Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now?

ABSTRACT Introduction Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of type 2 diabetes (T2D) management due to their cardio-renal benefits, their glucose-lowering efficacy and weight loss (WL) maintenance. However, the response to GLP-1 RA monotherapy is heterogeneous. Additionally, the majority of GLP-1 RAs are injectable treatments. Oral GLP-1 RAs and injectable combinations of GLP-1 with other entero-pancreatic hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin) are under development for T2D and obesity management. Areas covered Herein, we review the data on (i) oral GLP-1 RAs (oral semaglutide 25/50 mg and orforglipron) and (ii) dual/triple agonists (tirzepatide, cagrilintide 2.4 mg/semaglutide 2.4 mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management. Expert opinion We are in a new era in T2D management where entero-pancreatic hormone-based treatments can result in ≥15% WL and euglycemia for many people with T2D. Multiple molecules with different mechanisms of action are under development for T2D, obesity and other metabolic complications. Data on their cardio-renal benefits, long-term efficacy and safety as well as their cost-effectiveness will better inform their position in treatment algorithms.

Herein, we review the data on (i) oral GLP-1 RAs (oral semaglutide 25/50 mg and orforglipron) and (ii) dual/triple agonists (tirzepatide, cagrilintide 2.4 mg/semaglutide 2.4 mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management.

Type 2 diabetes (T2D) is a chronic disease affecting more than half a billion people worldwide – its prevalence has almost doubled since 1990 and it is estimated that by 2050 over 1.3 billion people will live with T2D, posing a major public health challenge with substantial impact on healthcare systems, patients and their families [ 1 ]. Obesity is the strongest risk factor for T2D and the obesity epidemic is heavily contributed to the rise of T2D prevalence, especially the increased rates of young-onset T2D [ 2 ]. For example, in the UK, approximately 60% of adults with a diagnosis of T2D and age 16–39 years old are living with obesity [ 3 ]. Obesity and T2D share key pathophysiological mechanisms and are both associated with increased risk for (i) metabolic complications [such as hypertension, dyslipidemia, obstructive sleep apnea (OSA) and metabolic-dysfunction associated steatotic liver disease (MASLD)] and (ii) cardiovascular disease [ 2 , 4 ]. Among individuals with T2D, obesity increases mortality risk by sevenfold when also increases the risk for micro- and macrovascular complications, suggesting that the co-existence of obesity with T2D accelerate the disease process [ 5–7 ]. Intensive glycemic control in the early stages of T2D can reduce the subsequent risk of microvascular complications; yet its impact on macrovascular outcomes is less clear and takes time to become evident [ 8 , 9 ]. On the other hand, for many people with overweight/obesity and T2D, a weight-centric approach has recently been proposed in the ADA/EASD 2022 guidelines [ 9 ]. Weight loss (WL) of 10–15% or more in people with T2D and obesity can have a disease-modifying effect leading to diabetes remission, but also results in improvement in quality of life and multiple risk factors for cardiometabolic disease [ 9 ]. Moreover, prospective observational data from bariatric surgery (SOS study) suggest that ≥ 15% mean WL and weight maintenance over a period of 15 years in people with T2D and obesity could lead not only