Abstract
Diabetes and obesity are closely interlinked. Obesity is a major risk factor for the development of type 2 diabetes mellitus and appears to be an important risk factor for diabetic micro- and macrovascular complications. Management of hyperglycaemia in people with diabetes is important to reduce diabetes-related complications. Previously, there was a significant tension between management of hyperglycaemia and mitigating weight gain. Older drugs, such as sulfonylureas, glitazones, and insulin, although effective antihyperglycaemic agents, tend to induce weight gain. There is now an increasing recognition in people with obesity and diabetes that the focus should be on aiding weight loss, initially with improvements in diet and physical activity, possibly with the use of low-calorie diet programmes. Subsequent addition of metformin and newer agents, such as sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogues, will aid glucose control and weight reduction, and offer cardiovascular and renal protection. These drugs are now much higher in the therapeutic pathway in many national and international guidelines. Bariatric surgery may also be an effective way to manage hyperglycaemia or induce remission in individuals with both obesity and diabetes.
Introduction
The link between obesity and hyperglycaemia is well established, and the prevalence of both is increasing worldwide. World Health Organization data suggest that 13% of all adults aged 18 and over are obese, whereas the number of people diagnosed with diabetes has increased by more than threefold over the past 40 years.1,2 Prospective observational data over 16 years of follow-up suggest that being overweight or obese is the single most important predictor for the development of type 2 diabetes mellitus (T2DM).3 Furthermore, the most common tools used to measure obesity, such as body mass index (BMI), waist-to-hip ratio and waist circumference, are positively associated with the development of T2DM in people with prediabetes or impaired glucose tolerance (IGT).4
The key mechanism that links hyperglycaemia and obesity is insulin resistance (Fig 1). The role of adipose tissue is thought to be pivotal in this process.5 Adipose tissue increases circulating non-esterified fatty acids (NEFAs), leptin, and adipocytokines, which act synergistically to promote a proinflammatory state and insulin resistance. NEFAs affect insulin secretion, but prolonged increased plasma NEFA levels was found to negate the effect of hyperglycaemia on insulin secretion and reduce insulin sensitivity in men with obesity.6,7 There is also thought to be a direct effect on pancreatic β cell function resulting from glucolipotoxicity in patients with obesity.8
Metabolic effects of central obesity. HDL = high-density lipoprotein; LDL = low-density lipoprotein.
Diabetes is a direct cause of one in nine deaths among adults aged 20–79 years.9 Obesity is the single most modifiable risk factor for the development of hyperglycaemia and, although the prevalence of non-diabetic-range hyperglycaemia worldwide is not elucidated, it is clear that obesity is the predominant predictor of IGT.10 In this review, we discuss the current management options for hyperglycaemia in patients with obesity.
Why is the treatment of hyperglycaemia important in people with obesity?
People with diabetes and obesity develop more cardiovascular, renal, and neuropathic complications compared with those who are not obese.11 The effects of obesity on the development of chronic kidney disease (CKD), cardiovascular disease (CVD), obstructive sleep apnoea (OSA), non-alcoholic fatty liver disease (NAFLD), and cancer are well recognised.12 These outcomes might not necessarily be potentiated through insulin resistance or hyperglycaemia. However, the presence of hyperglycaemia compounds the risk of developing these complications. More recently, people with obesity who contracted severe acute respiratory syndrome-coronavirus 2019 (SARS-CoV-2; Coronavirus 2019 (COVID-19)) had significantly higher mortality rates when accounting for other known risk factors.13 Obesity is also independently associated with the development of CVD, neuropathy, and CKD in people with either type 1 diabetes mellitus (T1DM) or T2DM.14 Furthermore, obesity appears to be a significant risk factor for retinopathy in people with T1DM.14
Weight loss appears to lead to improvements in glycaemic control.15 The weight loss required to significantly improve glycaemic control could be as little as 5% of the initial body weight,16 and significant weight loss within 6 years of diagnosis from T2DM can lead to its remission.17 In the DiRECT study, incorporating meal replacement therapy and frequent clinical contact, almost half of the people who entered the study lost weight, with a mean weight loss of 10 kg in the intervention group at 1 year. Remission rates were seen in a weight loss-dependent manner: people who lost more weight had higher remission rates. This may occur as a result of reduced insulin resistance, and hepatic and pancreatic fat loss, leading to improved β cell function and insulin sensitivity.18–20
