Keywords

Why Should We Address Low Body Mass Index Patients with Type 2 Diabetes?

It is estimated that 643 million individuals will be affected by type 2 diabetes mellitus (T2DM) by 2030. T2DM is a major cause of death in the USA, given its relation to kidney failure, blindness, amputations, heart attacks, and other conditions such as erectile dysfunction and gastroparesis [1].

The therapeutic cornerstones for T2DM are dieting, exercise, and medications. Long-term success rates of lifestyle modifications can be disappointing, and despite new drug therapies are continuing to improve the medical therapy for this disease, most patients never reach the defined targets for success and are susceptible to the severe effects of this disease [2].

In individuals where lifestyle interventions and medical treatment do not achieve adequate glycemic control, gastrointestinal surgery has been advocated as a powerful alternative in patients with grade 1 obesity, mainly due to previous experience with bariatric surgery and the favorable outcomes. However, this practice remains controversial.

Bariatric surgery leads to significant weight loss maintenance and improvement of obesity-related diseases in patients with a body mass index (BMI) above 35 kg/m2. In this population, procedures such as Roux-en-Y gastric bypass resulted in better glucose control and weight loss at 1 or 2 years compared with clinical intervention. Approximately 80–85% of patients with obesity grade 2 and 3 (BMI >35 kg/m2 with comorbidities or above 40 kg/m2) who undergo bariatric surgery experience full remission of T2DM, lowering the diabetes-related deaths as well as overall mortality. Furthermore, metabolic amelioration occurs in a few days or weeks, long before significant weight loss, suggesting that the mechanisms behind such changes are independent of weight loss [3]. Metabolic surgery can be defined as any intervention over the gastrointestinal tract that can control the glycemic and other metabolic syndrome components initially through weight-independent mechanisms and weight loss. Moreover, weight loss is an important outcome to be achieved to obtain glycemic control and prevent or resolve micro- and macrovascular complications of T2DM [4].

Such encouraging results observed after bariatric surgery in patients with T2DM and obesity grades 2 and 3, along with mounting evidence, suggest that bariatric surgery engages weight-independent antidiabetic mechanisms and prompted considerations of bariatric surgery in individuals with less severe obesity and T2DM.

Most people with T2DM fall in grade 1 obesity (BMI between 30 and 35 kg/m2). Despite lifestyle modifications and pharmacotherapy, millions of persons with obesity suffer from poorly controlled T2DM. Moreover, this group of patients does not satisfy the current criteria for bariatric surgery [5]. Additionally, the medical community is still skeptical about accepting surgery as a treatment modality for T2DM, particularly in patients with lower BMI.

The full risk-benefit ratio of surgical versus medical treatments for T2DM was not adequately ascertained until recently.

Results of Metabolic Surgery over Glycemic Control in Patients with Type 2 Diabetes and BMI Below 35 kg/m2

A meta-analysis published in 2016 including 94 studies and about 95,000 patients analyzed showed that the control of T2DM (HbA1c <7%, with or without medication) was 70% in patients with obesity [24]. Panunzi et al. [6] showed that metabolic surgery in patients with T2DM and obesity had a higher rate of effectiveness (64%) compared with drug therapy (15%) with respect to T2DM remission, glycemic control (fasting glucose and Hba1c) as well as a decrease in the waist circumference ratio [6].

In 2017, we published a systematic review and meta-analysis of five randomized clinical trials (RCTs) evaluating T2DM and grade 1 obesity treatment [7]. The primary outcome was T2DM remission. In the long-term follow-up, metabolic surgery significantly improved the total and partial remission of T2DM. This meta-analysis reinforces the view that adding metabolic surgery to the best clinical treatment in patients with uncontrolled T2DM is an excellent option in those with a BMI ≥30 kg/m2 [7].

Laparoscopic Adjustable Gastric Banding (LAGB)

In 2008, Dixon et al. [8] published an RCT including 60 patients with early onset (<2 years) T2DM and a BMI range of 30–40 kg/m2 assigned to either medical/lifestyle treatment or LAGB plus conventional diabetes care. After 24 months, T2DM remission, defined as fasting plasma glucose (FPG) level below 126 mg/dL and HbA1c less than 6.2%, was observed in 73% of patients in the LAGB group versus 13% in the purely medical/lifestyle group. As expected, weight loss was the primary driver of glycemic improvement since only few participants achieved T2DM remission when weight loss was less than 10% of the initial weight. However, the efficacy of this procedure in achieving T2DM remission should be assessed with caution because all patients in this study had early onset T2DM, were taking only oral antidiabetics, and were followed for a short time.

