Series
Bariatric surgery 1 Metabolic surgery: shifting the focus from glycaemia and weight to end-organ health Alexander D Miras, Carel W le Roux
Bariatric surgery is the most effective treatment for weight loss and glycaemic control. The focus of clinical studies and clinical experience has predominantly been on the numerical reductions of bodyweight and glucose after surgery. In this Series paper, we examine evidence on the efficacy of bariatric surgery for pancreatic, renal, retinal, peripheral nervous, cardiovascular, hepatic, and reproductive end-organ damage or disease. The overall conclusions are that, in most cases, patients’ end-organ damage is expected to either stabilise or improve postoperatively. However, some of these clinical outcomes have not been assessed with robust methods and, in many cases, do not have support from randomised controlled clinical trials comparing bariatric surgery with non-surgical interventions. Such trials are urgently needed to inform patients and clinicians on whether the risks of surgery outweigh the significant benefits for end-organ health.
Introduction The exorbitant rise in the prevalence of severe and complex obesity is a major threat to the health of millions of people around the globe, and also to the financial viability of public and private health-care providers. Depending on the definition of metabolic health, 20–44% of individuals might have a BMI within the severely obese range, but have no metabolic complications from their obesity.1 A controversial idea is that the morbidity and mortality of this obese but metabolically healthy group might be similar to that of the population with healthy weight.2 However, obesity becomes much more risky and costly for patients who develop metabolic, cardiovascular, respiratory, reproductive, or neoplastic comorbidities, among other disorders. In particular, type 2 diabetes combined with obesity is increasingly prevalent, and its associated macrovascular and microvascular complications are major health burdens for the individual and for societies alike. Although treatments for other diseases have evolved and become more effective because of medical and basic science research, therapies for obesity are poor. Lifestyle modification incorporating reductions in dietary calorie intake and increases in exercise-induced energy expenditure are the cornerstone of weight-loss management. However, although most patients lose weight in the short term, only a few can maintain the weight loss in the long term.3 There are two main reasons for this disappointing outcome. First, because of financial and capacity constraints, lifestyle and behavioural interventions are often delivered by health-care professionals during a short period, with very little longterm follow-up and support; second, even with the best efforts and commitment of health-care professionals and patients, these interventions are strongly resisted by physiologically robust mechanisms activated during weight loss. These previously protective responses to weight loss include increased hunger, decreased www.thelancet.com/diabetes-endocrinology Vol 2 February 2014
satiation, pre-occupation with high-calorie foods, and decreased energy expenditure.4–7 These responses are mediated through hormonal and neural signals, and promote weight regain.4 Nevertheless, lifestyle interventions are effective in bodyweight maintenance.8–10 In view of the fact that gradual weight gain is almost unavoidable, the health benefits of weight maintenance cannot be underestimated. In the context of type 2 diabetes and obesity, studies from the Look AHEAD Research Group showed that intensive lifestyle modification did not reduce cardiovascular events or death, but led to significant improvements in events including sleep apnoea,11 diabetes remission,12 and mobility.13 The development of pharmacotherapy for obesity has involved more failures than successes, leaving clinicians in Europe with only one effective drug, orlistat, which reduces weight by a mean of 2·9 kg.14 Although the magnitude of weight loss in clinical trials was small, the effect was enough to improve glycaemic control in type 2 diabetes, and prevent its development, while improving blood pressure and hyperlipidaemia.14 However, these benefits do not translate to reductions in mortality or cardiovascular morbidity. More recently, two new drugs—lorcaserin and a combination preparation of topiramate and phentermine—were approved for treatment of obesity by the US Food and Drug Administration. The clinical efficacy of these drugs seems to be superior to that of orlistat, but long-term data for obesity-associated comorbidities are not yet available.15,16 The most effective and durable treatment for both obesity and type 2 diabetes is bariatric surgery. Results of prospective case-controlled studies and randomised controlled clinical trials have shown that bariatric surgery enables a mean total bodyweight loss of 20–40% and a mean absolute reduction in HbA1c of 1·8–3·8% (with a baseline HbA1c of 7·8–9·5%).17–21 Surgery seems to lead to reductions in overall and cardiovascular mortality
Lancet Diabetes Endocrinol 2014; 2: 141–51 This is the first in a Series of four papers about bariatric surgery See Comment pages 98 and 100 See Series page 152 Molecular and Metabolic Imaging group, Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital, London, UK (A D Miras MRCP); and Diabetes Complications Research Centre, UCD Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland, and Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (C W le Roux FRCP) Correspondence to: Dr Alexander D Miras, Molecular and Metabolic Imaging group, Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK [email protected]
