Episode Summary
Before we get into the science, I should say — as a pharmaceutical physician, I spend my career surrounded by these drug names and I still think pharmaceutical naming is its own art form. So I’ll exag
📄 Full Transcript
SARAH MITCHELL:
Welcome to ClinicaliQ Drug Class Explainers — a series where we break down the most important drug classes in modern medicine in plain, practical English. I'm Sarah Mitchell, and with me is Dr Anzal Qurbain, pharmaceutical physician. Today we're tackling GLP-1 agonists — a drug class that has genuinely transformed how we treat both type 2 diabetes and obesity. Anzal, let's start with the basics. What actually is a GLP-1 agonist?
DR ANZAL QURBAIN:
Before we get into the science, I should say — as a pharmaceutical physician, I spend my career surrounded by these drug names and I still think pharmaceutical naming is its own art form. So I'll exaggerate the syllables as much as I can to make each one clear, and I apologise in advance if I don't always do them justice. Right — So GLP-1 stands for glucagon-like peptide-1. It's a hormone your gut naturally produces after you eat. Its job is to tell the pancreas to release insulin, tell it to stop releasing glucagon — which is the hormone that raises blood sugar — and it also slows down how quickly food leaves your stomach. So it's a natural brake on blood sugar after a meal. GLP-1 agonists are drugs that mimic and amplify that effect. They bind to the same receptor as natural GLP-1, but they last much longer in the body.
SARAH MITCHELL:
So the natural GLP-1 hormone breaks down quite quickly?
DR ANZAL QURBAIN:
Very quickly — within a few minutes. The natural hormone gets broken down by an enzyme called DPP-4. The GLP-1 agonists we use clinically are modified so that enzyme can't break them down, which is why some last 24 hours and some last a full week.
SARAH MITCHELL:
And that's where you get once-weekly injections like semaglutide?
DR ANZAL QURBAIN:
Exactly. Semaglutide — brand names Ozempic for diabetes and Wegovy for weight management — is the one most people have heard of. It's given once a week by subcutaneous injection. Tirzepatide, brand name Mounjaro, is also once weekly and actually works on two receptors — GLP-1 and another called GIP — which is why we sometimes call it a dual agonist, and it tends to produce even greater weight loss. Then you have liraglutide, which is daily, and dulaglutide which is also once weekly.
SARAH MITCHELL:
So they all work similarly but with differences in how often you inject and how potent the effect is?
DR ANZAL QURBAIN:
That's a good way to put it. They all lower blood sugar through the same core mechanism. The differences are mainly in their duration of action, their potency particularly for weight loss, and their cardiovascular evidence base. And that cardiovascular evidence is really what elevated this class from just glucose-lowering drugs to something far more important.
SARAH MITCHELL:
Tell us about that — because that seems to be the big shift in how clinicians think about them.
DR ANZAL QURBAIN:
It was a genuine paradigm shift. The LEADER trial with liraglutide and SUSTAIN-6 with semaglutide both showed that these drugs didn't just lower HbA1c — they actually reduced the risk of major cardiovascular events. Heart attack, stroke, cardiovascular death. And this was in patients who already had established cardiovascular disease or high cardiovascular risk. So suddenly GLP-1 agonists weren't just a third or fourth-line add-on for glucose control — they became a drug you should actively consider in any type 2 diabetic with cardiovascular risk, regardless of where you are on the glucose-lowering pathway.
SARAH MITCHELL:
And then the SELECT trial took it even further?
DR ANZAL QURBAIN:
The SELECT trial was remarkable. It looked at semaglutide specifically in people who were overweight or obese but did not have type 2 diabetes. And it still showed a significant reduction in cardiovascular events. So the cardiovascular benefit appears to be partly independent of the glucose-lowering effect — it's driven by weight loss, improvements in blood pressure, inflammation, and probably direct effects on the heart and vessels.
SARAH MITCHELL:
Let's talk about weight loss because that's what most patients have heard about. How much weight loss are we actually talking?
DR ANZAL QURBAIN:
It's substantial — and that's what makes this class genuinely different from anything before it. With semaglutide at the full weight management dose, clinical trials showed around 15% body weight reduction on average. With tirzepatide in the SURMOUNT trials, some patients lost over 20% of their body weight. To put that in context — the previous best we had pharmacologically was maybe 5 to 8%. So this is a step change. For the first time, we have drugs that come close to the weight loss you see with bariatric surgery.
SARAH MITCHELL:
And the mechanism behind the weight loss — is that just the slowing of gastric emptying?
DR ANZAL QURBAIN:
Gastric emptying is part of it, but the bigger driver is central appetite suppression. There are GLP-1 receptors in the brain — particularly in the hypothalamus, which is the appetite control centre. When you activate those receptors, patients genuinely feel less hungry, feel full sooner, and have fewer cravings. It's not willpower — it's a pharmacological change in appetite signalling. Patients often describe it as the food noise going quiet.
SARAH MITCHELL:
That's a really helpful way to explain it to patients. What about side effects — because nausea seems to come up a lot?
DR ANZAL QURBAIN:
Nausea is the most common side effect, and it's important to counsel patients about it upfront so they don't stop the drug at the first sign of it. It's almost always dose-dependent and tends to be worst in the first few weeks as you're titrating up. The key is to start at the lowest dose and increase slowly — most drugs in this class have a standard titration schedule precisely for this reason. Taking the injection with food helps. For most patients the nausea settles within four to eight weeks.
