Bariatric surgery has now emerged as an effective means of glycemic control in individuals with diabetes and obesity. However, long-term data show recurrence of hyperglycemia years after the procedure. Although the exact prevalence of diabetes relapse is unknown because of attrition and limited data on long-term follow up after the surgery, a significant percentage of patients experience relapse of diabetes. The mechanism of diabetes relapse is not completely understood and is not always linked to weight regain. The clinical implications of hyperglycemia after bariatric surgery for patients and healthcare providers is reviewed.
The prevalence of obesity and type 2 diabetes mellitus in North America and across the world has been increasing at alarming rates. Obesity is a critical risk factor for the development of type 2 diabetes. The relative risk for type 2 diabetes in individuals with obesity (body mass index [BMI] ≥ 30 kg/m2 ) is 10 times greater than in those with normal BMIs (≥18.5 to ≤24.9 kg/m2 ). In addition, 90% of all individuals with type 2 diabetes are overweight or obese (1). Although intensive lifestyle modification, with diet-induced weight loss, exercise and intensive medical therapy can result in good control and even remission (2,3) of type 2 diabetes, the majority of patients find it difficult to achieve sustained control of blood glucose. In addition, intensification of medical therapy can lead to hypoglycemia and weight gain.
Therefore, many have turned to bariatric surgery (BS) or metabolic surgery for treatment of obesity and type 2 diabetes. Surgical weight loss provides marked improvement in glycemic control, with the rate of type 2 diabetes remission varying from 24% to 95% at 2 years, depending on the type of surgery, the definition of remission and the type of subjects enrolled (2,4-6). The definition of remission varies from study to study but is generally defined as normoglycemia and glycated hemoglobin (A1C) levels below 6%, without the need for glucose-lowering medications for at least 1 year (7). Recent long-term data, however, suggest that relapse of type 2 diabetes is common in the years following BS. Here we review clinical studies of type 2 diabetes relapse after BS and discuss pathophysiology and determinants of type 2 diabetes relapse and its clinical implications.
Bariatric Surgery and Diabetes Remission
Anecdotal evidence of improved glycemic control after gastrointestinal surgery in patients undergoing gastric resection for peptic ulcer disease or gastric cancer was reported as early as the first half of the 20th century (8). In the early 1980s, surgeons recognized firsthand that many patients with type 2 diabetes undergoing Roux-en-Y gastric bypass (RYGB) experienced resolution of their type 2 diabetes. Pories et al conducted a retrospective singlecohort study of 298 patients with type 2 diabetes or impaired glucose tolerance who underwent RYGB (9). Of those patients, 91% maintained normal fasting glucose and A1C levels, with follow up as long as 14 years in some patients and with only 4% attrition. Those who did not remitwere older (48 years vs. 40.7 years) and had known type 2 diabetes for longer durations (4.6 years vs. 1.6 years).
The rate of remission of type 2 diabetes after BS varies depending on the procedure; socalled malabsorptive procedures, such as RYGB and biliary pancreatic diversion (BPD), were shown to be more effective than strictly restrictive procedures, such as vertical sleeve gastrectomy (VSG) or adjustable gastric banding (AGB). A meta-analysis of 621 studies published between 1990 and 2006, including 135,246 patients undergoing AGB, gastroplasty, RYGB or BPD, showed that 78.1% of subjects experienced resolution of type 2 diabetes, and 86.6% had improvement or resolution after surgery (10). The length of follow up after surgery varied among studies from 1 year to 15 years. Unfortunately, most studies were of short duration and often reported data after fewer than 2 years of follow up. When stratified by procedure, BPD resulted in type 2 diabetes resolution in 95.1% of patients, RYGB in 80.3%, gastroplasty in 79.7% and AGB in 56.7% 1 year after surgery (10).