in long-term diabetes remission for a significant proportion of them (around 30%), but also in reduction of micro- and macrovascular complications compared to the control group [ 10 , 11 ]. Despite that sleeve gastrectomy and gastric bypass, the two most commonly performed bariatric procedures today, can result in sustained long-term WL ≥ 20–25% in people with obesity and T2D and in multiple cardiometabolic benefits, bariatric surgery is an intervention which is not scalable in population level and people can be hesitant to this option due to the risk of postoperative complications [ 12 , 13 ]. On the other hand, intensive lifestyle interventions could be implemented easier and result in up to 10% mean WL; however, there is large heterogeneity in response and long-term weight maintenance is challenging due to compensatory increases in appetite and reduction in energy expenditure during the WL state [ 14–16 ]. The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of T2D management over the last years, due to their cardio-renal benefits in high cardiovascular risk populations, but also due to their glucose-lowering effects and the clinically important and sustained WL. The efficacy of the injectable GLP-1 RAs semaglutide and liraglutide in inducing WL and weight maintenance through appetite reduction has led to clinical trials assessing higher doses of these molecules as treatments for obesity and both semaglutide 2.4 mg once weekly and liraglutide 3 mg once daily have now received approval for chronic weight management [ 17 , 18 ]. However, the efficacy of GLP-1 RAs, especially on WL, can vary between individuals – for example, even with subcutaneous semaglutide 2.4 mg once weekly (currently, the most efficacious approved GLP-1 RA monotherapy for chronic weight management), only 46% of people with overweight/obesity and T2D will achieve ≥ 10% WL and 68% will achieve an HbA1c ≤ 6.5% [ 19 ]. Additionally, a proportion of people are not able to tolerate the higher doses of GLP-1 RAs due to dose-dependent adverse events making even more difficult for them to achieve the individualized metabolic and WL targets [ 17 , 20 ]. Looking for the next step in the treatment for T2D and overweight/obesity, combinations of GLP-1 with other entero-pancreatic hormones with diverse metabolic actions, such as glucose-dependent insulinotropic peptide (GIP), glucagon, and amylin ( Figure 1) are currently under development with the potential of achieving euglycemia together with ≥ 10% and even ≥ 15% WL for many people living with T2D. Tirzepatide, a dual GLP-1 and GIP RA became the first combination of entero-pancreatic hormones approved for T2D management (2022) and chronic weight management (2023) ( Figure 2) [ 21 , 22 ]. In addition, a number of oral GLP-1 RAs are under development to offer an alternative option to people reluctant to injectable treatments, with early data for some of them suggesting simila

Orforglipron, an oral, non-peptide, G-protein biased GLP-1 RA (resulting in lower activation of the beta-arrestin pathway) is currently under development for the treatment of T2D and obesity [ 29 ]. Orforglipron is a small molecule and may offer a less burdensome administration for individuals with T2D compared to the oral semaglutide as it has minimal dosing requirements (i.e it does not require to be taken on an empty stomach) [ 30 ]. In a phase 2 trial, the safety and efficacy of multiple doses of orforglipton once daily (ranging from 3 mg to 45 mg) were assessed [ 30 ]. After 26 weeks of treatment, the mean change in