Obesity and diabetes: a different perspective

The links between obesity and diabetes are well-recognised. Now it looks as if a class of antihyperglycaemic agent may show promise in helping control obesity as well as blood glucose. We examine the evidence for this claim

The management of diabetes involves the use of pharmacological interventions to improve glycaemic control and reduce the risk of cardiovascular complications. In type 2 diabetes, important risk factors include central obesity. Along with other therapy options glucagon-like peptide-1s (GLP-1s) have been used to treat both hyperglycaemia and obesity in people with type 2 diabetes. However, new research suggests that one GLP-1 — liraglutide — may have a role in treating obesity in people without a history of diabetes.

In this article we will examine the evidence for using liraglutide as a treatment for obesity and consider how this evidence could influence the way we address the rising tide of obesity and potentially prevent some cases of type 2 diabetes in the future.

OBESITY AND TYPE 2 DIABETES

People who are overweight or obese are at increased risk of developing type 2 diabetes (T2D) and being overweight following a diagnosis of type 2 diabetes will increase the risk of poor control and future complications.¹ Management of obesity is therefore central to the prevention of diabetes and its complications. There has been a suggestion that significant weight loss through a very low calorie diet (600kcalorie/day) or through bariatric surgery in people who are overweight and have recently been diagnosed with T2D, may even lead to remission of the condition.^2,3 However, more modest weight losses (5-10% of starting weight) have been shown to improve glycaemic control and reduce the risk of developing diabetes in people who have impaired fasting glycaemia or impaired glucose tolerance.⁴ Various drug options have been tried over the years to help people to lose weight but many have been withdrawn from the market due to unacceptable adverse drug reactions. These made the risk: benefit profile of these drugs unacceptable. A relatively recent example is rimonabant, which was withdrawn in 2008 due to psychiatric side effects such as depression. Currently the only drug which has a licence for prescription in the UK to help support weight loss is orlistat. Recent research into the role of liraglutide as a weight loss treatment has now proved promising and may offer another tool in the armoury against obesity.

GLP-1 ANTAGONISTS FOR T2D

In the early part of the 20th century, the discovery was made that insulin secretion increased more in response to an oral glucose load than it did to an intravenous glucose load. This was called the 'incretin effect' and was shown to be related to the activity of gut peptides, including two which were similar to glucagon and were therefore called 'glucagon-like peptides' (GLPs). Of these, GLP-1 was found to be the most powerful insulin stimulator, and people with T2D are thought to have a poor GLP-1 response. GLP-1 agonists were eventually developed to prolong and optimise the activity of GLP-1 to reduce blood glucose levels and, after many years of research, GLP-1 agonists were licensed for use in type 2 diabetes.⁵ These agents are injectable therapies, given subcutaneously. Unlike sulfonylureas which will continue to 'spank the panc' no matter how high or low the blood glucose level, GLP-1 agonists will only work if they have glucose available to work with. This direct relationship to oral glucose load means that their hypoglycaemia (hypo) risk is very low, only increasing when they are used with other drugs known to cause hypos. As well as stimulating and prolonging insulin secretion, they have a range of other effects including reducing post-prandial glucose levels, inhibiting glucose neogenesis in the liver and delaying gastric emptying by slowing down the digestion process, leaving the patient feeling fuller for longer — this is the action which leads to weight loss in some patients.⁶ There are now four different types of GLP-1 analogues available: standard exenatide (Byetta) 5—10mcg, which is injected twice daily; the newer, long-acting version of exenatide 2 mg (Bydureon), which is injected just once weekly; liraglutide (Victoza) 0.6—1.2 mg and lixisenatide (Lyxumia) 10—20 mcg, which are both injected once daily. Liraglutide also comes in a dose of 1.8mg but this is not often used and is not endorsed by NICE in the treatment of diabetes unless recommended by a specialist. The NICE guidelines state that any patients treated with a GLP-1 should ideally achieve a glycaemic improvement of around 10 mmol/mol (1%) and/or a weight loss of 5% in the first 6 months of treatment. Failure to achieve one of these targets means the treatment should be reviewed as it may not be cost-effective. Failure to reach either target should result in the treatment being stopped.

THE SCALEâ„¢ STUDY

Recognising the potential for GLP-1 analogues to lead to weight loss, a programme of research studies (SCALEâ„¢) has been underway for several years and has examined the use of liraglutide* in both facilitating weight loss and helping people to maintain it.⁷ In the latest phase, the SCALEâ„¢ Obesity and Pre-diabetes study compared the amount of weight lost with treatment with liraglutide combined plus dietary interventions and increased exercise, with diet and exercise plus placebo. The trial lasted 56 weeks and the findings were presented at the 23rd Annual Congress of the American Association of Clinical Endocrinologists (AACE) earlier this year. The results showed that the group treated with liraglutide 3mg (a notably higher dose than those currently used to treat T2D) demonstrated a significantly greater weight loss versus placebo for adults with obesity. Over the trial period, people treated with liraglutide lost an average of 8.4kg (8%) of their baseline weight, compared with 2.8kg (2.6%) in the placebo group.*

All participants were given a low-calorie diet and advice on increasing physical activity. Using 5% as the meaningful target for weight loss from baseline, the proportion of adults achieving this was 64% in the active treatment arm compared with 27% in those treated with diet, exercise and placebo. In addition to these findings, those taking liraglutide 3mg were three times more likely to achieve weight losses of 10% or more compared with those on placebo.

