Five-Year Data: Surgery Betters Medical Therapy for Diabetes

Becky McCall

September 09, 2015

Bariatric surgery is more effective than medical treatment alone for the long-term control of type 2 diabetes in obese patients, finds the first 5-year follow-up study, prompting a call for a rethinking of the diabetes care pathway with more emphasis on surgery.

Overall, 50% of patients who underwent surgery showed sustained remission of type 2 diabetes (defined as HbA1c less than 6.5%) without any medication upon 5-year follow-up, compared with none in the medically treated group.

"These people had nondiabetic glycemia for 5 years without ever taking a single antidiabetic drug," said Francesco Rubino, MD, senior author of the study and chair of bariatric and metabolic surgery at King's College London, United Kingdom.

And over 80% of surgically treated patients maintained the American Diabetes Association's (ADA's) treatment goal of HbA1c concentration below 7.0%, with just diet and/or metformin.

"This is a spectacular result," added Dr Rubino, although he acknowledged that the study involved only a small number of patients and was conducted at a single center.

The results were published in the September 5 issue of the Lancet by Geltrude Mingrone, MD, of the Catholic University of the Sacred Heart, Rome, Italy, and colleagues, including Dr Rubino.

Like Cancer Treatment, Surgery Should Be Option in Diabetes

In an accompanying editorial, two other bariatric surgeons, Dimitri Pournaras, PhD, MRCS, and Carel le Roux, MBChB, PhD, both from Imperial College London, United Kingdom, draw a parallel with multimodal cancer treatment, where the best surgical treatment combined with the best medical treatment is better than either alone.

"This model could be followed for diabetes, with use of best medical care to maintain remission, which is often only possible with surgery," they write.

They suggest that future randomized controlled trials should assess the optimal point at which to use surgery, but that "all surgical groups should receive intensive medical treatment and close follow-up at some stage because, as [Dr] Mingrone and colleagues have now shown, not doing so results in relapse of diabetes."

Dr Rubino concurred, noting that the management of type 2 diabetes could come to resemble that of cardiovascular disease, with treatments ranging from diet and exercise, to drugs, to endoluminal stents or surgical bypass.

"Introducing surgical treatment in diabetes management allows escalation" of therapies according to disease severity and enables risk stratification, he told Medscape Medical News in an interview.

"If you know that surgery is an option, you give diet and drugs a reasonable time to work; if they fail, surgery should be considered," he added.

First to Compare Bypass Surgery and Medical Treatment for 5 Years

The open-label, randomized controlled trial is the first to compare gastric-bypass or biliopancreatic-diversion surgery with medical therapy with follow-up of 5 years.

Previous trials with gastric-bypass surgery and another bariatric surgical procedure that is rapidly gaining ground, laparoscopic sleeve gastrectomy, have shown that there is benefit in type 2 diabetes, but only to 3 years maximum.

However, a recent retrospective analysis of sleeve-gastrectomy procedures has revealed weight regain and a decrease in remission rates for type 2 diabetes at 5 years' follow-up.

"The 5-year mark is important because it provides a measure of durability of remission while also allowing a look at other aspects that are not assessable over the short term — for example, quality of life or disease-related complications," explained Dr Rubino.

The current single-center study was carried out at Catholic University, Rome, Italy. Participants had a body mass index (BMI) of at least 35 kg/m2, were aged 30 to 60 years, had a history of type 2 diabetes lasting at least 5 years, and an HbA1c concentration of 7.0% or more (≥53 mmol/mol). The majority of patients had previously received medical treatment, with many on insulin.

Of the 60 patients included in the study, 20 were randomly assigned to receive medical therapy (glucose-lowering drugs, insulin, and glucagonlike peptide-1 [GLP-1] agonists); 20 to Roux-en-Y gastric-bypass surgery; and 20 to the biliopancreatic-diversion procedure. The vast majority (88%) completed 5 years of follow-up.

The primary end point was the rate of diabetes remission at 2 years, defined as a fasting glucose concentration of 5.6 mmol/L or less and HbA1c concentration of 6.5% or less (≤47.5 mmol/mol). Importantly, patients were required to achieve this without active drug treatment for at least 1 year (2009 ADA definition of remission).

