Recent developments in GLP‐1RA therapy: A review of the latest evidence of efficacy and safety and differences within the class

As of 2021, 9 % of the global population is now affected by type 2 diabetes mellitus (T2DM). In the United Kingdom, 20% of National Health Service in-patients suffer from diabetes as a co-morbidity, while 10% of healthcare expenditure is linked to diabetes. Failed attempts to reduce the diabetes epidemic are due to an inability to halt rising levels of obesity and sedentary lifestyle. This has led to the development of an abundance of therapeutic agents to control hyperglycaemia and in the United States, there are now 12 different classes of glucose-lowering medication. The glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) act in a glucose-dependent manner by enhancing insulin secretion and reducing production of glucagon. GLP-1RAs are peptides that are resistant to dipeptidyl peptidase and provide supra-physiological stimulation of the GLP-1 receptor. They also retard gastric emptying and increase satiety; these effects in tandem lead to weight loss in a substantial proportion of people with T2DM. Exenatide was the first GLP-1RA to be launched and was based on the exendin-4 molecule (isolated from Gila Monster lizard saliva) and is administered by twice-daily subcutaneous injection at meal times due to its short half-life.1 Subsequent GLP-1RAs were longer acting, once daily (OD) preparations (liraglutide and lixisenatide) administered without regard to meals.2, 3 Then in 2011, the European Medicines Agency (EMA) issued authorisation for the first long-acting GLP-1RA, a once-weekly (QW) version of exenatide.4 Currently, the most widely prescribed GLP-1RA is liraglutide, however, the convenience of less frequent dosing has led to an expansion of new prescriptions of the once-weekly GLP-1RAs.5 Unfortunately, exenatide extended-release (ER) is manufactured as microspheres suspended in a vehicle of medium-chain triglycerides, which requires vigorous shaking (>15 seconds) prior to injection.6 Injection-site swelling is also a prevalent issue due to the slow clearance of the co-formulated polymer, which does not resolve itself until several weeks following injection. As a result, exenatide ER is less frequently prescribed and this review will focus on dulaglutide and semaglutide. Dulaglutide was launched in 2014 and is a polypeptide analogue of human GLP-1 covalently linked to the Fc arms of human immunoglobulin G4.7 This structure reduces immunogenicity and is soluble allowing for simple administration of a clear solution. Dulaglutide is administered in four doses (0.75, 1.5, 3.0 and 4.5 mg QW) and the lower two doses have no need for up-titration. More recently, the long-acting GLP-1RA semaglutide was approved (20188). This molecule is 94% homologous with human GLP-1, differing by only two amino acids. There is an 18-carbon fatty di-acid chain attached to amino acid 26 of the molecule that provides strong binding to albumin and facilitates prolonged activity. A benefit of the long-acting GLP-1RA semaglutide is its administration as a clear solution that does not require resuspension. It is initiated at a dose of 0.25 mg QW titrated after 1 month to a maintenance dose of 0.5 mg with the option for further up-titration to 1.0 mg QW. The dulaglutide phase 3 clinical trial programme was known as AWARD (Assessment of Weekly AdministRation of LY2189265 dulaglutide in Diabetes) and assessed its glucose-lowering efficacy versus commonly prescribed second-line therapies. The spectrum of patients with T2DM was broad, extending from treatment-naïve to those needing insulin, and the primary end-point in each trial (AWARD 1-6) was a change in HbA1c.9-14 The primary endpoint was assessed at 26 weeks in AWARD 1 and 3 to 6 and at 52 weeks in AWARD 2 (versus insulin glargine U100). Doses of 0.75 and 1.5 mg QW dulaglutide were assessed and all studies had extended periods of observation (4-78 weeks) allowing for the collection of additional safety data. Both doses of dulaglutide achieved statistically superior glucose-lowering to the following active comparators: metformin; sitagliptin; exenatide and insulin glargine U100. The higher dose of dulaglutide was also non-inferior to liraglutide 1.8 mg OD. From a baseline HbA1c of 59.6 to 69.4 mmol/mol (7.6%-8.5%), the reductions in HbA1c were 7.8 to 17.4 mmol/mol (0.71%-1.59%) for dulaglutide 0.75 mg QW and 8.5 to 17.9 mmol/mol (0.78%-1.64%) for dulaglutide 1.5 mg QW. Post-launch, the dose of dulaglutide for glucose-lowering was increased following the AWARD 11 trial.15 This assessed the efficacy of dulaglutide 3.0 and 4.5 mg QW versus dulaglutide 1.5 mg QW and reported additional glucose-lowering