How GLP-1 agonists help in type 2 diabetes

GLP-1RAs mimic the action of the naturally-occurring incretin GLP-1 to increase insulin secretion, reduce glucagon secretion, maintain or increase the numbers of pancreatic beta cells and delay gastric emptying.  Tirzepatide is a dual-incretin acting on both the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1) receptors. Tirzepatide treatment leads to significant weight loss and normoglycaemia for many patients with type II diabetes.  Retatrutide is a tri-incretin – an agonist of the GIP, GLP-1 and glucagon receptors – that is currently being evaluated patients with type II diabetes.

Should GLP-1 agonists should be used earlier in type 2 diabetes?

In future, GLP-1RAs could be used early in treatment for type II diabetes and this could have an important impact on slowing the onset of cardiovascular complications. “They’ve got good outcome data – so there’s data around not just the weight loss and the HbA1c-lowering but specifically around protection for cardiovascular events”, says Ms Beba.  Sodium-glucose cotransporter-2 (SGLT2) inhibitors are also associated with good cardiovascular outcomes but GLP-1RAs offer additional benefits in terms of stroke prevention.

An oral, non-peptide GLP-1RA would be useful for management of type II diabetes in needle-phobic patients. Orforglipron might fulfil this requirement in future, but it is still in the early stages of development at present.

Lifestyle interventions remain the first step in the management of type II diabetes but GLP-1RAs could be used at an early stage in high-risk patients to preserve organ function. “Time is heart, it’s kidney, it’s eyes. It’s all of these things and you know when you’re not doing something damage is happening”, says Ms Beba.

What does a consultant pharmacist in diabetes do?

The work of a consultant pharmacist in diabetes spans clinical duties and leadership tasks including education and mentoring. There are at present only three consultant pharmacists in diabetes in the UK but the development of more highly-specialised positions in diabetes could be the stepping stone to more of these, Ms Beba suggests.

It is still unusual for a patient to see a consultant pharmacist in diabetes so dealing with the situation calls for some sensitivity. “I’m really transparent about the fact that I’m a pharmacist I think it’s very important”, says Ms Beba.

The development of more highly-specialised posts in diabetes would be a good way to move forward. Some pharmacists would choose to remain at that level and others would progress to become consultants. “It’s the right time to invest in a pathway for clinical leadership for pharmacists”, concludes Ms Beba.

About Hannah Beba

Hannah Beba is a consultant pharmacist in diabetes at Leeds Health and Care Partnership. Her clinical work involves care of patients with complex type II diabetes in community services, GP practices and primary care networks. She also has senior leadership roles; she chairs the Cardio-renal Metabolic Expert Working Group and the Diabetes Steering Group, both of which feed into the Long-term Conditions Board.

Read and watch the full series on our website or on YouTube.

Ms Beba is involved in the care of both patients with type I diabetes in secondary care and patients with complex type II diabetes in community services, GP practices and in Primary Care Networks. Her senior leadership roles include chairmanship of the Cardio-renal Metabolic Expert Working Group and the Diabetes Steering Group, both of which feed into the Long-term Conditions Board. “I have an amazing team of consultant medics and nurses and [various] other professions and also managers and payers and, you know, the right people around the table, which makes a huge difference to our health economy and what we what we spend our money wisely on”, she says. Education and mentorship are also important parts of her job. “I do lots of mentorship with people who are getting towards their consultant pharmacist posts and I also do lots of just education webinars [and conference presentations]. ….. It’s a lovely varied and very exciting job that I enjoy greatly”, she says.

Explaining the role to patients

It is still unusual for a patient to see a consultant pharmacist in diabetes so dealing with the situation calls for some sensitivity. “I’m really transparent about the fact that I’m a pharmacist I think it’s very important ……. To be absolutely honest, I don’t really care whether I’m called consultant or not – somebody else has made that decision for me, as to what the name of the post is, but I think the main thing is that it’s a recognition …. of the years put in [and] the expertise across all the pillars”, says Ms Beba.

