The 2021 Diabetes Professional Care conference provided many insights and updates for healthcare professionals into the management of diabetes. One of the hot topics was Cardiovascular Renal Metabolic (CVRM) medicine putting both sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) at the centre of the discussions.
Both classes of medicines are widely used for the management of type 2 diabetes mellitus (T2DM), but GLP1-RAs are usually initiated at later stages of the disease progression in clinical practice. The delay in the initiation of GLP1 therapy is multifaceted but one of the reasons for clinical inertia has been related to a barrier with initiating injectable therapies.
T2DM requires long-term treatment, and many patients will eventually progress into injectable therapies. Therefore, initiating subcutaneous GLP1-RAs may help to prepare people for injecting insulin in the future. However, patients do often strongly prefer to take oral medicines, and up until recently, this meant that they could not benefit from GLP1 therapy. A newcomer on the market – oral semaglutide (Rybelsus®) – is aiming to bridge this gap and ensure that patients who are averse to injectables also have the option to receive a GLP1-RA.
The science behind developing an oral GLP1 agonist
GLP1 is an intestinal hormone of the incretin family, which amplifies insulin secretion, suppresses glucagon release, causes a delay in gastric emptying, and decreases insulin resistance. An additional effect of this hormone is the promotion of physiological satiety, which it achieves via its peripheral effects on reduction of energy intake and its action as a neurotransmitter on the brainstem and hypothalamus. Such effects make GLP1-RAs an attractive treatment option for T2DM, which along with hyperglycaemia and insulin resistance is also commonly associated with obesity.
A very promising new GLP1-RA option for patients with type 2 diabetes who are unable or unwilling to progress to injectable drugs
Until recently, GLP1-RAs were only available as injectable peptide-based drugs, such as once-weekly subcutaneous semaglutide (Ozempic®). The challenge for oral administration of peptide-based molecules is the significant acid and enzymatic degradation they undergo in the stomach, which results in poor bioavailability. The Rybelsus® formulation overcomes this challenge via the addition of a novel sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) protein to the semaglutide molecule. The SNAC protein enhances transcellular permeation by increasing the molecule’s lipophilicity and attenuates the acid and enzymatic digestion of semaglutide by increasing the local gastric pH.
Efficacy of once-daily oral semaglutide
Glycaemic control & weight loss
The effect of oral semaglutide on glycaemic control was tested across a series of randomised-controlled trials from the Peptide InnOvatioN for Early diabetes tReatment (PIONEER) clinical programme.
The world’s first oral GLP1-RA showed significantly greater reductions in HbA1c when compared to placebo alone (see PIONEER 1, PIONEER 5 and PIONEER 8 publications) or in a combination with metformin or metformin and an SGLT2 inhibitor. It has also demonstrated significantly greater reductions in HbA1c than liraglutide, dulaglutide, empagliflozin (when added to metformin), and sitagliptin (when added to metformin and/or a sulfonylurea).
A recent systematic review also examined the effects of oral semaglutide versus other injectable GLP1-RAs(dulaglutide, exenatide, liraglutide, lixisenatide, and its own injectable version) in T2DM patients, inadequately controlled on insulin. In this study, oral semaglutide (14mg daily) demonstrated superior reductions in HbA1c than all injectable GLP1-RAs, except injectable semaglutide (1mg weekly).
In the PIONEER studies, oral semaglutide also showed an additional benefit by achieving a more pronounced bodyweight reduction in comparison to placebo or other competitors. Furthermore, it demonstrated greater weight reduction than injectable dulaglutide, exenatide, liraglutide and lixisenatide, but failed to show superiority to injectable semaglutide (1mg weekly) in the systematic review.
Oral semaglutide has demonstrated satisfactory blood glucose- and weight-lowering effects in the initial trials, but its advantage over its own injectable version is still questionable and warrants further data from real-world practice.
Cardiovascular and renal outcomes
Besides improving glycaemic control, reduction in diabetes-related complications is one of the main goals of therapy in T2DM patients. Cardiovascular disease is the primary cause of death in patients with T2DM. Since the discovery that some glucose-lowering medicines (thiazolidinediones) can paradoxically increase the risk of adverse cardiovascular events, there is now a requirement that new antidiabetic agents must demonstrate cardiovascular safety before being released on the market.
Chronic kidney disease (CKD) is also a major cause of morbidity and mortality in patients with diabetes, and, reversely, T2DM is also one of the most common causes of CKD. Agents, such as SGLT2 inhibitors and some GLP1 agonists, which demonstrate cardiovascular and renal risk reduction are favoured and are climbing up the ladder in the international diabetes guidelines’ therapy recommendations.