SARAH MITCHELL:
What about the more serious side effects — pancreatitis comes up in the literature.
DR ANZAL QURBAIN:
It does, and it's worth putting in perspective. There is a signal in the prescribing information, and it's appropriate to avoid GLP-1 agonists in patients with a personal or family history of pancreatitis. But the population-level risk appears to be very low, and large cardiovascular outcome trials with hundreds of thousands of patient-years of exposure haven't shown a dramatic excess. The more important contraindication to know is personal or family history of medullary thyroid carcinoma or a condition called MEN2 — multiple endocrine neoplasia type 2 — because rodent studies showed thyroid C-cell tumours with liraglutide. The clinical relevance in humans is uncertain, but it's a hard contraindication in the prescribing guidance.
SARAH MITCHELL:
And in terms of hypoglycaemia — is that a risk?
DR ANZAL QURBAIN:
This is one of the genuinely reassuring things about GLP-1 agonists. Because their insulin-stimulating effect is glucose-dependent — meaning they only push insulin release when blood sugar is actually elevated — hypoglycaemia is not a meaningful risk when they're used on their own. The risk only increases if you're combining them with a sulphonylurea or insulin, in which case you'd consider reducing the dose of those agents.
SARAH MITCHELL:
What about kidney safety? There's been discussion about whether GLP-1 agonists protect the kidneys the way SGLT2 inhibitors do.
DR ANZAL QURBAIN:
The evidence is building. FLOW — the renal outcome trial for semaglutide — published in 2024 and did show meaningful kidney protection, including a reduction in the composite renal endpoint. It's not as mechanistically direct as SGLT2 inhibitors — GLP-1 agonists seem to work through blood pressure reduction, weight loss, and anti-inflammatory effects rather than the direct tubuloglomerular feedback mechanism of SGLT2s. But the clinical message increasingly is that in a high-risk patient with type 2 diabetes, using both an SGLT2 inhibitor and a GLP-1 agonist together is often the right answer.
SARAH MITCHELL:
Speaking of combinations — how do they fit into the treatment pathway now? Because NICE guidance has shifted on this.
DR ANZAL QURBAIN:
Significantly. For a long time the pathway was metformin first, then add-ons, and GLP-1 agonists came in quite late. The current thinking — and this is reflected in updated NICE guidance and ADA-EASD consensus — is that if a patient has type 2 diabetes with established cardiovascular disease, heart failure, or chronic kidney disease, a GLP-1 agonist with cardiovascular evidence or an SGLT2 inhibitor should be considered very early, sometimes even as second-line after metformin, or in some frameworks alongside it from the outset. The emphasis has shifted from purely glycaemic control to cardiometabolic risk reduction.
SARAH MITCHELL:
And for patients using them purely for weight management, without diabetes — that's a separate pathway?
DR ANZAL QURBAIN:
Yes — in the UK that's accessed through specialist weight management services or via Tier 3 obesity pathways, and patients need to meet BMI criteria. Wegovy — semaglutide 2.4mg — is the licensed dose for weight management, which is higher than the diabetes dose in Ozempic. Mounjaro is now also licensed for weight management in the UK. There has been significant supply pressure on both, which has caused real-world prescribing challenges, but access is improving.
SARAH MITCHELL:
One practical question — patients sometimes ask whether the oral form of semaglutide is as effective as the injection. What do you tell them?
DR ANZAL QURBAIN:
It's a reasonable option for patients who genuinely can't or won't self-inject, but the bioavailability is much lower with the oral form — around 1% — so you need a much higher dose to achieve a comparable effect, and it has to be taken in very specific conditions: fasting, with no more than a small sip of water, and no food for 30 minutes afterwards. The injection is more reliable for most patients. That said, for patients where adherence to injections is a barrier, oral semaglutide is a clinically valid choice.
SARAH MITCHELL:
Final question — what's the one thing every clinician prescribing in this space should know?
DR ANZAL QURBAIN:
Titrate slowly and set expectations clearly. The number one reason patients stop GLP-1 agonists prematurely is nausea in the early weeks. If you counsel patients properly — tell them the nausea is expected, it will settle, start low and go slow — persistence rates go up significantly. The drugs only work if patients stay on them. And for weight management, they need to be combined with lifestyle change — diet and physical activity — because when you stop the drug the weight does tend to come back. That's a conversation to have upfront so patients understand this is a long-term treatment, not a short course.
SARAH MITCHELL:
That's really practical and clear. Thank you Anzal. So to summarise — GLP-1 agonists work by mimicking a natural gut hormone to lower blood sugar, suppress appetite, and slow gastric emptying. They reduce cardiovascular risk, support significant weight loss, and have an emerging kidney protection signal. The class is now recommended early in patients with type 2 diabetes and cardiovascular or renal risk. Key side effects are GI and manageable with slow titration. And the main contraindications are personal or family history of medullary thyroid cancer or MEN2. For more on individual drugs in this class — including SGLT2 inhibitors and how the two classes work together — that's our next episode. Thanks for listening to ClinicaliQ Drug Class Explainers.