However, longer-term follow-up of people with T2DM and weight loss has not established an improvement in mortality. A prospective analysis in people with both overweight and T2DM examining 9-year mortality rates showed that people who tried intentionally tried to lose weight had a reduced risk of all-cause mortality independent of whether they lost weight, whereas those who lost weight unintentionally were at higher mortality risk.21 Unintentional weight loss might be pathologically driven as a result of another illness or disease, and the weight loss might not in fact correlate with a reduction in adipose tissue, but in skeletal mass, instead or might be related to a decompensation in diabetes control. The limitations of most studies examining whether weight loss can confer mortality benefits are potential confounders, such as age, multiple health conditions, and duration of diabetes.22
Management of hyperglycaemia with diet and lifestyle changes
Lifestyle management is the first-line management for patients with a new diagnosis of diabetes. The DiRECT trial introduced participants to an intensive weight management programme, where they received total diet replacement (825–853 kcal/day) with stepped food reintroduction and support to maintain weight loss.17 This led to the remission of diabetes in almost half of the participants. Other studies have shown that structured weight-loss programs using a low-calorie diet are beneficial in improving glycaemic control in people with T2DM who have overweight or obesity.23 A low-calorie (1,500 kcal/day for women and 1,800 kcal/day for men) Mediterranean diet, comprising a diet rich in vegetables and whole grains and low in red meat, was found to be associated with a greater reduction in glycated haemoglobin (HbA1c) levels, and greater rates of diabetes remission compared with a low-fat diet group.24
Furthermore, a study examining whether the short use of very-low-calorie diets (330 cal/day) followed by isocaloric diets after 40 days found that there was an almost 5.0 mmol/l reduction in fasting plasma glucose levels, which persisted after 40 days, in those following a isocaloric diet. The study suggested that there are weight loss-independent mechanisms in which very-low-calorie diets can improve glycaemic control.25 A major concern is the possibility of weight regain, and whether such low-calorie diets can be adhered to long term.
Physical activity has also been shown to improve insulin sensitivity. Even a single session of physical activity can improve insulin-stimulated glucose uptake in the short term, although the sensitivity wears off quickly when exercise stops.26 It has also been found that regular exercise, regardless of weight loss, will promote improved insulin sensitivity. The Finnish Diabetes Prevention study assessed how lifestyle could affect people with IGT.27 Over 4 years of follow-up, people who achieved moderate–vigorous levels of long-term physical activity were almost 50% less likely to develop T2DM when changes in diet and body weight were adjusted for compared with those who achieved lower levels.
Similarly, the Chinese Da Qing Diabetes prevention outcome study has data from almost 600 people over 30 years with IGT.28 In people who underwent an intensive weight loss programme and improved lifestyle, a median delay in developing T2DM of almost 4 years was seen, along with a lower burden of CVD (hazard ratio 0.74) and CV death (hazard ratio 0.67). The Diabetes Prevention Study compared metformin with an intensive weight loss programme and found that lifestyle changes were more effective in preventing or delaying the development of T2DM from IGT compared with metformin only (58% vs 31%).29 The lifestyle intervention included a goal of at least 7% weight loss and 150 min of physical activity per week.
Diet and physical activity are two cornerstones of managing hyperglycaemia in people with obesity. It is clear that lifestyle intervention, especially early in the condition, can prevent the progression of IGT to T2DM, induce remission in people with T2DM, or at least lead to improved glycaemic control. Creating and sustaining lifestyle interventions for clinicians and patients can be challenging. It has been demonstrated that the improvement in glycaemic control from a low-calorie diet and increased physical activity is not only mediated through weight loss. However, when weight loss is achieved, there appear to be better cardiovascular outcomes for patients, although this appears to require a minimum 5% weight loss. The intensive interventions require frequent contact with healthcare professionals, a commitment to adhere to calorie restrictions, and regular exercise. Whether this can be replicated and sustained on a population scale remains to be seen.
Pharmacological management of hyperglycaemia in obesity
There are now several pharmacological therapies available to treat hyperglycaemia in people with T2DM. A major challenge is managing the balance between adverse effects on weight and positive effects on glycaemia. Table 1 outlines the mechanism of action and effects of commonly used anti-hyperglycaemic agents. Figure 2 summarises the effects of the antihyperglycaemic agents in the body, and Fig 3 conveys the effect of these agents on pancreatic β cells.
Overview of antidiabetic medication
Summary of the mechanisms of action of antihyperglycaemic agents.
Summary of the effects of antihyperglycaemic agents on pancreatic islet β cells. c-AMP = cyclic-AMP; DPP4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like-peptide-1; GLUT2 = glucose transporter 2.