of 1.9 mmol/mol (0.17%) and 3.7 mmol/mol (0.34%), respectively, which were both statistically significant after 36 weeks treatment. Phase 3 clinical trials of semaglutide were named SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 diabetes) and included 8416 people with T2DM (SUSTAIN 1-5).16-20 Semaglutide was assessed in people across the spectrum of T2DM, from treatment-naïve, through combinations with oral glucose-lowering agents and insulin. All were randomised controlled trials (RCTs) and assessed HbA1c lowering over 30 to 56 weeks versus placebo, sitagliptin, exenatide ER and insulin glargine U100. The fall in HbA1c was significantly greater for both doses of semaglutide versus comparator and ranged from 13.2 to 16.0 mmol/mol (1.2%-1.5%) for 0.5 mg QW and 16.8 to 20.2 mmol/mol (1.6%-1.9%) for semaglutide 1.0 mg QW. An application to the Food and Drug Administration (FDA) for a 2.0 mg QW dosing of semaglutide for glucose-lowering was refused in March 2021 but resubmission is anticipated.21 The SUSTAIN 7 trial was a direct comparison of semaglutide with dulaglutide.22 Patients with T2DM and suboptimal glycaemic control on metformin were randomised to dulaglutide 0.75 or 1.5 mg QW versus semaglutide 0.5 or 1.0 mg QW. The mean BMI was 33.1 to 33.7 kg/m2 and diabetes duration 7.0 to 7.7 years. The mean baseline HbA1c was 66.1 to 67.2 mmol/mol (8.2%-8.3%) and fell significantly in all treatment cohorts after 40 weeks. Comparison of the low and high doses of each drug showed a significant advantage for semaglutide over dulaglutide (semaglutide 0.5 mg QW 16.5 mmol/mol (1.5%) versus dulaglutide 0.75 mg QW 12.1 mol/mol (1.1%) and semaglutide 1.0 mg QW 19.4 mmol/mol (1.8%) versus dulaglutide 1.5 mg 14.9 mmol/mol 1.4%). Dulaglutide 1.5 mg QW and exenatide exhibited similar effects on bodyweight in AWARD-1 but patients receiving the 0.75 mg QW dose experienced a small weight gain compared with exenatide.9 In the AWARD-3 monotherapy study, there was similar weight loss with dulaglutide 1.5 mg QW compared with metformin but significantly less with the lower 0.75 mg QW dose.11 In AWARD-5, weight loss was significantly greater for both dulaglutide doses compared with sitagliptin 100 mg OD13 and in the two head-to-head comparisons with insulin glargine U100 (AWARD-2 and AWARD-4), there was a significant weight advantage for dulaglutide.10, 12 In AWARD-6, patients taking dulaglutide 1.5 mg QW showed significantly less weight loss versus liraglutide 1.8 mg OD.14 In the AWARD-11 trial, the higher doses of dulaglutide led to increased weight loss compared with 1.5 mg QW (0.9 Kg for 3.0 mg QW and 1.6 kg for 4.5 mg QW).15 Reduction in weight was a secondary endpoint in the SUSTAIN programme and weight loss with semaglutide 0.5 and 1.0 mg QW was significantly better than placebo, sitagliptin and insulin glargine U100.22 Semaglutide 0.5 mg QW was associated with 3.5 to 4.6 kg weight loss, equivalent to 3.7% to 4.8% reduction of baseline body mass. The 1.0 mg QW semaglutide dose achieved reductions of 4.5 to 6.5 kg (4.7%-7.0% baseline body mass). Significant weight loss was also seen when semaglutide was added to basal insulin therapy. Finally, in the head-to-head comparison of semaglutide versus dulaglutide, weight loss data showed highly significant findings for the comparison of the two doses of semaglutide versus dulaglutide, with reductions of 4.6 and 6.5 kg (semaglutide 0.5 and 1.0 mg QW) versus 2.3 and 3.0 kg (dulaglutide 0.75 mg and 1.5 mg QW), respectively.22 The clear advantage of semaglutide over dulaglutide in weight loss has led to the former being assessed in high dose as an anti-obesity agent.24 The Semaglutide Treatment Effect in People with obesity (STEP) programme is made up of five studies of overweight individuals (mean BMI 35.7-38.5 kg/m2). STEP 1 assessed the efficacy and safety of subcutaneous semaglutide 2.4 mg QW versus placebo in 1961 adults treated for 68 weeks.25 The trial met both co-primary endpoints with a statistically significant bodyweight reduction with semaglutide 2.4 mg QW compared to placebo. Semaglutide-treated subjects achieved a mean weight loss of 14.9% (from baseline bodyweight of 105.3 kg) compared to a 2.4% weight loss with placebo; 86.4% achieved weight loss >5% compared to 31.5% with placebo. The most common adverse events (AEs) among people treated with high-dose semaglutide were gastrointestinal (GI) and these were typically transient and mild or moderate in severity. STEP 2 assessed semaglutide 2.4 versus 1.0 mg QW and placebo in 1210 overweight or obese adults with type 2 diabetes again treated for 68 weeks.26 Estimated change in mean bodyweight was −9.6% with semaglutide 2.4 mg QW versus −3.4% with placebo; 