HbA1c with orforglipron ranged from −1.19% to −2.10% (maximum effect with orgorglipron 45 mg) compared to −0.43% with placebo and −1.10% with dulaglutide 1.5 mg once weekly ( Table 3 , Figure 3) [ 30 ]. Moreover, mean body weight reduced by 9.6% with orforglipron 45 mg, compared to −2.2% with placebo and −4% with dulaglutide 1.5 mg. The AE profile associated with orforglipron closely resembled that of other GLP-1 RAs in similar stages of development with 12%-19% of participants discontinuing the medication due to AEs. The majority of AEs were gastrointestinal, they were typically of mild to moderate severity, they were associated with dose escalation and were more present in the rapid dose escalation groups [ 30 ]. Table 3. Efficacy and safety data for completed phase 2 trials in people with type 2 diabetes. Medication Orfoglipron 3, 12, 24, 36*, 45*mg [ 30 ] CagriSema 2.4 mg/2.4 mg [ 64 ] Survodutide^ 0.3, 0.9, 1.2, 1.8, 2.7 mg [ 73 ] Mazdutide^ 3, 4.5, 6 mg [ 72 ] Retatrutide 0.5, 4†, 8†, 12 mg† [ 77 ] Route and frequency PO, OD SC, OW SC, 0.3, 0.9, 1.8, 2.7 OW or 1.2, 1.8 mg BW SC, OW SC, OW Comparator vs (i) dulaglutide 1.5 mg vs (ii) placebo vs (i) semaglutide 2.4 mg vs (ii) cagrilintide 2.4 mg vs (i) semaglutide 1 mg vs (ii) placebo vs (i) dulaglutide 1.5 mg vs (ii) placebo vs (i) dulaglutide 1.5 mg vs (ii) placebo MOA GLP-1 GLP-1 + Amylin GLP-1 + Glucagon GLP-1 + Glucagon GLP-1 + GIP + Glucagon Trial Duration (weeks) 26 32 16 20 36 Participants 278 vs (i) 50 vs (ii) 55 31 vs (i) 31 vs (ii) 30 302 vs (i) 50 vs (ii) 59 149 vs (i) 50 vs (ii) 51 184 vs (i) 46 vs (ii) 45 Background therapy Diet and exercise± metformin Metformin ± SGLT2i. Metformin ± Metformin and/or diet and exercise. diet and exercise± metformin Diabetes duration (years) 5–7.9 6.4–10.7 6.1–8.8 3.3–4.4 7.2–10.5 Baseline BMI (kg/m 2 ) 34.1–36.4 34.4–36.2 33.4–34.9 26.7–28 33.8–36.3 Main efficacy outcomes HbA1c change (%) −1.19 to −2.1 vs (i) −1.1 vs (ii) −0.4 −2.20 vs (i) −1.8 vs (ii) −0.9 −0.91 to −1.71 vs (i) −1.46 vs (ii) −0.25 −1.41 to −1.67 vs (i) −1.35 vs(ii) −0.03 −0.54 to −2.16 vs (i) −1.36 vs(ii) −0.30 HbA1c ≤ 6.5% 45–84% vs (i) 41% vs (ii) 15% 75% vs (i) 48% vs (ii) 17% NA 28%-56% vs (i) 46% vs (ii) 8% 15%-82% vs (i) 43% vs (ii) 8% HbA1c < 7% 65–96% vs (i) 64% vs (ii) 24% 89% vs (i) 69% vs (ii) 33% NA 54%-74% vs (i) 60% vs (ii) 18% 37%-82% vs (i) 60% vs (ii) 22% Weight change −3.7% to −10.0% vs (i) −4.0% vs(ii) −2.2% −15.6% vs (i) −5.1% vs (ii) −8.1% −1.9% to −9.0% vs (i) −5.4% vs (ii) −1.2% −4.1% to −7.1% vs (i) −2.7% vs(ii) −1.4% −3.3% to −16.9% vs (i) −2.0% vs(ii) −3.0% ≥5% WL 33–81% vs (i) 35% vs (ii) 22% NA 8%-57% vs (i) 38% vs (ii) 7% 24%-57% vs (i) 18% vs (ii) 10% 32%-94% vs (i) 17% vs (ii) 25% ≥10% WL 8–48% vs (i) 6% vs (ii) 8% 71% vs (i) 14% vs (ii) 23% 2%-35% vs (i) 16% vs (ii) 0% 10%-25% vs (i) 0% vs (ii) 0% 5%-75% vs (i) 2% vs (ii) 2% ≥15% WL 0–24% vs (i) 2% vs (ii) 2% 54% vs (i) 0% vs (ii) 7% NA NA 0%-63% vs (i) 0% vs (ii) 2% SBP change (mmHg) −6.7 to −8.7 vs (i) −7.9 vs (ii) −5.5 −13.0 vs (i) +1.0 vs (ii) −2.5** NA −6.1 to −8.9 vs (i) −3.5 vs (ii) −1.3 −2.8 to −8.8 vs (i) −1.5 vs(ii) +1.5** DBP change (mmHg) −1.1 to −2.3 vs (i) −2.5 vs (ii) −1.8 −4.5 vs (i) 0 vs (ii) −0.1** NA −1.6 to −4.5 vs (i) −1.9 vs (ii) −0.8 −1.6 to −3.9 vs (i) 0 vs (ii) −1.2** Main safety outcomes Any AE 62–89% vs (i) 56% vs (ii) 62% 68% vs (i) 71% vs (ii) 80% 66–86% vs (i) 52% vs (ii) 53% 76–84% vs (i) 76% vs (ii) 65% 55–79% vs (i) 67% vs (ii) 62% SAE 0–11% vs (i) 2% vs (ii) 6% 0% vs (i) 6% vs (ii) 13% 2–8% vs (i) 0% vs (ii) 5% 0–6% vs (i) 8% vs (ii) 8% 4–8% vs (i) 2% vs (ii) 7% AE leading to discontinuation 12–19% vs (i) 4% vs (ii) 6% 0% vs (i) 3% vs (ii) 0% 8–30% vs (i) 4% vs (ii) 5% 0% vs (i) 1% vs (ii) 0% 0–17% vs (i) 2% vs (ii) 4% GLP-1 = glucagon-like peptide-1; GIP = glucose-dependent insulinotropic polypeptide; GCG = glucagon; PO = oral; SC = subcutaneous; OD = once daily; OW = once-weekly; BW = twice weekly; MOA = mechanism of action; BMI = body mass index; AEs = adverse events; SAEs = serious adverse events; WL = weight loss; SBP = systolic blood pressure; DBP = diastolic blood pressure; NA = data not available. Data presented as mean change (for continuous data) or proportion of participants (%, for categorical data) and as efficacy estimand unless stated otherwise; ^ efficacy estimand not available, so primary

From patient perspective, oral therapies are generally associated with improved convenience, acceptance and adherence compared to injectable treatments, hence a significant opportunity exists for entero-pancreatic hormone-based oral molecules [ 33 ]. Oral semaglutide, a peptide-based treatment which acts on the GLP-1 receptor similar to the native GLP-1 peptide, appears to have similar efficacy to semaglutide 2.4 mg once weekly at the dose of 50 mg once daily. However, despite that oral semaglutide has addressed some of the burdens associated with injectable treatments, it requires a complex dosing regimen involving food and water restrictions. The development of small molecules which interact with the GLP-1 receptor slightly different compared to native GLP-1 (biased toward G protein activation over β-arrestin recruitment at the GLP-1 receptor) hold potential for less burdensome administration and improved efficacy. Orforglipron is the first small molecule GLP-1 RA reaching phase 3 trials after demonstrating good efficacy and safety in early phase clinical trials. Moreover, small molecules may be easier to produce compared to peptide treatments and as a result their supply may be easier scalable to meet the constantly increasing demand for obesity pharmacotherapies [ 34 ]. Other oral, small molecules, GLP-1 RA are currently in early phase clinical trials, whilst oral combinations of entero-pancreatic hormones are also in development [ 20 ].

Amylin is a pancreatic hormone secreted by β-cells in response to food intake. It slows down the gastric emptying and inhibits the glucagon secretion – both these actions improve glycemia [ 60 ]. Amylin also increases satiety and reduces food intake through actions on the area postrema at the brainstem, and the reduction in food intake is not accompanied by the expected decrease in energy expenditure [ 61 ]. Cagrilintide, a once weekly administered amylin analogue, is currently under investigation as treatment for obesity. In a phase 2 study, cagrilintide in doses ranging from 0.3 mg to 4.5 mg resulted in up to 10.8% WL in people with overweight/obesity without diabetes compared to 9% with the GLP-1 RA liraglutide 3 mg and 3% WL with placebo [ 62 ]. The mechanisms leading to glycemic improvement and WL with the amylin RAs have several overlapping pharmacological effects with the GLP-1 RAs (including a marked reduction in food intake, delay of gastric emptying and inhibition of glucagon secretion), however amylin RAs and GLP-1 RAs act also in different sites and through different mechanisms of action [ 63 ]. Combinations of GLP-1 RA with amylin RA are under investigation for treatment of T2D and/or obesity, aiming to enhance the effect of GLP-1 RA [ 60 , 64 ]. Indeed, experimental studies in