O’Brien et al. [9] published an RCT including 80 patients with a BMI of 30–35 kg/m2 assigned to LAGB versus an intensive medical treatment intervention. Although both groups lost a similar amount of weight (13.8%) by 6 months, the surgical group continued to lose weight during the following 18 months, while the medical treatment group regained much of the weight that was lost initially. Metabolic syndrome was initially present in 15 (38%) patients in each group, but after the study it was present in 8 (24%) nonsurgical patients and 1 (3%) surgical patient.

Sleeve Gastrectomy (SG)

SG has been widely used as a standalone procedure for treating obesity, even in patients with T2DM. However, limited data are available regarding T2DM resolution with a considerable follow-up time.

Many published studies verified the superiority of SG when compared with medical treatment procedures with no intestinal bypass component, such as LAGB [10]. Indeed, some hormonal profiles may suggest early postoperative improvement in insulin sensitivity, but other confounding factors such as calorie restriction may play a role in improved metabolic outcomes.

Berry et al. [11] retrospectively analyzed 252 patients with BMI 30–35 kg/m2 who had undergone SG. Only 9% had T2DM. There were 2.4% of major complications, two reoperations, and no mortality. However, in 36 months of follow-up, 60% of the patients with T2DM achieved remission focused on glucose endpoints (glucocentric approach) remission and 22.1% of total body weight loss. In this retrospective cohort, SG was safe and delivered reasonable weight loss and glucose control after 3 years.

In an RCT by Lee et al. [12] which compared the single anastomosis gastric bypass versus the SG, 47% of patients with poorly controlled T2DM and BMI between 30 and 35 kg/m2 achieved T2DM remission of the 60 patients enrolled (30 RYGB × 30 SG), all completed the 12-month follow-up. Remission of T2DM was achieved by 28 (93%) patients in the gastric bypass group and 14 (47%) in the SG group (remission defined as FPG less than 126 mg/dL and HbA1c more than 6.5%, without any medication) [12]. Such patients were less likely to achieve T2DM remission when compared to gastric bypass, demonstrating an important role of duodenal exclusion in order to achieve better T2DM control.

No further level 1 studies determine either the glucocentric or renal and cardiovascular outcomes after SG in patients with T2DM and BMI 30–35 kg/m2.

Roux-en-Y Gastric Bypass (RYGB)

RYGB was first associated with T2DM remission in persons with obesity. Based on the favorable outcomes, some authors proposed this type of treatment for low BMI patients with medically uncontrolled T2DM, and most surgeries are performed under internal review board protocols.

Our group, in 2012 [13], published the largest and longest-term study to date, examining the efficacy and safety of RYGB to treat medically uncontrolled T2DM in patients with grade I obesity (BMI 30–25 kg/m2). All patients had severe, long-standing T2DM, with a mean disease duration of 12.5 years and a mean HbA1c of 9.7% despite insulin and/or oral antidiabetic medication use. In the follow-up period of 1–6 years, 88% of patients achieved complete T2DM remission (HbA1c <6.5%, without any antidiabetic medication), with improvement in an additional 11% (HbA1c <7.0%, under oral antidiabetic therapy). Moreover, postoperative changes in c-peptide and glucose response to a mixed meal test demonstrated improvement in beta cell function, suggesting that RYGB can reverse the progressive beta cell failure in patients living with T2DM.

These results were accompanied by other significant improvements, such as substantial reductions in hypertension and dyslipidemia, yielding significant improvements in predicted cardiovascular disease risk from fatal and nonfatal coronary heart disease and strokes. No mortality or significant surgical morbidity, excessive weight loss, or malnutrition was observed in this series [13].

Lee et al. [14] reported T2DM remission rate of 80% (HbA1c <6.5%) at 2 years of follow-up in 62 patients with a BMI of 23–35 kg/m2 at 2 years of follow-up. Mean HbA1c decreased from 9.7% to 5.9%. The authors also documented a significant decrease in insulin resistance as measured by the homeostatic model assessment (HOMA) index and an increase in early insulin secretion, as determined by the insulinogenic index.

Shah et al. [15] reported the effects of RYGB in 15 patients with T2DM and a BMI of 22–35 kg/m2. At 3 months and thereafter, 100% were euglycemic and no longer required medication (mean HbA1c of 6.1%). The predicted 10-year cardiovascular disease risk calculated by the UK Prospective Diabetes Study (UKPDS) risk engine decreased substantially for fatal and nonfatal coronary heart disease and stroke. There was no mortality, major surgical morbidity, or excessive weight loss.