Some patients are just pleased to be seeing someone and there are others who want to know more about Ms Beba’s post and why they are seeing her and not a consultant physician. “Some people have waited a long time to see a consultant doctor and then they see me instead. ….. Some people react fine to that and others not, so you know they want to know more, but I’ve never had anybody get up and walk out of my room – so that’s a good thing!”, she says.  She explains that there is still the option to see a consultant doctor if the patient wishes, “or …. you can stay on my list, depending on where we’re at and how you’re feeling – so I just leave it really open and …. with them as to how they’re feeling.  I think that’s the best thing”.

Why are there not more consultant pharmacists in diabetes?

Growing numbers of pharmacists are taking an interest in diabetes and roles are starting to develop in Primary Care Networks (PCNs). “In Leeds, for example, we’ve just put out our first specialist diabetes post within a Primary Care Network, which is really exciting. So, I’m hoping there’ll be a lot more of that – where people see the benefit that a pharmacist can bring to diabetes care”, says Ms Beba. However, the step up to a consultant post “is definitely not for the faint-hearted”, she adds. The breadth of work required is time-consuming and demanding and it can be challenging to achieve a satisfactory work-life balance, she emphasises.  “What I would like to see is the development of more highly-specialist posts – so that’s a step to consultant – and some people may stay at that level – [others] may progress up then on to consultant. …. I think that’s maybe why we don’t get there with a lot of people – they don’t have that post to move into where they can develop themselves, where they can get some more exposure to some of the different elements of the portfolio”, she suggests.

“It’s the right time to invest in a pathway for clinical leadership for pharmacists – so I would love to see that”, concludes Ms Beba.

About Hannah Beba

Hannah Beba is a consultant pharmacist in diabetes at Leeds Health and Care Partnership. Her clinical work involves care of patients with complex type II diabetes in community services, GP practices and primary care networks. She also has senior leadership roles; she chairs the Cardio-renal Metabolic Expert Working Group and the Diabetes Steering Group, both of which feed into the Long-term Conditions Board.

Read and watch the full series on our website or on YouTube.

GLP-1 receptor agonists (GLP-1RAs) are already well-established in diabetes care pathways. “The main attraction, I suppose, so far with the GLP-1s that are already on the market is that they’ve got good outcome data – so there’s data around not just the weight loss and the HbA1c-lowering but specifically around protection for cardiovascular events”, says Ms Beba.  “People with type II diabetes have a very high cardiovascular risk and some of them have already had cardiovascular events. We need to protect them from having further events or from having their first event ……. and these drugs are very efficacious for doing that. So, they’ve got a good outcome data to show that you’re less likely to go on and have a further event and that you’re less likely, if you have an event, to die from that event”, she continues.  SGLT2 inhibitors are also associated with good cardiovascular outcomes but GLP-1RAs offer additional benefits in terms of stroke prevention. “The GLP-1s kind of come into their own around around stroke”, she adds.

The GLP-1RAs that have been launched so far are all peptides that have to be injected in order to exert their effects. The one exception is Rybelsus which contains semaglutide co-formulated with the absorption enhancer N-(8-[2-hydroxylbenzoyl] amino) caprylate (SNAC). “It was really nice to have an oral option – there are people who are needle-phobic or they really are very resistant to starting an injectable therapy and so with the oral agent it gives you this option”, says Ms Beba. However, in order for Rybelsus to be effective, the administration instructions need to be followed carefully. This means taking the drug at least 30 minutes before any other oral medicines or food. Ms Beba acknowledges that patients may not always follow the instructions to the letter and so an oral GLP-1RA that did not come with elaborate dosing instructions would be welcome.  Orforglipron is just such a product, although it is still in the early stages of development. “We’ve got a whole cohort of people who really would rather not be on an injectable therapy……..  Some of them have relatives who have been on insulin had very traumatic experiences around insulin admin and particularly if it’s been a parent or a grandparent where they’ve been on, like ……. massive needles with their insulin…….  So you can buy some time for them, I suppose, in the sense that this will give us something which is efficacious without needing to go on to insulin or needing to go on to injectable GLP-1. It’s almost like another step for me”, says Ms Beba.