Semaglutide, in its injectable form, has already shown cardiovascular benefits on blood pressure, vascular endothelium, atherosclerosis progression, and myocardial ischaemia in the SUSTAIN-6 study. The PIONEER 6 studyinvestigated the oral form of semaglutide and confirmed safety in a 16-month follow-up, but it was not powered to assess for superiority in reduction of cardiovascular events compared to placebo. A longer study (the SOUL trial), which will assess oral semaglutide for cardiovascular superiority, is currently in progress and is expected to finish in 2024.
With regards to renal outcomes, the only data available for oral semaglutide is from the PIONEER 5 study, whose whole participant population consisted of patients with moderate renal impairment. This study demonstrated the safety of oral semaglutide with short-term use, as renal function remained stable at the 31-week follow-up. However, unlike SGLT2 inhibitors, thus far, no clinical trial has investigated the long-term renal outcomes of any GLP1-RAs.
The first randomised, double-blinded, parallel-group, placebo-controlled trial (the FLOW study), dedicated solely to examining the safety and impact of injectable semaglutide on major adverse renal outcomes in people with T2DM, commenced in 2019 and is expected to be completed in 2024. This study will provide new insights on the management of patients with T2DM and renal disease and may also open the door for more renal outcomes trials for other GLP1-RAs, including oral semaglutide.
Safety of once-daily oral semaglutide
Oral semaglutide showed a consistent safety profile in all PIONEER trials. Unsurprisingly, the most reported adverse events were gastrointestinal disorders (nausea, vomiting, diarrhoea, constipation, dyspepsia, abdominal pain,) – a similar profile to all GLP1-RAs. The rate of these events increased with increase in the dose from 3mg to 7mg and to 14mg, but this did not result in higher drop-out rates than its competitors in the trials. Adherence to oral semaglutide was similar in the PIONEER trials to the adherence reported with injectable semaglutide in the SUSTAIN-6 trial.
Hypoglycaemia events were not common in the PIONEER trials. The only severe hypoglycaemic episodes were reported in the PIONEER 8 study. These were observed in patients, who were also receiving basal insulin in combination with semaglutide. This finding has been carefully considered in clinical practice and resulted in the recommendations that insulin dose reductions should be considered prior to initiating oral semaglutide.
Practical use of oral semaglutide
The dose of oral semaglutide should be gradually increased as follows to minimise the risk of gastrointestinal side effects: 3mg once daily for 30 days, then increasing to 7mg once daily, and if necessary, to 14mg once daily. It should be noted that the above-mentioned effects on glucose-lowering and weight loss demonstrated in the PIONEER studies were achieved with the highest (14mg) dose of oral semaglutide, which is also less likely to be tolerated due to higher rates of gastrointestinal adverse effects.
To optimise exposure and ensure the efficacy of oral semaglutide, patients should be advised to:
- administer the tablets on an empty stomach upon waking with half a glass of water (up to 120mL)
- ensure tablets are taken whole, rather than split or crushed
- after taking oral semaglutide, wait minimum of 30 minutes before eating, drinking, or taking any other oral medicines
- skip the dose and take their normal dose the following day, if the dose of semaglutide is missed in the morning and they have remembered about it after breakfast or after taking other morning medicines
- not to use two 7mg tablets to make up a 14mg dose as the effects of this approach have not been studied.
The effects of oral semaglutide in clinical trials were achieved by following these strict administration requirements. In real-life practice, adherence may not be entirely as homogenous, which may lead to less pronounced effects on weight loss and glucose control than those seen in the trials.
Oral semaglutide is safe to use in a combination with other commonly used medicines, such as warfarin, statins, digoxin, oral contraceptives, furosemide or lisinopril. However, total exposure to levothyroxine has been found to increase by 33 percent when administered with oral semaglutide due to the delay in gastric emptying caused by the oral GLP1-RA. Therefore, patients should be advised to administer levothyroxine at a different time of the day, such as by changing levothyroxine administration time to night time. However, the manufacturer does not provide any advice on co-administration of oral semaglutide with other commonly used tablets, which also need to be taken first thing in the morning on an empty stomach, such as once-weekly bisphosphonates.
Oral semaglutide is a brilliant technological achievement, which will open the door for further research in the use of SNAC proteins as vessels for the oral delivery of peptide-based drugs. It was widely discussed among clinicians at the 2021 Diabetes Professional Conference as a very promising new GLP1-RA option for patients with T2DM, who are unable or unwilling to progress to injectable drugs.
However, based on the currently available evidence, injectable GLP1-RAs with proven efficacy for cardiovascular prevention (semaglutide, liraglutide and dulaglutide) remain the preferred choice for patients with established cardiovascular disease or those who are at high risk of cardiovascular events. Further research and real-world data for the effects of oral semaglutide is necessary as it may influence these recommendations.
The opinions expressed in this article are those of the author. They do not purport to reflect the opinions or views of the UKCPA or its members. We encourage readers to follow links and references to primary research papers and guidance.
Competing interest statement:
The author declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.