Well-designed randomized controlled trials (RCT) are required to provide additional data showing the benefits of metabolic surgery over conventional treatment. They are also required to test the efficacy and safety of metabolic surgery in treating patients with T2DM and low BMI.

Schauer et al. [16] in an RCT not powered for lower BMIs (mean BMI of 37 kg/m2, slightly higher than the upper limit of this chapter’s target population, but 25% of the patients had BMI from 27.5 to 35 kg/m2) showed better glycemic control and better weight loss in the surgical groups (RYGB and SG) than the medical group [15]. T2DM control, defined as HbA1c less than 6.0% with or without medication, was achieved by 42% of patients receiving gastric bypass and 37% of patients receiving SG, compared with only 12% of patients in the medical arm. Although the surgical arms had similar results on glycemic control, there was a potential trend toward better outcomes in the RYGB group. It reflected by the three times lower use of antidiabetic medications in the RYGB group when compared with SG [16].

Kashyap et al. [17] published an extended follow-up of 24 months of Schauer et al. study [16]. The authors report a more durable glycemic control in the RYGB group, with a substantially greater number of patients achieving HbA1c levels below 6.0%, despite similar weight loss compared to the SG group. Insulin sensitivity measured by the Matsuda index and insulin secretion determined by the insulinogenic index were higher in the RYGB group. This adds another critical piece of knowledge that backs up the importance of food rerouting metabolic procedures.

So far, many studies have observed that the remission rate of T2DM after RYGB in patients with low BMI is comparable to the reported rates of 80–85% after RYGB in patients with T2DM and obesity grades 2 and 3 [6]. Similarly, RYGB in patients with low BMI appears as safe as it is in patients with more severe obesity. Although excessive weight loss is a theoretical concern for patients with grade 1 obesity when undergoing weight loss surgery, it did not occur in any previous studies. RYGB for patients with T2DM and grade 1 obesity seems to be as efficient as or even more efficient than expected in patients with higher BMI [7, 13].

Biliopancreatic Diversion (BPD)

Available data support that the rate of remission of metabolic complications is highest with biliopancreatic diversion (BPD) in people with obesity. However, due to the higher incidence of mid-/long-term nutritional complications BPD has not gained too much acceptance as a treatment modality for patients with low BMI. So far, only two studies evaluating the role of BPD in individuals with T2DM and low BMI have been published. Scopinaro et al. [18] reported the outcomes of 30 patients (mean BMI 30.6; BMI range 25–35 kg/m2 after BPD) and found that 83% reached an HbA1c <7% without medication, while the remaining patients had improvement in their HbA1c levels [18]. No significant nutritional deficiencies were reported in the first 12 months, although a longer follow-up in this type of patient should be attempted to identify potential severe nutritional complications.

Chiellini et al. [19] reported the metabolic outcome of five patients with T2DM and a mean BMI of 30.9 kg/m2 post-BPD. At 1 year, the HbA1c levels were reduced from 8.5% to 5.6%. There was also a significant increase in insulin-mediated glucose uptake as measured by a euglycemic-hyperinsulinemic clamp, showing that the rapid postoperative remission of T2DM is primarily related to improved insulin sensitivity [19].

BPD seems to positively affect the glucose metabolism, even in patients with low BMI, without causing excessive weight loss. However, larger clinical studies are needed to verify the long-term efficacy and safety.

Non-Glucocentric Endpoints

Currently, the primary outcomes to be achieved for patients with T2DM are more focused on preventing or treating microvascular complications (mainly nephropathy) and decreasing cardiovascular risk factors, events, and mortality [20].

Renal Outcomes

Obesity and T2DM are risk factors for kidney disease. Metabolic surgery is recognized as a treatment with beneficial effects on kidney disease, such as improving albuminuria and other microvascular complications [21].

Early stages of kidney disease, characterized by microalbuminuria, are associated with future cardiovascular events and early mortality as well as worsening of kidney disease in patients with obesity and T2DM [22].

In 2020, we compared [23] the effects of RYGB with the best clinical treatment in a randomized and controlled study, including glucagon-like peptide 1 analogs and sodium/glucose cotransporter 2 inhibitors, in patients with T2DM and grade 1 obesity after 2 years of follow-up. This study showed remission of microalbuminuria in 55% of medically treated patients and 82% of operated patients. Improvement in renal function occurred in 48% in the clinical group versus 82% in the surgical group [23].

