Treating the Obese Diabetic

Julia Kenkre; Tricia Tan; Stephen Bloom

Disclosures

Expert Rev Clin Pharmacol. 2013;6(2):171-183. 

In This Article

The Effect of Antiobesity Treatments on Glycemic Control

Nonpharmacological Treatments

Lifestyle Measures. Lifestyle measures – that is, physical activity and dietary measures, in some cases with concomitant behavioral modification – are part of all recommendations to achieve weight loss in Type 2 diabetics. There is evidence to support a role for lifestyle measures, both in the prevention and treatment and possibly in the reversal of Type 2 diabetes.

First, lifestyle measures are effective at producing weight loss in Type 2 diabetics. The recently terminated Look AHEAD study sought to examine the effect of intensive lifestyle measures on reduction in CV events in Type 2 diabetes.[46] It found that at 1 year those in the intensive lifestyle arm lost an average 8.6% of their initial weight versus 0.7% in usual care. A greater proportion of the intensive group had reductions in their requirement for diabetes, hypertension and lipid-lowering medicines. Mean HbA1c dropped from 7.3 to 6.6% in the intensive group versus from 7.3 to 7.2% in the usual care arm. Despite this, there was disappointingly no reduction in rates in myocardial infarction or strokes in the intensively treated group.[202]

A concern regarding lifestyle interventions is that the weight loss achieved is not sustained. A systematic review of 21 study groups involving a total of 3030 participants looking at the long-term effects of dietary intervention in obesity between 1931 and 1999 found a median success rate of 15% of those who undertook a dietary intervention in either maintaining all weight loss initially achieved or at least 9–11 kg of initial weight loss.[47] A Cochrane review suggested that lifestyle measures are effective but limited at producing sustained weight loss in Type 2 diabetics: 22 studies were included covering 4659 participants with Type 2 diabetes, with follow-up of between 1 and 5 years. The pooled weight loss achieved by any non-pharmacological intervention in comparison to usual care in 517 of the participants was 3.1% of baseline bodyweight.[48] The fact that there was also significant weight loss in the comparison groups may in part explain the small size of the effect seen in the intervention group.

Can lifestyle measures reverse established diabetes in a similar way to bariatric surgery? Eleven people with Type 2 diabetes of short duration (less than 4 years) were given a very low calorie (600 kcal) diet for 8 weeks. After 1 week of the diet fasting plasma glucose had returned to normal along with hepatic insulin sensitivity and during the study period of 8 weeks the first-phase insulin response increased. Average weight loss during the 8 weeks of dietary intervention was 15.3 ± 1.2 kg, equivalent to 15 ± 1% of initial bodyweight.[49] While the subjects were followed-up for a period of 12 weeks post intervention and showed some weight gain and an increase in fasting plasma glucose during this period, data regarding longer term follow-up would be helpful to assess the outcome after return to a normal diet.

Bariatric Surgery. In a properly selected patient, bariatric surgery is a cost-effective[50] treatment that prevents and treats Type 2 diabetes,[51] providing long-term control for obesity and long-term remission for Type 2 diabetes.[52] As well as being useful as a treatment for diabetes, bariatric surgery is more effective at preventing onset of Type 2 diabetes than usual care.[51] Bariatric surgery is associated with decreased overall mortality[53,54] and a lower incidence of myocardial infarction in Type 2 diabetics.[55] There are increasing numbers of people undergoing bariatric surgery: in the USA, from 1990 to 2000, the annual rate of bariatric surgery increased from 2.4 to 14.1 per 100,000 adults.[56] Worldwide in 2008, 344,221 bariatric surgery operations were performed, the majority in the USA and Canada.[57]

Current recommendations from the ADA,[58] NICE and the International Diabetes Federation[59] suggest bariatric surgery should be considered in Type 2 diabetics with a BMI ≥35 kg/m2. There is also accumulating evidence for its use in some Type 2 diabetics with a lower BMI.[60] The variants of bariatric surgical procedures are shown in Figure 1.

Figure 1.

Bariatric surgical procedures and putative effects on gut hormones glucagon-like peptide-1 and peptide YY. LAGB involves percutaneous placement of an adjustable band applied to the upper stomach. In VGB a small stomach pouch is created by use of a band and staples. More recently, sleeve gastrectomy, whereby a large part of the stomach is removed leaving behind a 'sleeve' of stomach, is being used as a standalone procedure where previously it was used in the first of two stages for high-risk patients, the second stage being a conversion to a bypass procedure. Much less commonly used is BPD, which involves a partial gastrectomy; the residual upper stomach is connected to a lower part of the small intestine and BPD with DS, which preserves the antrum, pylorus and part of the duodedum leaving an intact vagal nerve. RYGB is where the stomach is divided into a small pouch and a gastric remnant, which are attached to a rearranged small intestine.
BPD: Biliopancreatic diversion; DS: Duodenal switch; GLP-1: Glucagon like peptide-1;LAGB: Laparoscopic adjustable gastric banding; PYY: Peptide YY; RYGB: Roux-en-Y gastric bypass; VGB: Vertical gastric banding.