68.8% of subjects on semaglutide 2.4 mg lost >5% of bodyweight compared with 28.5% on placebo (P 5% baseline bodyweight versus placebo (P < Treatment due to in of semaglutide compared with placebo. STEP reported on weeks treatment with subcutaneous to 2.4 mg QW were randomised to drug versus placebo with for a further The to semaglutide had a further mean weight loss of over the of the trial those to placebo a mean of a of in of semaglutide. This that maintenance of semaglutide is to weight reduction and weight As a of the STEP programme the has approved once-weekly semaglutide for weight a for this has not in the European The in and is a trial to the of semaglutide 2.4 mg QW on in overweight or obese with not have The primary endpoint is a of the adverse events or The is due to with in and is the first trial in obesity to of a therapeutic GLP-1RAs are known to the and to reduce are not approved as lowering Dulaglutide was assessed in a and over a subjects with T2DM dulaglutide 0.75 mg dulaglutide 1.5 mg QW or placebo and were to periods of 26 the fell by (dulaglutide 0.75 mg QW) and mg in of and 0.5 were of and 3.5 were seen at 26 weeks for the 0.75 and 1.5 mg dulaglutide In the SUSTAIN phase 3 with semaglutide 0.5 mg QW was associated with a fall in of 2.4 to the 1.0 mg QW dose led to a fall of to This was significantly greater than that seen with for placebo in SUSTAIN and dulaglutide in SUSTAIN was also to a and not significantly different from from SUSTAIN 7 semaglutide achieved a reduction than the semaglutide an increase in of 1 to In SUSTAIN semaglutide 1.0 mg QW showed a greater increase in than dulaglutide 1.5 mg QW versus 2.4 trials were by the in the United in for new glucose-lowering This on from a as to a an increase in in people with T2DM are at a significantly increased Both dulaglutide and semaglutide have in The with a Weekly in was the for dulaglutide and people with T2DM, HbA1c < and an The mean of was were and not have known were dulaglutide 1.5 mg QW or placebo on of of The primary end-point was the of is by the and requires management of and of in diabetes as as for equivalent glucose-lowering in each of the trial In of dulaglutide the primary endpoint was versus placebo, and in a of with and the statistically significant of dulaglutide was (P The trial had the and placebo of the diabetes This was only a of trial had prior as with or on or It is of that the was in both the primary and secondary that the was not by the from This was in to from the trial for liraglutide, which to benefit in semaglutide was in the SUSTAIN 6 which was as a study, to be by a following drug SUSTAIN 6 and than were to semaglutide 0.5 and 1.0 mg QW or placebo, in to of SUSTAIN 6 people with T2DM at high and was both and patients 2 to trial was by two and an 3 or or of classes or and or more The primary once the which in people receiving semaglutide versus placebo This reduction in for the primary endpoint statistically significant safety for semaglutide (P < a for was also significant (P < this was not was the the of subcutaneous semaglutide was Both dulaglutide and semaglutide have safety and over placebo in with differing levels of trial Both are now as second-line for glucose-lowering after metformin in people with T2DM and or as prior to in of the of the in both and SUSTAIN 6 that was significantly in these In dulaglutide 1.5 mg QW the by and in SUSTAIN 6 the was An further in In the trial, were or or The was to severity. the of of to dulaglutide and of placebo from a Dulaglutide the of but not the of Dulaglutide was also to reduce the of or and Treatment not the of The was that of dulaglutide reduce in people with T2DM but not severity. of on In the study, both the and were to The primary was the first of a on or that was 1.5 or more the baseline mean in the and were for trial of dulaglutide and placebo. In dulaglutide the in 100 versus 100 in receiving placebo a for baseline the for was by in those dulaglutide that reduce in people with T2DM. A on data from two semaglutide was to A of patients with of were included in this and AEs were for the GLP-1 patients and patients were with the development of a significant of in of the GLP-1 treatment. A of semaglutide in people with is due to in There are small studies in that exenatide and a of exenatide ER is with are studies that semaglutide have a in of the effects of semaglutide in the and showed and with of A clinical trial semaglutide in patients is In common with diabetes the trial efficacy and safety from the primary An of was with the to the of dulaglutide on the of the This was as the first of new a in of or more from or therapy. subjects had and mean was the in in the dulaglutide and in placebo The