GLP-1 analogues in clinical practice beyond diabetes – the obesity pandemic

GLP-1 agonists can help patients with obesity achieve significant weight loss and associated health benefits

We need to see obesity predominantly as a disease state, which has evolved in the context of an obesogenic environment. There has been a rapid rise and almost tripling in obesity in the last 40 years. The economic burdens are immense and there is a log-linear risk with mortality, and the predominant mortality is driven by cardiovascular (CV) disease. The pathophysiology is increased fat mass and what is now being referred to as ‘sick fat’.¹

In terms of fat, ‘sick fat’ refers to dysfunctional fat which drives inflammation and insulin resistance. The ‘non-sick’ fat, however, still reflects a burden of biomechanical heaviness that impedes mobility and exercise and promotes conditions such as obstructive sleep apnoea (OSA).

The aetiology is quite mixed (diet/psychological/socioeconomic) and includes a genetic ‘footprint’, but it is clear that genetics is not the primary driver. Our genetic profiles (in Ireland for example) have not changed, but the environment has, and hence obesity rates have spiralled.²

Obesogenic foods, which in essence are highly-processed foods, are critical as a causal factor here and looking at US studies, at least 40 per cent of their diet is processed foods. Many foods are ‘sugar blended’ and certain processed sugars will target the brain and result in satisfaction.³ Energy intake is greater with highly processed foods, which ‘fuel hunger’ and subsequent weight gain.

If we look at population studies in the US (where there is a massive obesity epidemic), it is very interesting that people are not eating more, but they are exercising more. Yet their weight has not changed. When you ‘drill down’ in exercise though, fat mass and waist measurement both decrease. One might preferably say to patients – “look at your waist and not your scales”.

But the critical aspect of exercise is its influence in response to glucagon-like peptide 1 (GLP-1) analogue therapy, which in Ireland currently includes semaglutide and tirzepatide. The effect of exercise in tandem with these injectable treatments means greater loss of body weight, greater loss of body fat, and a lower likelihood of weight regain over time.⁴

There is no one single diet that will improve either weight loss or metabolic parameters. All diets drive weight loss in the order of 5 to 10 per cent, but the difficulty is in sustaining them long-term.

The best proven diets in terms of CV risk-reduction appear to be the Mediterranean diet, vegetarian, and low-fat diet. The food plan essentially needs to be a ‘non-processed food’ plan over ultra-processed foods.

Social media has overwhelmed us with ‘healthy lifestyle’ content – of which few, if any, are in fact evidence-based interventions. Lifestyle really refers to three pillars of intervention – (1) when we eat, (2) what we eat, and (3) how much we eat. Time-restricted eating such as eight to 10 hours’ ‘eating time’ and 14 hours fasting are proven to have CV benefit.⁵ Timed eating, however, is not the best approach for all, but there seems to be a preferential benefit in metabolic syndrome.⁶

Ultimately, we need complementary therapies for safe and durable weight reduction.

And there is no doubt that the GLP-1 (and newer GLP-1-GIP) drugs are game-changers. But exercise is imperative in facilitating and maintaining the weight loss, and avoiding recidivism of weight loss.

Clinical Case 1: A 65-year-old man with a BMI of 35. He has OSA and worries about the effect of weight gain on his mobility. He has tried various dietary interventions, calorie restriction, and the gym, but has ‘hit a plateau’. What might you suggest?

There are currently three main available drugs in the field of weight loss (liraglutide, semaglutide, and tirzepatide), and each has evolved as being more powerful.

You can swap and change between the drugs according to effect and response.

And you can personalise the impact of the weight loss you are aiming for. For example, if you have a BMI [body mass index] of 40, your percentage weight loss needs will be different to that of someone with a BMI of 30.

On average, one can expect an approximately 5 per cent body weight loss with liraglutide 3mg (SCALE trial), 15 per cent with semaglutide 2.4mg (STEP trials), and 20 to 22 per cent with tirzepatide (SURPASS trials).⁷

It is not unlike choosing different statins according to their efficacy and tolerability.

If you ‘undershoot’, you switch to something more powerful (or up the dose). If you overshoot, you equally can transition to a milder one or a lower dose.

Clinical Case 2: You start patient on drug.¹ He returns after six months and has had <5 per cent
weight loss. What do you do next?

It is important to be aware of two facts:

1. Not everyone loses weight on these drugs.

2. If you do not respond to one drug, it does not imply that you would not respond to another one.

3. Going on these drugs and responding or not does not preclude the option of bariatric surgery – providing of course the ‘new’ BMI does not now fall below the surgical criteria.

Not everyone loses weight on GLP-1 analogues, or even the newer dual agent.

In the SCALE trials with liraglutide 3mg, about 25 per cent of people did not achieve meaningful weight loss, which in statistically-relevant terms means <5 per cent weight loss.