Bariatric surgery gives a higher chance of remission from Type 2 diabetes than conventional care. Buchwald et al. performed a meta-analysis using a dataset that included 621 studies and a population of 135,246 patients. Type 2 diabetes resolved in 78% and resolved or improved in 87% of patients undergoing bariatric surgery.[61] A more rigorous study reviewed 1006 patients who underwent Roux-en-Y gastric bypass (RYGB), banding or sleeve gastrectomy and utilized the ADA's definition of remission – that is, normal glucose measurements off all hypoglycemic medications 1 year postsurgery. The remission rates over a median follow-up of 23 months, using this stricter definition, were lower at 41% with RYGB, 26% with sleeve gastrectomy and 7% with gastric banding.[62] Two recent RCTs have shown better glucose control in patients with long-standing Type 2 diabetes following bariatric surgery compared with either standard or intensive medical therapy. The STAMPEDE trial, whose participants had poorly controlled diabetes (mean HbA1c: 9.2 ± 1.5%), compared intensive medical therapy to medical therapy plus either RYGB or sleeve gastrectomy. The primary outcome of an HbA1c of ≤6%, 12 months after surgery or treatment was achieved by significantly more participants in the surgical arm (RYGB: 42%; sleeve gastrectomy: 37%), compared with only 12% of those on medical therapy alone. There was a reduction in the number of antidiabetic, antihypertensive and hypolipidemic medications used by surgically treated patients.[63] The DIBASY trial compared RYGB and biliopancreatic diversion (BPD) to standard medical therapy and found that diabetes remission at 2 years (defined as fasting glucose of <100 mg/dl and HbA1c <6.5% off all diabetic medications) occurred in 75% of those in the RYGB group, 95% in those who had BPD and none in the standard medical therapy arm.[64]

While bariatric surgery is a very effective treatment for the obese diabetic patient, it comes with certain caveats. As with all surgical procedures, there is a risk of postoperative complications, including death (Table 3). Bariatric surgery is relatively expensive, as it requires specialist facilities and surgical teams. Depending on the procedure, it can be irreversible. Patients are at risk of hypoglycemia if diabetic medications are not adjusted postoperatively and depression can be seen in those with severe weight loss.

The mechanism by which glycemic control is improved following bariatric surgery is complex and not entirely understood. All procedures result in improvement in Type 2 diabetes but they vary in efficacy and time-course of effect. BPD and RYGB are most effective at improving glycemic control, leading to an approximately 95% and an approximately 80% resolution in diabetes, respectively.[61] The excess weight loss at 3–5 years varies slightly among procedures: RYGB gives an excess weight loss of approximately 60%, laparoscopic adjustable gastric banding approximately 50% loss, BPD or duodenal switch approximately 75% and sleeve gastrectomy 50–60%. Over the long term, the decrease in weight and subsequent reduction in insulin resistance is likely to be contributory to the enduring effects on glycemia; those procedures with the most weight loss have been shown to have the largest effects on insulin resistance.[65]

The rapidity of the resolution of diabetes, especially following bypass procedures such as RYGB,[66] suggests this effect cannot be explained by weight loss alone. Certainly, the postsurgical calorie restriction can acutely improve insulin secretion and sensitivity, as mentioned above.[49] All procedures involve calorie restriction, but the resolution rates for Type 2 diabetes vary as already noted. This suggests that an alternative mechanism to improve glycemia operates to a greater or lesser degree depending on type of procedure.

Postoperative alterations in gut hormone production have been postulated to play a major role in both the change in appetite[67] and the improvement in glycemia observed. Patients who have undergone RYGB have consistently been found to have increased fasting and postprandial levels of GLP-1 and peptide YY (PYY).[68] In experimental infusion studies, both PYY[69] and GLP-1 inhibit food intake[30] and in combination produce a synergistic reduction in food intake.[70] In addition, PYY and GLP-1 are both thought to have a beneficial effect on glucose regulation. GLP-1, as previously discussed, is insulinotropic and has an inhibitory effect on glucagon. In mice, PYY3–36 enhances insulin-induced glucose disposal independently of food intake and bodyweight.[71] Other gut hormone changes have been seen to occur. Oxyntomodulin, which has been shown to reduce appetite and increase energy expenditure, has increased secretion in response to an oral glucose load post-RYGB.[72–74] It has also been shown to improve glucose homeostasis in mice with diet-induced insulin resistance.[75] Secretion of the orexigenic, prodiabetic hormone ghrelin has been shown to be decreased after gastric bypass surgery.[76] GIP, an incretin with a role in fat metabolism, is thought to be reduced in diabetics undergoing RYGB.[77] Despite being insulinotropic and having a positive effect on β-cell proliferation, Type 2 diabetics do not appear to benefit from GIP's potentially favorable effects on glycemia.[78] Since it has also been shown to have an anabolic effect on adipose tissue including increasing fatty acid incorporation into adipose tissue,[79] a reduction following RYGB may have beneficial effects on diabesity.

It is speculated that these changes in gut hormone secretion are due to increased delivery of incompletely digested nutrients to the distal gut causing excess stimulation of the enteroendocrine L cells, causing them to release gut hormones. Another hypothesis is that altered delivery of bile salts to the small intestine stimulates GLP-1 and PYY secretion.[80] Finally, a possible role for alterations in host–gut microbiome interactions has been mooted to play a key part. Since the gut microbiota is thought to have a role in obesity via changing the host's ability to harvest energy,[81] changes that take place in this after RYGB may have a role in producing the beneficial metabolic effects observed postbypass.[82]

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