animals have shown that combining a GLP-1 RA and an amylin RA exert a synergistic suppression of food intake [ 65 ]. Moreover, studies in high fat diet fed rats have shown that the combination of the GLP-1 RA liraglutide with a dual amylin and calcitonin receptor agonist (DACRA) results not only in more WL, but also in improvement in glycemia compared to liraglutide monotherapy and DACRA monotherapy, demonstrating the potential for combining GLP-1 RA with amylin RA in T2D management [ 66 ]. In a phase 2 study, the co-administration of cagrilintide 2.4 mg and semaglutide 2.4 mg (cagrisema) once weekly for 32 weeks led to HbA1c reduction of −2.2% compared to −0.9% observed with cagrilintide 2.4 mg once weekly monotherapy and −1.8% with semaglutide 2.4 mg once weekly monotherapy [ 64 ]. Data from continuous glucose monitoring demonstrates also that at week 32, time in range (defined as 3.9–10.0 mmol/L [70–180 mg/dL]) was 89% with cagrisema compared to 76% with semaglutide 2.4 mg and 72% with cagrilintide 2.4 mg. Additionally, cagrisema led to 15.6% WL compared to 5.1% WL with semaglutide 2.4 mg monotherapy and 8.1% with cagrilintide 2.4 mg monotherapy [ 64 ]. Gastrointestinal AEs were more commonly seen with cagrisema compared to the monotherapies, however the serious adverse events (SAEs) and the AEs leading to treatment discontinuation were similar between groups [ 64 ]. Cagrisema is currently being evaluated in a series of phase 3 trials as treatment for T2D (REIMAGINE programme) and/or obesity (REDEFINE programme). REIMAGINE-2 is the first study from the phase 3 programme assessing cagrisema as treatment for T2D, when REDEFINE-2 will evaluate the use of cagrisema in people with overweight/obesity and T2D ( Figure 4) . Additionally, the REDEFINE-3 will assess the impact of cagrisema on cardiovascular events in people with and without T2D and preexisting cardiovascular disease.

Survodutide is another dual glucagon/GLP-1 RA which has completed a phase 2 trial in people with T2D, assessing the safety and efficacy of multiple doses of survodutide (ranging from 0.3 mg to 2.7 mg once weekly and 1.2 mg and 1.8 mg twice weekly) [ 73 ]. After 16 weeks of treatment, the mean HbA1c reduction ranged from −0.91% to −1.71% (maximum effect with survodutide 1.8 mg once weekly) compared with −1.46% with semaglutide 1 mg and −0.25% with placebo [ 73 ]. In this phase 2 trial, the mean WL with survodutide was up to −8.95% (with survodutide 1.8 mg twice weekly) compared to 5.4% WL with semaglutide 1 mg and 1.3% WL with placebo [ 73 ]. Most common AEs with survodutide were gastrointestinal and in total 15.9% of participants experienced AEs leading to treatment discontinuation at survodutide groups (discontinuation rate ranged from 7.8% with survodutide 1.2 mg twice weekly to 30% with survodutide 2.7 mg once weekly) compared to 4% with semaglutide 1 mg and 5.1% in the placebo group [ 73 ]. Survodutide (3.6 mg and 6 mg once weekly) is currently undergoing phase 3 trials as treatment for obesity (SYNCHRONIZE programme) and the SYNCHRONIZE-2 study will assess the efficacy and safety of survodutide in people with overweight/obesity and T2D. Moreover, a phase 2 study in adults with MASH and liver fibrosis with and without diabetes is ongoing ( NCT04771273 ). There are also other dual GLP-1/glucagon co-agonists under assessment as treatments for obesity and/or MASH (pemvidutide, efinopegdutide); however, these molecules did not demonstrate a clinically important effect in HbA1c in early phase clinical trials in people with T2D [ 74 , 75 ].