Additional benefits were achieved in the active treatment arm of the trial, in that reductions in waist circumference were statistically significantly greater in the liraglutide-treated group, compared with the placebo arm: a reduction of 8.19cm was seen in those on active treatment compared to 3.94cm with placebo. Central obesity is known to be related to insulin resistance, hypertension and dyslipidaemia as seen in metabolic syndrome so this is an important finding. Interestingly, then, treatment with liraglutide 3mg improved blood glucose levels, blood pressure and lipids levels — all of which are known to influence cardiovascular risk in people with diabetes.⁸

In general, the treatment was well tolerated, even at this dose, which, as previously mentioned is much higher than the usual 1.2mg dose used when treating T2D. The most frequently reported side effects were gastrointestinal (nausea and diarrhoea), which were mild to moderate, occurred shortly after liraglutide initiation, and were transient. Previous concerns about the possible risk of gall bladder disease and pancreatitis with GLP1s,⁹ were addressed in this study and it was reported that the overall incidence of both was low; nonetheless, the incidence was higher in the treated group than in those in the placebo group. The actual figures demonstrated that gallbladder disorders occurred at a rate of 2.7 events per 100 patient-years of exposure (PYE) with liraglutide 3mg treatment compared with 1.0 events per 100 PYE for placebo; pancreatitis rates were recorded as 0.3 events per 100 PYE with liraglutide 3mg compared with 0.1 events per 100 PYE with placebo. Again, these figures underline the point that the relative risk of developing one of these conditions is low and the findings support the advice from the FDA and EMA,^10,11 when using GLP-1 agonists in people with diabetes. Nonetheless, it is recommended (and has been for some time) that the relative risks and benefits are discussed with the patient prior to starting treatment to allow each individual to make an informed decision.⁶

* Liraglutide is not currently licensed in the UK for weight loss

IMPLICATIONS FOR PRACTICE

These findings are impressive; however, it is essential that the cost of these drugs is borne in mind — the GLP-1s are a very expensive family of drugs as a whole and NICE guidance recognises this when it states that targets must be achieved for the cost of any GLP-1 to be outweighed by its benefits. The State of the Nation report underlines the importance of recognising that whilst 10% of the total NHS spend goes on treating diabetes, most of that is spent on treating the complications of diabetes^12,13 and that we should be considering how to spend funds better to prevent those complications. This may include more appropriate use of better treatments aimed at improving glycaemic control, along with other interventions to reduce cardiovascular risk. However, the developing role of drugs used to treat diabetes in preventing diabetes means that a different approach to those resource implications should be considered. When a tidal wave of obesity-related disease threatens to engulf the NHS, any opportunity to dam the flow should be considered.

REFERENCES

1. NICE Public Health Guidance 38. Preventing type 2 diabetes, 2012. Available at http://nice.org.uk/PH38

2. Lim EL, et al. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011;54(10):2506-2514

3. Spanou M, Tziomalos K. Bariatric surgery as a treatment option in type 2 diabetes mellitus World J Diabetes 2013;4:14-18

4. Villareal DT, et al. Effect of lifestyle intervention on metabolic coronary heart disease risk factors in obese older adults. Am J Clin Nutr 2006;84(6):1317—1323.

5. Vilsbøll T, Knop F (2013) History and development of incretin therapy. Available at: http://www.diapedia.org/management/8104193110/history-and-development-of-incretin-therapy

6. NICE (2009) Type 2 Diabetes - newer agents (partial update of CG66) Available from www.nice.org.uk/CG87

7. Wadden TA, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013;37(11):1443-51

8. Gaede P, et al. Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes. NEJM 2008;358:580-591

9. Singh S, et al. Glucagon-like peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus. JAMA Intern Med 2013;173(7): 534—9

10. Egan AG, et al. Pancreatic Safety of Incretin-Based Drugs "” FDA and EMA Assessment. N Engl J Med 2014;370:794-797. Available at: http://www.nejm.org/doi/full/10.1056/NEJMp1314078

11. European Medicines Agency. Investigation into GLP-1 based diabetes therapies concluded, 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/07/WC500146619.pdf

12. Kerr M. Inpatient Care for People with Diabetes - The Economic Case for Change, 2011. Available at: http://www.diabetes.nhs.uk/areas_of_care/emergency_and_inpatient/

13. Hex N, et al. Estimating the current and future costs of Type 1 and Type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabetic Medicine 2012;29(7): 855-862.