Drugs that induce weight gain
Many older agents used in the treatment of T2DM induce weight gain. Sulfonylureas are commonly used for patients with T2DM, show good efficacy in lowering glucose, and were previously used second line to metformin.30 Increased risk of hypoglycaemia is a major concern, particularly in older people. By virtue of their non-glucose-dependent stimulation of pancreatic insulin release, they also cause weight gain.30–32 The evidence for whether this weight gain translates to increased CVD risk and subsequent morbidity and mortality is unclear.33,34
Pioglitazone is a thiazolidinedione that works by its agonist action at peroxisome proliferator-activated receptor-γ (PPARγ). It is not commonly used because of potential adverse effects around fluid retention, heart failure, and increased fracture risk in postmenopausal women.35 Although the action of pioglitazone appears to improve insulin sensitivity, it does cause significant weight gain. Therefore, it is used third, or perhaps fourth line in most guidelines.
Insulin therapy is commonly needed in people with T2DM as a result of β cell exhaustion after decades of diabetes. It remains one of the most common therapies used in the management of T2DM and might have to be used in people who have intolerance of other medications, or have failed to achieve adequate glucose control. Insulin is an anabolic hormone, and will frequently cause significant weight gain (∼1.56–5.75 kg), especially in people with obesity already; therefore, they might need relatively high doses of insulin for adequate glycaemic efficacy. Meta-analysis of 28 randomised control trials found that premixed insulin regimens were associated with more weight gain compared with long-acting insulin regimens, such as glargine or detemir.36 Furthermore, weight gain is positively associated with insulin dosage.37 Insulin regimens that incorporate the use of basal insulin might be better than prandial or biphasic insulin in terms of minimising weight gain,38 although biphasic and prandial insulin might lead to better glucose control. Mechanisms thought to induce weight gain with exogenous insulin therapy include direct effects on metabolism, such as stimulation of triglyceride production, reduction in glycosuria, and change in body composition with respect to adipose tissue and lean mass.39
Drugs that induce weight loss or that are weight neutral
Metformin has been the first-line treatment for T2DM for many years. It improves glycaemia with a low risk of hypoglycaemia. Most studies suggest that metformin can induce a modest weight loss, even in people with obesity but without diabetes.37,40 The mechanisms that underpin metformin-induced weight loss are poorly understood but are likely to be multifactorial, and there is evidence that metformin has effects on satiety at the hypothalamic level by modulating insulin and leptin sensitivity.41 Moreover, combining metformin with insulin might mitigate some of the weight gain commonly seen with insulin regimens on their own.40 There is also evidence that combining metformin with a sulfonylurea can reduce the weight gain usually associated with sulfonylureas.
Dipeptidylpeptidase-4 inhibitors (DPP-4i) are a further drug class used in therapy for T2DM.24 They block the breakdown of endogenous glucagon-like peptide-1 (GLP-1) and elevate its physiological levels. They cause few side effects, and an increased risk of pancreatitis (previously a concern), appears in recent studies to be very small.42 DPP-4is also appear to be weight neutral.37 However, they are not very efficacious in terms of glucose reduction and do not demonstrate protection from cardiovascular disease.43 One DPP-4i, linagliptin, is one of the few oral agents that can be used in severe CKD and does not cause hypoglycaemia.
Sodium-glucose transporter-2 inhibitors (SLGT-2i) are an important group of therapies for managing hyperglycaemia in T2DM. Weight loss of ∼2 kg is often seen with SLGT-2is, as a result of renal loss of glucose and reduced calorie absorption. Although there is an increased risk of urinary and genital tract infections, SLGT-2is show a good reduction in HbA1c depending on the level of renal function.44,45 SGLT-2is also demonstrate a reduction in blood pressure.46 These positive benefits on blood pressure, weight, glycaemia, and other metabolic effects might be responsible for the cardiovascular and renal benefits seen with these agents in people with and without diabetes.47–50 The National Institute of Health and Care Excellence (NICE) has updated its diabetes guidelines to encourage the use of SLGT-2is either first or second-line therapy.51 Patients at high risk of CVD or who have established CVD or renal disease should be considered for SLGT-2i therapy. People without diabetes but with heart failure or CKD can also be offered SLGT-2is. A meta-analysis of studies using SGLT-2is in patients with obesity and overweight but without diabetes showed a statistically significant reduction in body weight of 1.42 kg (BMI −0.47 kg/m2).52
GLP-1 analogues significantly reduce glucose and augment weight loss. Although oral formulations are available, subcutaneous once-weekly preparations appear to be most efficacious. Semaglutide is a once-weekly injection that has shown significant weight loss: 15% of body weight reduction was reported over 68 weeks.53 It is also associated with better glycaemic efficacy compared with other antidiabetic agents, such as sitagliptin, liraglutide, and dulaglutide.54 The main side effects are gastrointestinal and, rarely, pancreatitis.