Tirzepatide, a dual GLP-1/GIP RA, marks a new era in T2D management where HbA1c ≤ 6.5% together with ≥ 15% WL and improvement in multiple cardiometabolic risk factors is a feasible target across the T2D spectrum with pharmacotherapy. Multiple other molecules with different routes of administration (such as oral GLP-1 RAs) and/or different mechanisms of action (such as injectable combinations of entero-pancreatic hormones) have shown promising data in early phase clinical trials and are currently undergoing phase 3 trials as treatments for T2D, obesity and other metabolic complications (e.c MASH, HFpEF) with some of them having the potential to induce even more WL and/or metabolic benefits compared to tirzepatide. Data on the cardio-renal and metabolic outcomes, the long-term efficacy and safety as well as the cost-effectiveness for each of the novel pharmacotherapies will allow clinicians to offer better individualized care for people with T2D and will also provide a better understanding of their potential position at the T2D treatment guidelines.

A significant proportion of people with T2D have also other underlying metabolic and/or mechanical complications such as HFpEF, OSA, MASLD, CKD and knee osteoarthritis which could be improved with ≥ 10–15% WL, a feasible target with the novel T2D pharmacotherapies [ 86 ]. Ectopic fat deposition to the heart, kidneys and liver appears to contribute to the development of some of these complications and a number of the new molecules have direct and weight-independent actions on ectopic fat and may further enhance the potential for individualized treatment choices based on underlying comorbidities [ 20 ]. More specifically, in people with MASLD, the dual GLP-1/glucagon RAs achieve more liver fat reduction compared to GLP-1 RA alone after similar weight loss, likely due to direct action of glucagon on hepatic lipid oxidation [ 87 ]. Nevertheless, GLP-1 RAs such as liraglutide 1.8 mg once daily and semaglutide 2.4 mg once weekly have demonstrated their benefits in MASH resolution compared to placebo, without however improvement in fibrosis [ 57 , 88 ]. Currently, there is lack of data on the potential benefits of dual GLP-1/glucagon RAs or the triple agonist retatrutide on liver histology in people with MASH, but phase 2 trials assessing changes in liver histology with some of these pharmacotherapies are ongoing ( NCT04771273 , NCT05877547 ). In people with CKD and/or heart failure, SGLT-2i have shown remarkable benefits (independent of diabetes status) and are currently recommended as first line glucose-lowering treatments for these populations with T2D [ 9 , 89 ]. However, emerging evidence suggest that some GLP-1 RAs have also benefits in people with HFpEF and CKD. The FLOW study assessed the effect of semaglutide 1 mg compared to placebo on the progression of renal impairment in people with T2D and CKD – the composite primary endpoint was time to first kidney failure (persistent eGFR <15 ml/min/1.73 m 2 or initiation of chronic kidney replacement therapy), persistent ≥ 50% reduction in eGFR or death from kidney or cardiovascular causes – this trial has been stopped early due to efficacy after an interim analysis which met certain pre-specified criteria [ 90 ]. In people with HFpEF and obesity (with and without diabetes), semaglutide 2.4 mg once weekly for 52 weeks improved symptoms, physical function, exercise function and bodyweight compared to placebo (STEP HFpEF and STEP HFpEF DM clinical trials) [ 59 , 91 ]. For people without diabetes, the mean WL with semaglutide 2.4 mg once weekly at 52 weeks was 13.3% (vs 2.6% WL with placebo, STEP HFpEF trial), when for people with T2D mean WL with semaglutide 2.4 mg was 9.8% (vs 3.6% WL with placebo, STEP HFpEF DM trial) [ 59 , 91 ]. GLP-1 RAs reduce epicardial fat which is associated with increased risk of HFpEF and they may also impact on perinephric fat, suggesting the potential of weight-independent mechanisms on the effect of semaglutide on CKD and HFpEF [ 92 , 93 ]. Whether the novel GLP-1 based molecules (either oral GLP-1 RAs or those based on combinations of GLP-1 with other entero-pancreatic hormones) will also have similar impact on these metabolic complications will need to be assessed in future studies.

