the same diet. Results: DJBL did not improve the insulin sensitivity of hepatic glucose production (HGP) beyond the improvements achieved with caloric restriction. Conclusions: Caloric restriction may be the predominant driver of early increases in hepatic insulin sensitivity after the endoscopic bypass of the proximal small bowel. The same mechanism may be at play after RYGB and explain, at least in part, the rapid improvements in glycaemia

Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial

BACKGROUND: Natural amylin is a pancreatic hormone that induces satiety. Cagrilintide is a long-acting amylin analogue under investigation for weight management. We assessed the dose–response relationship of cagrilintide regarding the effects on bodyweight, safety, and tolerability. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial at 57 sites including hospitals, specialist clinics, and primary care centres in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the UK, and the USA). Eligible participants were adults aged at least 18 years without diabetes, with a body-mass index of at least 30 kg/m^{2} or at least 27 kg/m^{2} with hypertension or dyslipidaemia. Participants were randomly assigned (6:1) to subcutaneous self-injections of once-weekly cagrilintide (0·3, 0·6, 1·2, 2·4, or 4·5 mg), once-daily liraglutide 3·0 mg, or volume-matched placebo (for six placebo groups). The trial had a 26-week treatment period, including a dose-escalation period of up to 6 weeks, and a 6-week follow-up period without treatment. Participants and investigators were masked to the assigned study treatment with respect to active versus pooled placebo treatment, but not to different active treatments. The primary endpoint was the percentage change in bodyweight from baseline to week 26, assessed in all randomly assigned participants according to the trial product estimand (assuming all participants were adherent to treatment) and to the treatment policy estimand (regardless of adherence to treatment). Safety was assessed in all participants who received at least one dose of randomised treatment. This trial is registered with ClinicalTrials.gov, NCT03856047, and is closed to new participants. FINDINGS: Between March 1 and Aug 19, 2019, we randomly assigned 706 participants to cagrilintide 0·3–4·5 mg (100–102 per dose group), 99 to liraglutide 3·0 mg, and 101 to placebo. Permanent treatment discontinuation (n=73 [10%]) occurred similarly across treatment groups, mostly due to adverse events (n=30 [4%]). In total, 29 participants (4%) withdrew from the trial. According to the trial product estimand, mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0·3–4·5 mg, 6·0%–10·8% [6·4–11·5 kg]) versus placebo (3·0% [3·3 kg]; estimated treatment difference range 3·0%–7·8%; p<0·001). Weight reductions were also greater with cagrilintide 4·5 mg versus liraglutide 3·0 mg (10·8% [11·5 kg] vs 9·0% [9·6 kg]; estimated treatment difference 1·8%, p=0·03). Similar weight loss reductions were observed with the treatment policy estimand. The most frequent adverse events were gastrointestinal disorders (eg, nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0·3–4·5 mg had gastrointestinal adverse events compared with placebo (41%–63% vs 32%), primarily nausea (20%–47% vs 18%). INTERPRETATION: Treatment with cagrilintide in people with overweight and obesity led to significant reductions in bodyweight and was well tolerated. The findings support the development of molecules with novel mechanisms of action for weight management. FUNDING: Novo Nordisk A/S