Obesity is a serious global public health crisis that is associated with significant morbidity and mortality. SGH Endocrinology department shares more.
Obesity is a serious global public health crisis that is associated with significant morbidity and mortality. Excess body fat accumulation leads to metabolic and mechanical complications, notably type 2 diabetes (T2DM), hypertension, hyperlipidaemia, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, obstructive sleep apnoea (OSA), osteoarthritis and certain cancers.
In Singapore, the prevalence of obesity (BMI ≥ 30 kg/m2) has doubled from 5.5% in 1992 to 10.8% in 2010,1 and this is mirrored by a rise in T2DM. The case vignette below illustrates a typical scenario that is encountered by the general practitioner and highlights some of the issues when managing a patient with obesity and T2DM.
LIFESTYLE MODIFICATION
Although Mr T’s weight is substantially above his ideal weight range, it is worth noting that he does not have to lose all his excess weight to derive clinical benefit, and that even a modest weight loss of 5-10% of his body weight could result in significant clinical benefit and improvement of many of the obesityrelated complications, including T2DM.
This amount of weight loss can be realistically achieved with lifestyle interventions focusing on healthy diet and exercise, which remain the foundation of obesity and diabetes management. Several randomised controlled trials (RCTs) have shown that intensive lifestyle interventions can prevent or delay onset of diabetes,2 as well as improve glycaemic control in those with T2DM.3
However, the efficacy of lifestyle modification alone is limited due to physiological neurohormonal changes that drive weight regain and a variety of other therapies is often required.
PHARMACOTHERAPY FOR OBESITY AND DIABETES MELLITUS
In conjunction with lifestyle modification efforts, Mr T’s diabetes therapy was intensified to address the suboptimal glycaemic control in order to reduce risks of long-term microvascular complications.
The selection of appropriate anti-hyperglycaemic agents involves consideration of various factors, including efficacy, costs and side effect profile such as hypoglycaemia risk and propensity for weight gain.
Metformin is the established first-line therapy given its good efficacy, low cost, low hypoglycaemia risk and weight neutrality. There are numerous options that can be considered if combination therapy is required or if metformin is contraindicated or not tolerated, but it is logical that the preferred choice in individuals with obesity would be agents with a favourable weight profile.
Table 1 Common antidiabetic drugs and their effects on body weight4
Metformin (-0.6 to -1.2 kg)
GLP-1 receptor agonists (e.g. exenatide, liraglutide) (-1.8 to -2.5 kg)
SGLT-2 inhibitors (e.g. canagliflozin, dapagliflozin, empagliflozin) (-1.8 to -2.7 kg) | Acarbose
DPP-4 inhibitors (e.g. sitagliptin, linagliptin, vildagliptin) | Insulin (+1.5 to +3 kg)
Sulfonylureas (e.g. glipizide, gliclazide, tolbutamide) (+2 kg)
Metiglinides (e.g. repaglinide) (+1.8 kg)
Thiazolidinediones (e.g. pioglitazone) (+2.6 kg) |
Table 1 above summarises the common antidiabetic agents used, based on their effects on body weight. Whenever possible, medications chosen should promote weight loss or be weight neutral.
Recent cardiovascular outcome trials have also reported encouraging results with the use of some of these newer types of medications in T2DM patients at high cardiovascular risk.
The EMPA-REG trial has shown that empagliflozin, a sodium/glucose cotransporter 2 (SGLT-2) inhibitor, significantly decreased cardiovascular events by 14% (10.5% vs. 12.1% with placebo) and cardiovascular death by 38% (3.7%, vs. 5.9% with placebo) after 3.1 years.5
More recently, the LEADER trial showed that liraglutide reduced cardiovascular events by 13% (13.0% vs. 14.9% with placebo) and cardiovascular death by 22% (4.7% vs. 6.0% with placebo) after 3.8 years.6 The cardiovascular safety and favourable weight profile of these antidiabetic agents provide an attractive option for individuals with obesity and T2DM, especially for those at high cardiovascular risk.