GLP-1 analogues also achieve improved cardiorenal outcomes, although not as potently as SGLT-2is.43 GLP-1 analogues have also been used to promote weight loss in patients without diabetes. Tirzepatide is a novel polypeptide that acts on both the GLP-1 receptor as well as the glucose-dependent insulinotropic polypeptide (GIP) receptor. In a large study, over 2,500 participants were assigned to one of four groups (placebo, or 5 mg, 10 mg, or 15 mg of tirzepatide) over 72 weeks.55 Mean BMI at baseline was 38 kg/m2, with a mean body weight of 104.8 kg. The drug showed significant weight loss, with half of the patients who received the 10 mg weekly dose and 57% of patients who received the 15 mg weekly dose losing more than 20% of their total body weight.
Furthermore, at baseline, 97% of all groups had prediabetes. By the end of the study, 95.3% of the tirzepatide-treated groups reverted to normoglycaemia compared with 62% in the placebo group. The relatively high rate of normoglycaemia achieved in the placebo suggests that there is some benefit of just being part of a trial and having more contact with healthcare professionals, but the finding that almost every patient achieved normoglycaemia in the treatment groups is certainly encouraging.
Alpha-glucosidase inhibitors, such as acarbose, have been used to manage diabetes for several years. It is rarely used in the UK because of its gastrointestinal side-effects and contraindications in renal and hepatic disease. A meta-analysis comparing acarbose with DPP-4is found that, although the effect on glycaemic control was similar, acarbose was associated with greater weight loss,56 but a higher rate of withdrawal resulting mainly from gastrointestinal side effects. In a selected group of patients with obesity, there could be a role for using acarbose if the drug is tolerated, especially if other medications are contraindicated.
Surgical management of obesity and its effect on hyperglycaemia
It is well established that bariatric surgery significantly improves glycaemia and often induces diabetes remission. It has been debated whether other non-surgical weight loss strategies can be sustained. Bray et al discussed the effects of calorie restriction and exercise and explores the concept of ‘recidivism’ after intentional weight loss.57 The hypothalamus switches on pro-appetite hormones when it senses weight loss. This suggests that, to maintain weight loss, diet and exercise will have to be maintained lifelong. Long-term follow-up of patients who undergo bariatric surgery suggests that weight loss is maintained. Patients in a large Swedish study who underwent gastric bypass lost 32% of their weight after 1 or 2 years and 25% from baseline after 10 years.58 There was also a significant mortality benefit (hazard ratio 0.76) for patients who underwent any form of bariatric surgery compared with the control group, who received standard care.
The mechanisms that improve glycaemic control are likely related to increasing levels of circulatory satiety hormones, such as peptide YY (PYY) and GLP-1, and there is a mechanical effect of less food transit time, which serves to amplify these signals.59 Furthermore, better glycaemic control is achieved because of higher circulating insulin levels post-bariatric surgery, and patients are at risk of reactive hypoglycaemia after meals.60 A randomised controlled trial in which patients with a BMI >35 kg/m2 were selected to either receive conventional medical therapy or undergo bariatric surgery, analysed the rate of diabetes remission.61 No patients in the medical-therapy group achieved remission of diabetes after 2 years. By contrast, 75% of patients who underwent a gastric bypass achieved diabetes remission. Buchwald et al. found that 83.8% of patients who underwent gastric bypass and 98% of patients who underwent biliopancreatic diversion achieved complete resolution of diabetes.62
In summary, bariatric surgery is an effective method to treat both hyperglycaemia and obesity. There is greater evidence that weight loss can be maintained over a more extended period of time. Modern bariatric surgery techniques have improved the safety of these procedures, with perioperative mortality rates <0.2%.63 Some evidence is emerging to suggest that bariatric surgery has psychological effects when patients choose their meals.64 A cohort of patients might not be suitable for surgical intervention or might not want to opt for it, but bariatric surgery promises an avenue for improving hyperglycaemia in individuals with severe obesity.
Conclusions
Obesity and hyperglycaemia are common bedfellows. Obesity worsens insulin resistance, induces β cell exhaustion, and predisposes to the development of T2DM.
Treating hyperglycaemia in patients with obesity requires an approach that minimises weight gain and focuses on weight loss. Although diet and exercise have been shown to have considerable benefits, patients need to sustain these activities to reap the cardiometabolic rewards over time.
Pharmacotherapy using SLGT-2is and GLP-1 analogues demonstrate important weight-loss benefits, improved glucose control, and cardiorenal benefits. Therefore, individualisation of diabetes therapy based on weight is necessary, and recognised in national and international guidelines. Bariatric surgery has also demonstrated considerable benefits for patients with severe obese but requires careful patient selection.
- © Royal College of Physicians 2023. All rights reserved.
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