Schauer et al conducted a single-centre prospective trial to investigate clinical parameters associated with type 2 diabetes improvement in 191 individuals after RYGB (11). With a mean follow up of 19.7 months, 83% of patients saw remission of type 2 diabetes, and the other 17% saw significant improvement in glucose control. Improvement of type 2 diabetes was defined as fasting blood glucose levels being decreased by 1.38 mmol/L (25 mg/dL), A1C levels being decreased by more than 1% and/or significant reductions in usage of medications for type 2 diabetes (either by discontinuing 1 agent or by reducing the dosage by one half). Resolution of type 2 diabetes, defined as fasting glucose levels below 6.1 mmol/L and A1C levels below 6% and no longer taking type 2 diabetes medications, was less likely in those with longer durations of type 2 diabetes (10 years vs. 5 years) and with use of insulin prior to surgery (11).
During the past few years, many high-quality randomized controlled trials (RCTs) have compared differing types of BS to intensive or conventional medical therapy (MT). In the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial, patients were randomized to RYGB with MT, VSG with MT or intensive MT alone (2). Intensive MT consisted of an algorithm of metformin, thiazolidinedione, glucagon-like peptide-1 (GLP-1) agonist and insulin, along with lifestyle counselling, weight management and frequent home glucose monitoring. The MT group was supervised every 3 months at a single study centre by an experienced diabetologist. The primary endpoint was defined as A1C levels below 6.0%, with or without the use of medications at the time of evaluation. With 50 subjects in each arm, the primary endpoint was achieved in 12% of participants in the MT group, 42% in the RYGB and MT group, and 37% in the VSG and MT group at 1 year. The remitters after RYGB were not taking medications for type 2 diabetes, but one-third of the remitters in the VSG group required glucose-lowering drugs. It is to be noted that the study population had relatively advanced type 2 diabetes, with average durations longer than 8 years and A1C levels above 9%, and nearly a quarter of the study participants were taking insulin at the time of enrolment. The relatively low remission rate at 1 year, compared to that found in other studies, highlights the roles of duration and control of type 2 diabetes as being important determinants of remission (9,11).
Mingrone et al conducted a single-centre nonblinded RCT comparing type 2 diabetes remission in patients undergoing RYGB, BPD or conventional MT, including 20 patients in each arm (5). Conventional MT was administered by a multidisciplinary team that included a diabetologist and involved oral hypoglycemic agents and insulin along with diet and lifestyle modification. At 2 years, remission of type 2 diabetes was observed in 95% of patients after BPD, 75% after RYGB and 0 in the MT arm. In this study, no preoperative characteristics predicted the likelihood of remission
Dixon et al compared AGB to conventional MT and showed remission of type 2 diabetes in 73% of surgical patients and in only 4% among MT groups at 2-year follow up (4). Conventional MT was adjusted on a case-by-case basis by an experienced diabetologist at regularly scheduled intervals. The remarkable remission rate after AGB in that study can be explained by the selection criteria for participants who had well controlled type 2 diabetes of short duration, were minimally treated and had lower BMIs, and by the expertise in band adjustment of the Australian team that resulted in 20% total weight loss at 2 years, compared to 1.4% weight loss in the MT treatment group (4). In another RCT, Ikramuddin et al compared RYGB to intensive MT in individuals with BMIs between 30.0 and 39.9 kg/m2 and showed type 2 diabetes remission rates at 1 year to be 75% and 32% in the surgical and MT groups, respectively (12). The algorithm for the intensive MT included lifestyle and diet modifications and medications in the following order: metformin, GLP-1 agonist or dipeptidyl peptidase 4 (DPP4) inhibitor, sulfonylurea or pioglitaozone and insulin. In a prospective study, Pournaras et al compared RYGB and AGB in 34 patients and found the remission rate at 3 years to be 72% after RYGB and only 17% after AGB (13)
Although many prospective studies have been designed to assess short-term remission rates in those with type 2 diabetes, the observational Swedish Obese Subjects (SOS) study provides data concerning long-term outcomes in those with type 2 diabetes, up to 15 years after intervention (14). In a subgroup of patients with type 2 diabetes studied in this prospective, matched cohort study, 343 subjects underwent BS, and 260 had usual medical.