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and morbidity in individuals with and without type 2 diabetes.22,23 The most common procedures worldwide include the laparoscopic Roux-en-Y gastric bypass (RYGB), laparoscopic adjustable gastric banding (LAGB), and vertical sleeve gastrectomy (VSG), and have a mortality rate of less than 0·3%, which is equivalent to that for laparoscopic cholecystectomy.24 The biliopancreatic diversion (BPD) with or without a duodenal switch is more effective and has higher risk, but is done less often (table 1). The most serious complications associated with laparoscopic bariatric surgery include postoperative sepsis, anastomotic leaks, bleeding, and venous thromboembolism (table 1);25 these are more common after RYGB (4·8%) than after LAGB (1·0%).24 Factors associated with increased mortality and morbidity include male sex, age older than 65 years, reduced cardiorespiratory fitness, and surgical inexperience.30 Nutritional deficiencies can occur after bariatric surgery because of the resulting changes in the anatomy of the gastrointestinal tract.25 Deficiencies in vitamin B12, folate, and iron are not uncommon soon after surgery, and evidence of calcium, vitamin D, and trace-element deficiencies can occur months to years after the procedure.25 With longer follow-up becoming available, inadequate weight loss or substantial weight regain after bariatric surgery are now increasingly noted. These socalled failure rates are difficult to quantify, because the definitions of inadequate weight loss or weight regain are nebulous, and surgical techniques and postoperative care vary between centres. Additionally, some weight regain is physiological and expected after any weight-loss intervention (eg, lifestyle, pharmacotherapy, and surgery). With these caveats in mind, substantial weight regain within a 6 year period is observed in 10–20% of patients after RYGB,31 26% after VSG,32 and 20–50% after LAGB.33 The mechanisms of weight regain are poorly understood, and the choice of revision procedures can therefore be challenging. RYGB19–21,24–27
These procedures have taken decades to evolve, become safer, and find their place and role in the clinical management of patients with type 2 diabetes, obesity, or both. During this period, the focus of clinical studies and clinical experience has been predominantly on the numerical reductions of bodyweight and glucose. Although these two markers have some clinical use, they offer little information about overall and tissue-specific health. In this Series paper we therefore attempt to examine the available evidence on the efficacy of bariatric surgery on the main issues for patients and clinicians: prevention, delay, or even reversal of end-organ damage.
Pancreas The effects of bariatric surgery on pancreatic function have attracted substantial interest as a result of improvements in insulin secretion and glycaemic control in people with type 2 diabetes and obesity who undergo surgery. Metabolic surgery can often lead to complete glycaemic remission—ie, normal glucose tolerance without glucose-lowering drugs. In the absence of a systematic definition, a meta-analysis suggested that remission is achieved in about 78% of patients after surgery.26 However, this value is reduced substantially when the American Diabetes Association criteria are applied (panel);34 one cohort study and one randomised controlled trial have used the American Diabetes Association criteria, and reported that 34% and 41% of patients, respectively, had complete remission at least 1 year after surgery.19,35 In 2011, following a highprofile position statement on the use of bariatric surgery for the treatment of type 2 diabetes,36,37 the International Diabetes Federation introduced new criteria to define the optimisation and substantial improvement of the metabolic state (panel).37 These criteria include not only markers of glycaemia, but also weight loss, plasma lipids, rates of hypoglycaemia, blood-pressure control, and use of medicines. Using these criteria in a small
LAGB18,24–28
VSG19,25,26,29
BPD±DS24–27
Total bodyweight loss (%)
25–30%
15–25%
25–30%
30–40%
Absolute HbA1c reduction (%)
2·1–2·9%
1·8%
2·9%
3·8%
Baseline HbA1c (%)
8·6–9·3%
7·8%
9·5%
8·9%
30 day mortality (%)
Bariatric surgery 1 Metabolic surgery: shifting the focus from glycaemia and weight to end-organ health Alexander D Miras, Carel W le Roux
Bariatric surgery is the most effective treatment for weight loss and glycaemic control. The focus of clinical studies and clinical experience has predominantly been on the numerical reductions of bodyweight and glucose after surgery. In this Series paper, we examine evidence on the efficacy of bariatric surgery for pancreatic, renal, retinal, peripheral nervous, cardiovascular, hepatic, and reproductive end-organ damage or disease. The overall conclusions are that, in most cases, patients’ end-organ damage is expected to either stabilise or improve postoperatively. However, some of these clinical outcomes have not been assessed with robust methods and, in many cases, do not have support from randomised controlled clinical trials comparing bariatric surgery with non-surgical interventions. Such trials are urgently needed to inform patients and clinicians on whether the risks of surgery outweigh the significant benefits for end-organ health.