Patients were assessed annually for durability of diabetes remission (up to 5 years), overall glycemic and metabolic control, cardiovascular risk, medication use, quality of life, diabetes-related complications, and long-term surgical complications.

Five-Year Remission Postsurgery Is 50%, but Long-Term Follow-up Key

Diabetes remission at 5 years was seen in 19/38 (50%) of the surgical patients without any medication. Of these patients, seven of 19 [37%] were in the gastric-bypass group and 12 of 19 [63%] in the bilipancreatic-diversion group.

None of the 15 patients in the medical-treatment group achieved remission at 5 years.

And of those patients who received only metformin to achieve an HbA1c concentration below 7.0%, the proportion of surgical patients with major improvement of diabetes from baseline rose to over 80%, according to Dr Rubino.

"Remarkably, while almost 50% (47%) of surgical patients required insulin prior to surgery, alone or in combination with multiple other agents, all but one did not require insulin 5 years after surgery," he added.

A total of 15/34 (44%) patients (53% of gastric-bypass and 37% of biliopancreatic-diversion patients) who achieved 2-year remission with surgery later relapsed with hyperglycemia, but they maintained a mean HbA1c of 6.7% at 5 years with just diet and either metformin or no medication.

"The relapse of hyperglycemia, albeit mild, in almost half of the patients with initial remission, underscores the need for continued long-term monitoring of glycemia in all patients after surgery," stressed Dr Rubino.

Two patients on medical therapy, unable to achieve adequate control of glycemia despite taking multiple drugs and/or insulin for over 2 years, requested crossover to surgery, following which they immediately entered remission.

Dr Rubino pointed out the dramatic reduction in the total number of antidiabetes and cardiovascular medications in the surgical patients over the total 5 years, adding, "This has implications for cost-effectiveness."

In surgically treated patients, there was also a greater improvement in quality of life compared with the medically treated group, and the rate of diabetes-related complications was also lower.

"Five major diabetes-specific complications were observed in the medical group, including one death from heart attack, compared with only one in the gastric-bypass group and none in the biliopancreatic-diversion group," he noted.

Gastric Bypass Has the Best Risk/Benefit Profile

Regarding surgery, there were no major long-term complications or mortality after surgery, according to Dr Rubino.

Patients who underwent biliopancreatic diversion did experience more nutrient-deficiency side effects, however, including osteoporosis and osteopenia.

"The nutritional side effects of gastric bypass were both milder and less frequent by comparison," reported Dr Rubino. "For this reason, we suggest that despite the greater percent of stable remission of hyperglycemia after biliopancreatic diversion, gastric bypass has a better risk-to-benefit profile."

He acknowledged that the study was small but noted that the findings suggest that surgery might reduce future complications of diabetes.

"Five years of remission or optimal glycemic control should have a lasting impact on a patient's risk to develop diabetes-related complications."

Weight Loss Is Not the Whole Story

In their discussion, Dr Mingrone and colleagues observe that weight loss alone cannot explain the effects of surgery on diabetes in their study.

Indeed, "when we looked at the two groups of surgical patients, we found that those with sustained remission had [lost] the same weight as those who relapsed," said Dr Rubino.

A statistically significant difference in remission rates between gastric bypass and biliopancreatic diversion was also evident, but there was no difference in weight loss between these two procedures, either.

"This suggests that weight change does not tell the whole story," he added.

It is thought that gastrointestinal surgery activates weight-independent mechanisms of diabetes control, possibly hormonal. The differences in anatomy resulting from different surgical procedures are thought to explain at least some of the variance in clinical effectiveness resulting from these operations.

These observations imply that bariatric surgery should not be reserved only for obese patients with a BMI over 35 kg/m2. Dr Rubino pointed out that "diabetes surgery should be based on disease-specific criteria; BMI is not one of those."

Ultimate Question Is Whether Bariatric Surgery Reduces Deaths

In conclusion, and acknowledging that surgery for type 2 diabetes is safe and effective in terms of glycemic control and reduced diabetes complications, Drs Pournaras and le Roux note in their editorial that "the ultimate question is whether diabetes surgery is associated with reduced mortality."

"Extension of follow-up in the trials already done and future well-designed and appropriately powered studies will provide some much-needed answers," they conclude.

The authors and editorialists declare no relevant financial relationships.

Lancet . 2015;386:964–973, 936–937. Abstract, Editorial

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