In the STEP trials, in participants on semaglutide 2.4mg, 15 per cent did not achieve meaningful weight loss. In the SURMOUNT trials, approximately 10 per cent of patients on tirzepatide did not achieve meaningful weight loss.

The pearl here is that if a patient does not lose weight on one drug, you should try another.

It is important to know that Wegovy and Ozempic are the same drug. Ozempic is semaglutide (max dose 1mg licenced and reimbursed) for diabetes mellitus (DM) in Ireland, and Wegovy is semaglutide up to 2.4mg licenced for weight loss.

However, if a patient was prescribed Ozempic for weight loss, and did not achieve >5 per cent weight loss, then it is highly unlikely they will have any meaningful weight loss on Wegovy.

Clinical Case 3: A 65-year-old patient has returned on a new drug and has achieved 10 per cent weight loss so far. But he has read about ‘muscle wasting’.

These drugs are for everyone – young and old. We know that in weight loss there is fat mass weight loss, but also lean muscle weight loss. Sarcopaenia is a feature of ageing and may be enhanced by these agents. But one could argue that the muscle mass appears less only because you are moving fat out of the ‘fatty muscle’. I advise all my patients regardless to take up some form of complementary resistance exercises to maintain muscle mass.

Clinical Case 4: A 65-year-old returns after nine months. He has now lost 25 per cent of his total weight and is clearly a super responder. But he is gaunt and now feels he has lost too much weight. What do you do next? Will you stop the drug?

What do you do if you are a super-responder?

You do not stop the drug. It is very clear from the STEP 1 extension trial and the SURPASS trial that you will generally go into a situation of weight regain if you stop these drugs.

Therefore, you de-escalate the dose and I would suggest dropping to the next lower dose and maintaining that for at least three months to see where you reset.

Clinical question – is there any benefit to these drugs outside of weight loss?

These drugs also appear to have major pleiotropic effects in CV risk reduction, (STEP trials , SELECT trial, STEP HFpEF, SCRIBE, SUMMIT, SURMOUNT-MMO (completion 2027))  reversal of metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (SYNERGY NASH MASH), and non-progression if not reversal of chronic kidney disease (CKD) (FLOW trial). For those with pre-DM, they are less likely to progress and more likely to revert to normoglycaemia.

There is no doubt about their ‘multi-target’ benefits on (1) the beta cell, (2) glucose uptake, (3) central effects on satiety, (4) indirect effects of weight loss on inflammation, and (5) direct effects of weight loss in the CV benefit (Look AHEAD trial). One meta-analysis showed a relative risk reduction of 14 per cent of CV events, and the magnitude of the CV benefit was independent of weight loss.⁸

The SELECT trials enrolled 17,604 patients on semaglutide with a BMI >27 with risk factors (BMI >30 without). This was a dedicated CV outcome trial, enrolling high-risk overweight and obese patients (without DM type 2) and showed an early reduction in all-cause mortality and a 20 per cent RR reduction in hard end clinical endpoints. It was not a heart failure trial, but there was a 0.17 per cent reduction in events and those with pre-existing heart failure had a substantial reduction in events. Other trials, including the STEP HFpEF trial, show benefit in functionality, and the FLOW trail showed benefit in CKD.

As it stands currently, semaglutide (Wegovy) is the only proven GLP-1 agent in a CV outcome trial meeting safety and benefit. The trials are ongoing with tirzepatide, but we have no reason to believe they will not achieve the same outcome – the smaller SUMMIT trail with tirzepatide showed heart failure improvement.

We probably need to think of these drugs in the context of multiple disease treatment in tandem with obesity, such as those with metabolic syndrome, CVD, CKD, and MASLD.

Side-effects and risks

These drugs are not without risk. The risk of pancreatitis is low, but nonetheless, we advise against prescribing in those with a history of idiopathic pancreatitis, excess alcohol intake, and gall stone pancreatitis if they still have gallstones. There is a higher risk of gallstones, more likely linked to weight loss rather than the drug itself. Nausea, vomiting, diarrhoea, and constipation all occur, but the frequency and severity can be mitigated to a great extent by very slow dose titrations.

Other considerations

The next question is whether these drugs would precede bariatric surgery and selection criteria will be very important here. For example, you are unlikely to get a meaningful response with these drugs alone in, for example, a patient with a BMI of 60. But you may want to try to achieve a better and lower weight going into surgery, although there is no evidence thus far that this is of any benefit from a surgical perspective.

Author: Dr Maeve Durkan, Consultant in Diabetes, Endocrinology, and Metabolism, Bon Secours Hospital, Cork, and the Cork Clinic, and Senior Clinical Lecturer in Medicine at University College Cork