was < with of for in of or more and 0.75 for therapy. the for a in of was the led the to a of showed that dulaglutide was associated with a significantly of a of or more and or more are also of the findings from the This was a dulaglutide 0.75 and 1.5 mg QW with insulin glargine U100 in with T2DM and moderate or The trial reported glycaemic however, receiving dulaglutide experienced greater weight loss and less than those receiving insulin In was and was these were most when the In SUSTAIN were secondary and there was a significant reduction of the endpoint This was by a fall in new of versus trial experienced a of was a small and similar This in by reductions in than clinical is not and has seen with liraglutide and as with a 52 the a trial of semaglutide with primary endpoints is and to in The primary endpoint for this is to first of a of of greater than or to from or from or from A of from AWARD-5, and the of dulaglutide 1.5 mg QW on and in people with T2DM and in a with fatty or of in and in were to the In the population at 6 dulaglutide significantly and levels versus placebo. In the with more reductions in were with dulaglutide versus placebo there was no significant when the baseline was in the The of dulaglutide on was assessed in an adults with T2DM and at were to dulaglutide QW for weeks or Dulaglutide in a change in of and change of also showed a significant reduction in The that dulaglutide be for the treatment of in people with T2DM. semaglutide of and from SUSTAIN 6 and a weight management trial (semaglutide was In weight management trial with baseline as and reductions were seen in to (P < for doses and reductions to placebo (P < for and of in to of weight management trial subjects versus on placebo. baseline was in of SUSTAIN 6 In these no significant reduction was for semaglutide 0.5 mg QW a significant reduction versus placebo was seen for semaglutide 1.0 mg QW (P Treatment for in and however, not statistically significant after for weight a trial in people with and were randomised to doses of subcutaneous semaglutide or The primary end-point was of with no of and people with or were The of subjects the primary end-point was to of the patients and placebo; this was significant (P < for semaglutide mg versus placebo. A secondary end-point of of at in of semaglutide mg patients and of placebo (P The that treatment with semaglutide in a significantly higher of patients with than placebo, however, without an of The AEs seen with dulaglutide and semaglutide are and as with this of glucose-lowering In the SUSTAIN 7 direct AEs were reported in to of subjects receiving 0.5 and 1.0 mg QW semaglutide compared with to for 0.75 and 1.5 mg doses of dulaglutide.22 In the higher doses of dulaglutide and QW) had more AEs than the 1.5 mg QW AEs lead to in clinical trials and with GLP-1RA in the This be by a slow of people to and the of or fatty The an increased of and and have not for the GLP-1RA There is no significant increase in of or with dulaglutide or semaglutide. of are low with both An safety from SUSTAIN 6 was an increase in were reported for more people randomised to semaglutide subjects than to placebo subjects a of data from the SUSTAIN clinical trial in AEs was semaglutide with comparator in the SUSTAIN 1 to these was that patients were from were with active treatment and HbA1c were at to mmol/mol of which to SUSTAIN They also reported that the of semaglutide on events be a of the and of HbA1c reduction the first weeks of the the AEs were seen in individuals with high HbA1c at baseline and were receiving insulin. It is of that in there was a increase in events with dulaglutide, the in a trial with an HbA1c of mmol/mol The have an to further and semaglutide. This trial is people with T2DM and an Treatment of to are by and assessed by a The primary end-point of this trial is the of at 3 of The is to be An of semaglutide was approved in as a with mg is a small fatty acid that a increase in in the to higher and of the semaglutide peptide from It also the of semaglutide. The of is and and is It is with no and has co-formulated with as and to increase and is to be the be in the with no or than a small of for 30 of oral for this with these the of semaglutide is low and has significant and dosing is the of semaglutide the in daily drug and for high levels of This has in the for diabetes programme of phase 3 clinical assessed oral semaglutide across the spectrum of T2DM, from people were treatment through to those treated with insulin In patients with HbA1c treated with oral glucose-lowering and oral semaglutide has compared with mg sitagliptin 100 mg 3 and and liraglutide 1.8 mg The primary end-point in all but of these trials was change in