Gastric Band, Metformin Equally Prevent Diabetes in Short-Term

Miriam E. Tucker

October 16, 2018

BERLIN — Gastric banding and metformin may similarly stabilize or improve glucose levels over 2 years in moderately obese adults with prediabetes or recently diagnosed type 2 diabetes, new research suggests.

The findings from the Restoring Insulin Secretion (RISE) consortium were presented October 3 at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting and simultaneously published in Diabetes Care.

In the RISE Adult Surgery (BetaFat) study, which randomized 88 people to gastric banding or metformin as a comparator for 2 years, "gastric banding and metformin offered approximately equal approaches for improving insulin sensitivity in adults with mild-to-moderate obesity and impaired glucose tolerance or early, mild type 2 diabetes," said Thomas A. Buchanan, MD, chief of the endocrine division and codirector of the Diabetes and Obesity Research Institute at the University of Southern California, Los Angeles.

Buchanan added: "The predominant, but not sole, beta-cell response was a reduction in secretion to maintain relatively constant compensation for insulin resistance, with only a small improvement in glucose."

However, according to independent commentator Roy Taylor, MD, professor of Medicine and Metabolism and director of the Newcastle Magnetic Resonance Centre, Newcastle University Campus for Ageing & Vitality, UK, "Progression from prediabetes to diabetes is slow, and decrease in insulin secretory function happens over a relatively short time as diabetes comes on, so in 2 years no change in the primary endpoint is entirely understandable."

The bottom line, Taylor told Medscape Medical News, is that "longer-term follow up is required to show both the clinical effects of difference in diabetes incidence and the effect on insulin secretion." However, he believes that — as long as weight loss is maintained in the gastric band group — this strategy will ultimately win out and these patients will be less likely to progress.

Beta-Cell Function Improved Similarly Between Treatment Groups

The researchers explain by way of background that type 2 diabetes generally results from a progressive loss of beta-cell compensation for chronic insulin resistance, an important measure of beta-cell function. "There is very strong...evidence that beta-cell compensation declines for years before the development of diabetes, often reaching 50% of normal in people with impaired glucose tolerance (IGT) or early diabetes. This prediabetes period has been the target of efforts to slow or prevent the development of type 2 diabetes."

Among these diabetes prevention studies, interventions that target obesity or its adverse metabolic effects have produced the greatest reductions in diabetes incidence rates. And some of these have also shown that slowing or stopping progression to diabetes is associated with preservation of beta-cell function.

But none of the interventions used in these studies has so far been fully successful in preventing type 2 diabetes or preserving or restoring beta-cell function.

Regarding the choice of weight loss surgery in BetaFat, the researchers note that "the moderate obesity that we chose to study is common among people with IGT or early type 2 diabetes and better suited to gastric banding than more potent bariatric approaches such as gastric bypass." They chose metformin as a comparator because of its widespread clinical use as first-line therapy for type 2 diabetes and its demonstrated effectiveness in reducing diabetes risk in people with prediabetes.

The hypothesis was that weight loss induced by gastric banding and nutritional management would have a greater effect than metformin to preserve or restore beta-cell function.

The two prespecified primary outcomes in the study are deemed "state-of-the-art" for assessing different aspects of beta-cell compensation for insulin resistance: C-peptide concentrations during the steady-state period adjusted for mean plasma insulin concentration (M/I) and acute C-peptide response to arginine at maximum glycemic potentiation, also adjusted for M/I.

In terms of weight loss, at 2 years the gastric band group lost 10.7 kg, while the metformin group lost 1.7 kg (P < .01).

At 12 months, insulin sensitivity (M/I) had increased by 55% in the gastric band group (P < .0001) and by 45% with metformin (P = .007). By 24 months, M/I had dropped but still remained 45% higher than baseline in the band group (P = .0002) and 25% higher in the metformin group (P = .055). Insulin sensitivity didn't differ between the two groups at either time point (P > .14).

"Beta-cell responses fell in a pattern that maintained relatively, but not perfectly, stable compensation for insulin resistance," Buchanan said.

However, he added, "acute beta-cell compensation to glucose improved significantly with gastric banding, on both insulin and C-peptide parameters."

In contrast, "beta-cell compensation at maximal stimulation fell significantly with metformin."

These effects didn't differ between groups, however, and glucose levels improved only slightly. 

HbA1c fell at 12 and 24 months in the band group (P < .004) but only at 12 months (P < .01) in the metformin group (P > .14 between groups). Normoglycemia was present in 22% and 15% of participants in the band and metformin groups, respectively, at 24 months (P = .66 between groups).

Fasting glucose levels fell in both groups by 12 months (P < .002) and remained below baseline at 24 months in the band group (P = .003) and less so in the metformin group (P = .08), with no significant between-group differences at any time (P ≥ .55).

Provided Weight Loss Is Maintained, the Band Group Won't Get Diabetes

Taylor noted, "the most important predictor of progression from prediabetes to diabetes is fasting blood sugar. As this had become significantly less than baseline in the band group and not in the metformin group, the writing is on the wall — provided weight loss is maintained, the [gastric] band individuals will not develop type 2 diabetes."

While HDL cholesterol rose significantly with both interventions at 24 months (P = 0.001 and 0.004 for gastric band and metformin, respectively), only gastric banding significantly reduced VLDL cholesterol (P = 0.007) and total triglycerides (P = 0.007). Alanine aminotransferase (ALT) was significantly lowered in both groups (P = 0.001 and 0.04, respectively). 

Taylor told Medscape Medical News, "The new understanding of type 2 diabetes etiology is that excess fat builds up in the liver. Excess fat is exported from the liver, and this increases pancreas fat content. Beta-cell de-differentiation eventually happens due to the metabolic stress. All these steps are reversible."

So, he noted, "what we see in the [gastric] band group is a fall in plasma triglyceride — liver fat export has normalized — and a fall in ALT — hepatocytes are no longer stressed. All of this adds up to 'the process of moving to diabetes has been aborted.' "

Serious adverse events included two cases of band slippage requiring removal and a surgery for alcalculous cholecystitis in the band group, and hospitalization for elective gastric sleeve surgery in the metformin arm.

Other adverse events included stomach discomfort or pain in 25% of the metformin group versus none of the band patients, and diarrhea in 7% versus none in the band group.

Dysphagia occurred in one band patient, and port revision/replacement in two.

In conclusion, the researchers write, "In people with IGT or early, mild type 2 diabetes, we observed no improvement in beta-cell function and only modest improvements in glycemia despite large improvements in insulin sensitivity."

Taken together, these findings suggest that there is an evolution of beta-cell responses to improved insulin sensitivity. Relatively early in the development of hyperglycemia, short-term changes in insulin sensitivity are associated with reduced insulin output, relatively stable beta-cell compensation, and little if any change in circulating glucose.

"Once hyperglycemia is more fully developed, changes in sensitivity are attended by improved beta-cell compensation and lower glucose levels."

"Whether these interventions will have different effects on beta-cell function over the long-term," and will translate into long-term beta-cell protection, will require additional follow-up, Buchanan reiterated.

The BetaFat study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, Kaiser Permanente Southern California, and University of Southern California. Additional support was provided by the American Diabetes Association, Allergan, and Apollo Endosurgery. Buchanan has received research support from Allergan and Apollo Endosurgery. Taylor has reported no relevant financial relationships.

European Association for the Study of Diabetes (EASD) 2018 Annual Meeting; October 3, 2018; Berlin, Germany.

Diabetes Care. Published online October 3, 2018. Abstract

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