Introduction The exorbitant rise in the prevalence of severe and complex obesity is a major threat to the health of millions of people around the globe, and also to the financial viability of public and private health-care providers. Depending on the definition of metabolic health, 20–44% of individuals might have a BMI within the severely obese range, but have no metabolic complications from their obesity.1 A controversial idea is that the morbidity and mortality of this obese but metabolically healthy group might be similar to that of the population with healthy weight.2 However, obesity becomes much more risky and costly for patients who develop metabolic, cardiovascular, respiratory, reproductive, or neoplastic comorbidities, among other disorders. In particular, type 2 diabetes combined with obesity is increasingly prevalent, and its associated macrovascular and microvascular complications are major health burdens for the individual and for societies alike. Although treatments for other diseases have evolved and become more effective because of medical and basic science research, therapies for obesity are poor. Lifestyle modification incorporating reductions in dietary calorie intake and increases in exercise-induced energy expenditure are the cornerstone of weight-loss management. However, although most patients lose weight in the short term, only a few can maintain the weight loss in the long term.3 There are two main reasons for this disappointing outcome. First, because of financial and capacity constraints, lifestyle and behavioural interventions are often delivered by health-care professionals during a short period, with very little longterm follow-up and support; second, even with the best efforts and commitment of health-care professionals and patients, these interventions are strongly resisted by physiologically robust mechanisms activated during weight loss. These previously protective responses to weight loss include increased hunger, decreased www.thelancet.com/diabetes-endocrinology Vol 2 February 2014
satiation, pre-occupation with high-calorie foods, and decreased energy expenditure.4–7 These responses are mediated through hormonal and neural signals, and promote weight regain.4 Nevertheless, lifestyle interventions are effective in bodyweight maintenance.8–10 In view of the fact that gradual weight gain is almost unavoidable, the health benefits of weight maintenance cannot be underestimated. In the context of type 2 diabetes and obesity, studies from the Look AHEAD Research Group showed that intensive lifestyle modification did not reduce cardiovascular events or death, but led to significant improvements in events including sleep apnoea,11 diabetes remission,12 and mobility.13 The development of pharmacotherapy for obesity has involved more failures than successes, leaving clinicians in Europe with only one effective drug, orlistat, which reduces weight by a mean of 2·9 kg.14 Although the magnitude of weight loss in clinical trials was small, the effect was enough to improve glycaemic control in type 2 diabetes, and prevent its development, while improving blood pressure and hyperlipidaemia.14 However, these benefits do not translate to reductions in mortality or cardiovascular morbidity. More recently, two new drugs—lorcaserin and a combination preparation of topiramate and phentermine—were approved for treatment of obesity by the US Food and Drug Administration. The clinical efficacy of these drugs seems to be superior to that of orlistat, but long-term data for obesity-associated comorbidities are not yet available.15,16 The most effective and durable treatment for both obesity and type 2 diabetes is bariatric surgery. Results of prospective case-controlled studies and randomised controlled clinical trials have shown that bariatric surgery enables a mean total bodyweight loss of 20–40% and a mean absolute reduction in HbA1c of 1·8–3·8% (with a baseline HbA1c of 7·8–9·5%).17–21 Surgery seems to lead to reductions in overall and cardiovascular mortality
Lancet Diabetes Endocrinol 2014; 2: 141–51 This is the first in a Series of four papers about bariatric surgery See Comment pages 98 and 100 See Series page 152 Molecular and Metabolic Imaging group, Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital, London, UK (A D Miras MRCP); and Diabetes Complications Research Centre, UCD Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland, and Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (C W le Roux FRCP) Correspondence to: Dr Alexander D Miras, Molecular and Metabolic Imaging group, Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK [email protected]