Frontline practitioners – pharmacists, nurse and GPs – should now be explaining the breadth of benefits associated with GLP-1RA use.  There tends to be a degree of clinical inertia in practice and that means allowing patients to continue with raised HbA1c levels and weight gain for relatively long periods. “I appreciate that it’s all about the holistic management of somebody and we do need to put in lifestyle and dietary advice but there are circumstances where if somebody’s [got] a high or very high cardiovascular risk and a high HbA1c, we do need to action something relatively quickly. Time is heart, it’s kidney, it’s eyes. It’s all of these things and you know when you’re not doing something damage is happening”, she says.

Ms Beba acknowledges that, for some patients, diet and lifestyle interventions are the logical first step.  “We’ve got the remission program now at our disposal which {means that] within five years of diagnosis we can refer people to remission so there are there are some more efficacious, more intensive lifestyle options as well that would be certainly something that I would pursue for my younger people living with type 2 most certainly, in that very short window from diagnosis”, she says. However, some people will have more advanced disease and need more aggressive treatment: “We still need to be doing something and highlighting, certainly, the cardiovascular benefits and the protection to your kidneys. ….If  they’ve got albuminuria, then you know – “time is kidney”. At that point ….  you need to be doing as much as you possibly can to protect those kidneys”, she says.

There is also a need to ensure that frontline practitioners are themselves comfortable and familiar with this information so that they can “get that across effectively to people living with diabetes” and help them to obtain “the [treatments] that they need to be on”, she adds.

About Hannah Beba

Hannah Beba is a consultant pharmacist in diabetes at Leeds Health and Care Partnership. Her clinical work involves care of patients with complex type II diabetes in community services, GP practices and primary care networks. She also has senior leadership roles; she chairs the Cardio-renal Metabolic Expert Working Group and the Diabetes Steering Group, both of which feed into the Long-term Conditions Board.

Read and watch the full series on our website or on YouTube.

GLP-1 agonists mimic the action of the naturally-occurring incretin GLP-1 to increase insulin secretion, reduce glucagon secretion and maintain and even increase the mass of [insulin-secreting] pancreatic beta cells. In addition, they delay gastric emptying. “You’ll feel less hungry over a longer period of time, so it means that people just don’t want to eat the portion sizes that they would have done previously and people who do try to carry on eating as they were often will feel sick”, explains Ms Beba. This is a point that needs to be discussed with patients when they start treatment, she adds. The GLP-1 agonists available at present are all peptides that have to be injected, but unlike the earliest products that had to be injected frequently, semaglutide (Ozempic) is given by once-weekly subcutaneous injection.

Two new products tirzepatide (Mounjaro) and retatrutide are dual- and tri-incretins, respectively. Tirzepatide acts on both the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1) receptors. It is also given as a weekly injection. The results of trials so far suggest that it is more efficacious that the GLP-1 agonists available hitherto. The results from the SURMOUNT-2 trial showed that “more than 45 percent of people who were put on incremental dosing of tirzepatide will reach normoglycemia – which is incredible – and over 80 percent will get to a HbA1c of less than seven percent [53 mmol/mol]”, says Ms Beba. The associated weight loss amounted to “more weight loss than [with] some of our weight loss drugs”, she adds.

The weight loss can be up to 15 percent of body weight. “That’s really what people care about, if I’m being absolutely honest. If they start getting some significant weight loss it completely inspires them to carry on and then they’ll even …. make more lifestyle changes. What you find is people just need to get over that hump of … getting nowhere with diet and lifestyle”, she says.

Retatrutide is a tri-incretin – an agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon receptors. It is currently being evaluated patients with type II diabetes (TRIUMPH-2 trial). Early findings suggest that it might be even more efficacious than tirzepatide, but it is still a long way from being marketed.

About Hannah Beba

Hannah Beba is a consultant pharmacist in diabetes at Leeds Health and Care Partnership. Her clinical work involves care of patients with complex type II diabetes in community services, GP practices and primary care networks. She also has senior leadership roles; she chairs the Cardio-renal Metabolic Expert Working Group and the Diabetes Steering Group, both of which feed into the Long-term Conditions Board.

Read and watch the full series on our website or on YouTube.