The lean muscle mass loss is of particular interest with the new pharmacotherapies for T2D, especially for people with increased risk of sarcopenia (such as elderly, frail populations with T2D and those from Asian background) [ 97 ]. For example, 72 weeks of treatment with tirzepatide in people with obesity (without diabetes, SURMOUNT-1 trial), resulted in an overall improvement of the total fat mass: total lean mass ratio, but there was a 10.9% reduction of total lean mass at the end of the study [ 22 ]. Adequate nutrition with focus on protein intake and support for resistance exercise during the rapid WL phase, as well as slower dose titration schemes in high risk populations (to try and control the WL rate) may help people preserve their lean muscle mass and optimize further the physical function and body composition. Additionally, understanding the impact of each novel molecule on body composition will help us to determine the optimal strategies for integrating them with various lifestyle interventions. For example glucagon agonism has a suppressive effect on circulating amino-acids and whether the novel dual and triple agonists targeting the glucagon receptor impact negatively on lean muscle mass will need further research [ 77 , 98 ]. It should be noted that the majority of the phase 3 and phase 2 trials in people with T2D have been performed in populations with obesity, as the mean baseline BMI for the global studies included in this review was ranging between 32 and 36 kg/m 2 (only exception the mazdutide study that included Chinese population only). As a result, the efficacy of the novel medications on lean people with T2D has not been adequately studied. Long-term glycemic control is important for reducing the risk of microvascular complications, although transient worsening of retinopathy or neuropathy may occur during glucose control intensification. In SUSTAIN-6, treatment with semaglutide 1 mg led to the development of retinopathy-related complications in more people (3%) compared to placebo (1.8%) and the risk was higher for people with a history of proliferative or non-proliferative diabetic retinopathy at baseline, with higher baseline HbA1c and longer diabetes duration [ 99 , 100 ]. The magnitude and the rapidity of HbA1c reduction during the first few months after semaglutide 1 mg initiation has been suggested as the main underlying mechanism for the increased risk of retinopathy with this treatment. Data from SURPASS-2 study suggest that glycemic and WL targets were achieved significantly quicker with tirzepatide (at all the three doses, 5, 10 and 15 mg) compared to semaglutide 1 mg (for example time to reach HbA1c < 7% was 8.1 weeks for tirzepatide doses vs 12 weeks for semaglutide 1 mg) and this will be likely the case with the majority of the novel entero-pancreatic hormone-based therapies [ 101 ]. People with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy and macular edema have not been studied in the SURPASS program and in studies with other novel agents, so we need to be cautious on initiation of treatment in these populations, especially in those with uncontrolled glycemia. Slower titration of medication doses, retinal screening before treatment initiation and close monitoring from ophthalmology team may be required for this population. Similarly, the novel agents that include GLP-1 receptor agonism should be used with caution for those with a history of pancreatitis as this population has been excluded from the studies with the novel agents. In summary, apart from tirzepatide, there is a large pipeline of novel molecules with different mechanisms of action that have either completed phase 3 trials and awaiting approval (oral semaglutide 25 and 50 mg) or currently undergoing phase 3 trials for T2D management, obesity and/or metabolic complications (orforglipron, cagrisema, survodutide, mazdutide and retatrutide). Understanding better the full therapeutic potential of these molecules, but also the potential risks associated with their use in different populations through data from clinical trials and real-world evidence will give the opportunity to clinicians to develop personalized treatment plans for people with T2D.

D Papamargaritis has acted as a speaker for Novo Nordisk and has received grants from Novo Nordisk, Novo Nordisk UK Research Foundation, Academy of Medical Sciences/Diabetes UK, Health Education East Midlands and the National Institute for Health and Care Research (NIHR). M J Davies has acted as consultant, advisory board member and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi, an advisory board member Lexicon, Pfizer, ShouTi Pharma Inc, AstraZeneca, Zealand Pharma and Medtronic and as a speaker for AstraZeneca, Napp Pharmaceuticals, Novartis and Amgen. M J Davies has received grants from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Janssen, Sanofi-Aventis and Eli Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.