141
Series
and morbidity in individuals with and without type 2 diabetes.22,23 The most common procedures worldwide include the laparoscopic Roux-en-Y gastric bypass (RYGB), laparoscopic adjustable gastric banding (LAGB), and vertical sleeve gastrectomy (VSG), and have a mortality rate of less than 0·3%, which is equivalent to that for laparoscopic cholecystectomy.24 The biliopancreatic diversion (BPD) with or without a duodenal switch is more effective and has higher risk, but is done less often (table 1). The most serious complications associated with laparoscopic bariatric surgery include postoperative sepsis, anastomotic leaks, bleeding, and venous thromboembolism (table 1);25 these are more common after RYGB (4·8%) than after LAGB (1·0%).24 Factors associated with increased mortality and morbidity include male sex, age older than 65 years, reduced cardiorespiratory fitness, and surgical inexperience.30 Nutritional deficiencies can occur after bariatric surgery because of the resulting changes in the anatomy of the gastrointestinal tract.25 Deficiencies in vitamin B12, folate, and iron are not uncommon soon after surgery, and evidence of calcium, vitamin D, and trace-element deficiencies can occur months to years after the procedure.25 With longer follow-up becoming available, inadequate weight loss or substantial weight regain after bariatric surgery are now increasingly noted. These socalled failure rates are difficult to quantify, because the definitions of inadequate weight loss or weight regain are nebulous, and surgical techniques and postoperative care vary between centres. Additionally, some weight regain is physiological and expected after any weight-loss intervention (eg, lifestyle, pharmacotherapy, and surgery). With these caveats in mind, substantial weight regain within a 6 year period is observed in 10–20% of patients after RYGB,31 26% after VSG,32 and 20–50% after LAGB.33 The mechanisms of weight regain are poorly understood, and the choice of revision procedures can therefore be challenging. RYGB19–21,24–27
These procedures have taken decades to evolve, become safer, and find their place and role in the clinical management of patients with type 2 diabetes, obesity, or both. During this period, the focus of clinical studies and clinical experience has been predominantly on the numerical reductions of bodyweight and glucose. Although these two markers have some clinical use, they offer little information about overall and tissue-specific health. In this Series paper we therefore attempt to examine the available evidence on the efficacy of bariatric surgery on the main issues for patients and clinicians: prevention, delay, or even reversal of end-organ damage.
Pancreas The effects of bariatric surgery on pancreatic function have attracted substantial interest as a result of improvements in insulin secretion and glycaemic control in people with type 2 diabetes and obesity who undergo surgery. Metabolic surgery can often lead to complete glycaemic remission—ie, normal glucose tolerance without glucose-lowering drugs. In the absence of a systematic definition, a meta-analysis suggested that remission is achieved in about 78% of patients after surgery.26 However, this value is reduced substantially when the American Diabetes Association criteria are applied (panel);34 one cohort study and one randomised controlled trial have used the American Diabetes Association criteria, and reported that 34% and 41% of patients, respectively, had complete remission at least 1 year after surgery.19,35 In 2011, following a highprofile position statement on the use of bariatric surgery for the treatment of type 2 diabetes,36,37 the International Diabetes Federation introduced new criteria to define the optimisation and substantial improvement of the metabolic state (panel).37 These criteria include not only markers of glycaemia, but also weight loss, plasma lipids, rates of hypoglycaemia, blood-pressure control, and use of medicines. Using these criteria in a small
LAGB18,24–28
VSG19,25,26,29
BPD±DS24–27
Total bodyweight loss (%)
25–30%
15–25%
25–30%
30–40%
Absolute HbA1c reduction (%)
2·1–2·9%
1·8%
2·9%
3·8%
Baseline HbA1c (%)
8·6–9·3%
7·8%
9·5%
8·9%
30 day mortality (%)