In Mr T’s case, an SGLT-2 inhibitor was added. He lost 3 kg in body weight and his HbA1c improved to 8.2%. Liraglutide was subsequently commenced, with dual aims of promoting weight loss and improvement in diabetes control. The dose was started at 0.6 mg, and gradually escalated to 1.2 mg daily. He was unable to tolerate higher doses due to gastrointestinal side effects. The medication improved his adherence to caloric restriction, and he achieved an additional 5 kg weight loss bringing his weight to 110 kg, and his HbA1c improved to 6.9%.
METABOLIC-BARIATRIC SURGERY
Two years later, Mr T’s weight had increased to 130 kg (BMI 41.7kg/m2). His HbA1c had also risen to 9.2%. He had discontinued liraglutide 6 months ago due to cost constraints. He presented to the clinic as he was interested in metabolic- bariatric surgery (MBS).
Evidence and Guidelines on MBS in T2DM
At this point, it is useful to review the evidence and guidelines on the utility of MBS in T2DM.
In patients with T2DM, significant improvements in glycaemic control are observed after bariatric surgery in the majority of cases. Many patients are able to achieve remission of diabetes, defined as stable non-diabetic glycaemia off all diabetes medications.7 Several algorithms have been proposed to predict diabetes remission, and factors that are associated with increased likelihood of diabetes remission include higher baseline BMI, higher c-peptide levels (a marker of beta-cell function) and shorter duration of diabetes.8
RCTs have shown that treatment of obesity and T2DM with bariatric-metabolic surgery is superior to medical therapy in controlling hyperglycaemia and cardiovascular risk factors over the medium-term.9,10
A recent report from the large observational Swedish Obese Subjects study showed that bariatric-metabolic surgery was associated with reduced risk of microvascular complications over a median follow-up period of 19 years,11 implicating that improvement in glycaemia and other cardiovascular risk markers translate to reduced clinical events over the longer-term.
Pre-operative Preparation for T2DM Patients
After weighing the risks and benefits of surgery, Mr T decided to opt for a Roux-en-Y gastric bypass. Prior to MBS, weight loss with medical nutrition therapy can reduce liver volume and visceral adiposity, making surgery technically easier and leading to improved shortterm outcomes.12
This can reasonably be achieved using very low calorie diets (VLCD) consisting of meal replacements which provide ≤ 800 kcal/day. VLCD is started at least 2 weeks prior to surgery. The acute caloric restriction with VLCD leads to improved insulin sensitivity and significant improvement in glycaemic control.
During VLCD, patients with T2DM should self-monitor their capillary blood glucose regularly, especially if they are on insulin or insulin secretagogues. Reductions in insulin doses are often necessary whilst on VLCD, in order to prevent hypoglycaemia. Mr T’s glycaemic control improved with pre-operative VLCD, and surgery was uneventful, with no early surgical complications.
Post-operative Nutritional and Metabolic Follow-up
In patients with T2DM, adjustments to the antidiabetes agents are frequently necessary in the early post-operative period to prevent hypoglycaemia. Insulin secretagogues (sulphonylureas and metiglinides) should be discontinued, and insulin doses reduced as appropriate.
Metformin should be continued postoperatively, and withdrawal considered if stable non-diabetic glycaemia (HbA1c in the normal range for at least 6 months) is demonstrated.
Diabetes complications screening should continue even with diabetes remission, at least for the first 5 years.7
Six months after surgery, Mr T lost 25 kg (19% of his body weight). The SGLT-2 inhibitor and gliclazide was discontinued, and HbA1c was 6.1% on metformin monotherapy. His antihypertensive medications were reduced, and blood pressure was 124/76 mmHg on perindopril.
Appropriate multivitamin, multimineral, calcium and vitamin D supplementation were commenced and nutritional screening did not reveal any micronutrient deficiencies. Mr T was counselled on the importance of adherence to long-term post-operative follow-up to ensure a safe and successful outcome.
LOCAL GUIDELINES
In Singapore, the MOH guidelines have recommended that MBS may be considered in patients with:
- BMI >40 kg/m2, or
- Above 35 kg/m2 with an obesity- related comorbidity such as T2DM.1
As Asians have more adiposity for a given BMI, the BMI action points for Asians may be reduced by 2.5 kg/m2.