Outcomes on Hypertension

Schiavon et al. [24] conducted a study comparing RYGB and medical treatment in patients with hypertension with BMI between 30 and 40 kg/m2 undergoing RYGB. After 3 years of follow-up, 83% of the operated patients reduced the number of antihypertensive drugs compared with 12% in the nonoperated group. Remission of hypertension occurred in 35% in the operated group, against 2% in the clinical group [24]

Cardiovascular Events and Mortality

Many studies show a decrease in cardiovascular events after metabolic surgery [25].

Syn et al. [26] published a meta-analysis containing prospective randomized and paired cohort studies with approximately 174,722 patients, including a considerable number of patients with BMI below 35 kg/m2. A reduction in the risk of death and an increase in overall survival in patients who underwent metabolic surgery were observed in the primary endpoint. The subgroup analysis showed that patients with obesity and T2DM had lower morbidity and mortality rates. This meta-analysis again strengthens the overall benefit of metabolic surgery in patients with T2DM and obesity.

A Quick Note on Investigational Procedures

The metabolic results following “traditional” operations directed efforts toward operations that reroute the food through the gastrointestinal tract. These operations led to no or mild weight loss and followed some anatomical and pathophysiological patterns to achieve metabolic control in a population that, in theory, does not need massive weight loss. These procedures include ileal transposition and its variations, and duodenal jejunal bypass with or without sleeve gastrectomy.

Ileal Transposition

Several ileal transposition (IT) techniques were developed: IT alone, IT with sleeve gastrectomy (IT + SG), and IT with sleeve gastrectomy and duodenal exclusion (IT + SG + DE).

In an RCT comparing IT + SG with IT + SG + DE, De Paula et al. [27] found that both operations promoted significant T2DM remission; however, lower HbA1c levels were observed in the duodenal exclusion subtype of surgery. They reported that foregut exclusion plays an important role in T2DM remission, because duodenal exclusion was the only variant between the two studied groups.

In a more recent report [28], the same author published the outcomes of 202 patients with T2DM with a mean BMI of 29.7 kg/m2 submitted to IT + SG and IT + SG + DE. The mortality rate was 1%, and significant complications occurred in 11.9% of patients. Mean HbA1c decreased from 9.7% to 6.2%, and 90% of the patients had HbA1c less than 7% at 39 months. In this report, the authors did not compare differences between the individual procedures.

Although improvement in metabolic diseases has been reported following IT, complication rates are higher than that of other procedures [27, 28]. Some of them are specific to this type of procedure, such as ischemia of the transposed ileum and higher incidences of intestinal obstruction due to internal hernias. Such complications may lead to a higher mortality rate compared with standard bariatric procedures.

Duodenal Jejunal Bypass

The largest “classic duodenal jejunal bypass (DJB)” cohort was published in 2012 by our group [29] in which 36 patients with T2DM and grade 1 obesity (mean BMI of 28.5 kg/m2) were submitted to classic DJB. T2DM remission (HbA1c <7% and FPG < 126 mg/dL) occurred in 40% of patients at one-year follow-up. There was no relation between BMI variation and the decrease of HbA1c. Beta cell response to an oral glucose load was further assessed, showing that DJB improved beta cell function, although it did not normalize it. These findings suggest that altering the intestinal site of delivery of ingested nutrients has therapeutic effects, mainly with duodenal exclusion.

Summary

Every new T2DM treatment must be safe and effective. It must correct hyperglycemia and prevent or mitigate the complications of this chronic disease. The continuing morbidity and mortality in individuals with T2DM and lack of glycemic control even with new medications is a sign that the best management in maximizing metabolic control remains elusive. Given this scenario, the option of metabolic surgery should be considered in appropriately selected individuals. While more data is needed to determine the place of metabolic surgery in lower BMIs, it is important to highlight that all operations should be done based on the investigational protocols approved by internal review boards investigational protocols.

Key Learning Points

  • Bariatric surgery is a highly effective treatment for obesity and its related comorbidities.

  • Some of the antidiabetic effects of metabolic procedures are weight loss–independent considerations, prompting for surgery in patients with type 2 diabetes and grade 1 obesity.

  • Recent data from randomized controlled trials show that metabolic surgery is highly effective, with greater rates of type 2 diabetes remission when compared to medical therapy.