HbA1c at the of 26 weeks to trial The baseline of people to 1 to and were baseline to diabetes duration 3.5 to BMI to kg/m2 and HbA1c The higher maintenance dose of oral semaglutide mg a superior reduction in HbA1c versus all sitagliptin and In the trials that included the lower maintenance dose of 7 mg oral sitagliptin was statistically superior to placebo and sitagliptin 100 mg OD. In all five of these both doses of oral semaglutide achieved significantly higher of subjects an HbA1c mmol/mol versus The reductions in HbA1c seen with oral semaglutide were to for the mg the secondary end-point of change in in the studies oral semaglutide mg achieved statistically superior weight loss compared to placebo, sitagliptin, liraglutide and insulin. The mean weight loss seen after 26 weeks was to kg for oral semaglutide mg and only mg achieved a similar weight the trial the AEs were in as with the GLP-1RA There were no AEs and of were low and similar to 6 was the for oral were T2DM and increased and clinical of or moderate or and A of people were and randomised to oral semaglutide to the mg dose or placebo, on of of The primary end-point was the and is to that 6 was with the to as as after first had The mean at baseline was and of were The mean bodyweight was kg and HbA1c mmol/mol They had a mean duration of T2DM of and the had moderate 6 after only at which there had events in the semaglutide and in placebo, an of which (P < the was not (P however, there were reductions in both and both in of oral semaglutide. there was no for increased patients with or treatment from the The for the short duration of 6 was as was the for SUSTAIN was as a to safety with a to The trial of semaglutide of Semaglutide in Patients with Type 2 had in after the that only was a was that the effects of the semaglutide molecule be the of its of the trial which in is oral semaglutide with placebo in people with T2DM and or on of of It had a was by the and is for The trial duration is and be in The of the has also further that data from the SUSTAIN 6 and 6 had and with similar baseline that semaglutide has a on the across a of baseline similar to that reported with in the recently, that the the GLP-1 peptide and the of its receptor be achieved by small at GLP-1RAs are now in development and and of these has reported data from a Phase 1 the of the in was assessed in doses and mg and HbA1c by to mmol/mol versus mmol/mol for The and mg doses bodyweight by and respectively, compared to kg change with placebo. the of in the and were in the small than the This a less dosing that is for oral semaglutide. was with AEs with the GLP-1RA the short of there are to be attempts to a This also be to the that are most in the long-acting (QW) has now initiated Phase 2 studies in T2DM as as a Phase 2 in GLP-1RAs have as a glucose-lowering in T2DM for and have from a twice-daily subcutaneous treatment QW more recently, an oral In with GLP-1RAs are now the most common option when GLP-1RAs are with dulaglutide and semaglutide being the are the focus of this review of Both glucose-lowering with the secondary of weight loss and Reduction of bodyweight is more with high dose for which data from the STEP phase 3 clinical trial programme have is to be as an The safety and of both dulaglutide and semaglutide have with over placebo and of for dulaglutide and for semaglutide from the All of the safety for the GLP-1RA and have with no safety for dulaglutide and semaglutide. AEs for both are and as from the GLP-1RA there is the an increase in A significant increase was seen in the SUSTAIN 6 trial of semaglutide a for of was also seen for dulaglutide that this the of of seen with in on the of significant with insulin This is being by the trial of semaglutide in patients with which has a primary weight reduction and there are of the GLP-1RA for both dulaglutide and semaglutide and these are being for the in the trial, which has a primary There is also in the that these agents have and data that GLP-1RAs not only but also as and clinical trials are as as an additional included in the of oral semaglutide. The for GLP-1RA to as and which are seen as a of T2DM, have also in clinical will to be in people with diabetes and those with The of an oral GLP-1RA has the to increase to this of drug which has for people with type 2 diabetes. There is a that low levels of GLP-1RA to people have the for diabetes was due to a to in primary The phase 3 clinical trials that oral semaglutide has high efficacy in of glucose-lowering and weight however, the in of dosing and of and for 30 on efficacy this was not an issue for trial the small molecule GLP-1RA to be assessed in phase 2 clinical trials will this issue The review for this is at from