More recently, a joint statement by major international diabetes organisations proposed that MBS should be an established treatment option in the algorithm to manage T2DM,7 and is recommended for:
- All individuals with T2DM and BMI ≥ 40 kg/m2
- Individuals with BMI 35-40 kg/ m2 with inadequate glycaemic control despite lifestyle and optimal medical therapy
In addition, surgery may be considered in those with BMI between 30-35 kg/m2 and uncontrolled hyperglycaemia despite optimal medical therapy.7 However, the number of studies in this population is still limited and there is lack of long-term data demonstrating net benefit.
Most importantly, patients must be able, willing and motivated to adhere to the post-operative lifestyle changes, nutritional supplementation, and follow-up that are necessary to ensure safety and success.
PRACTICE POINTS
- In a patient with obesity and T2DM, lifestyle modification via dietary changes and increased physical activity, aiming for weight loss of 5-10% can result in significant improvement in glycaemic control.
- When selecting anti-hyperglycaemic agents, choose agents that have a favourable weight profile (either weight loss or weight-neutral).
- In the properly selected patient, bariatric surgery can result in significant glycaemic improvement, even to the point of diabetes remission.
- Bariatric surgery has been recommended as a treatment option for T2DM in Asian patients with BMI >32.5 kg/m2.
- Careful pre-operative assessment and post-operative follow-up with a focus on adjusting diabetes medications ensure a safe and successful outcome after surgery.
GPs can call for appointments through the GP Appointment Hotline at 6321 4402 for more information.
By: Dr Lee Phong Ching, Consultant, Department of Endocrinology; Obesity and Metabolic Unit, Singapore General Hospital
Dr Lee Phong Ching is a Consultant Endocrinologist at the Singapore General Hospital (SGH). His area of clinical interest is in obesity and its clinical, psychological and social impact on health. He recently spent a year-long clinical fellowship at the Baker IDI Institute in Melbourne with a focus on clinical obesity research and management.
He is actively involved with the multidisciplinary obesity management program at the Lifestyle Improvement and Fitness Enhancement centre at Singapore General Hospital.
References
1. Lee,Y.S.,et al.Health Promotion Board-Ministry of Health ClinicalPractice Guidelines:Obesity.Singapore Med J 57,292-300 (2016).
2. Knowler,W.C.,et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N EnglJ Med 346,393-403 (2002).
3. Look,A.R.G.,et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.N Engl J Med 369,145-154 (2013).
4. Apovian,C.M.,et al.Pharmacologicalmanagement of obesity:an endocrine Society clinical practice guideline.J Clin Endocrinol Metab 100,342-362 (2015).
5. Zinman,B.,et al.Empagliflozin,Cardiovascular Outcomes,and Mortail ty in Type 2 Diabetes.N Engl J Med 373,2117-2128 (2015).
6. Marso,S.P.,et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.N EnglJ Med 375,311-322 (2016).
7. Rubino,F., et al.Metabolic Surgery in the Tre 8. Dixon,J.B.,et al. Predicting the glycemic response to gastric bypass surgery in patients with type 2 diabetes.Diabetes Care 36,20-26 (2013).
9. Schauer,P.R.,et al. Bariatric Surgery versus Intensive MedicalTherapy for Diabetes- 5-Year Outcomes.N Engl J Med 376,641-651 (2017).
10. Mingrone,G.,et al. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label,single-centre,randomised controlled trial. Lancet 386,964-973 (2015).
11. Carlsson,LM.,et al.Long-term incidence of microvascular disease after bariatric surgery or usual care in patients with obesity,stratified by baseline glycaemic status:a post-hoc analysis of participants from the Swedish Obese Subjects study.Lancet Diabetes Endocrinol (2017).
12. Tamoff,M.,Kaplan,L.M. & Shikora,S. An evidenced-based assessment of preoperative weight loss in bariatric surgery. Obes Surg 18, 1059-1061 (2008).
