Efpeglenatide
Efpeglenatide is an investigational exendin-based GLP-1 receptor agonist in phase 3 clinical trials for type 2 diabetes.[371]Yoon KH, Kang J, Kwon SC, et al. Pharmacokinetic and dose-finding studies on efpeglenatide in patients with type 2 diabetes. Diabetes Obes Metab. 2020 Aug;22(8):1292-301.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383501
http://www.ncbi.nlm.nih.gov/pubmed/32175655?tool=bestpractice.com
It is administered as a subcutaneous injection. Results from the AMPLITUDE-O study showed that efpeglenatide reduced the risk of CV events versus placebo in patients with type 2 diabetes and either a history of CV disease or current kidney disease plus ≥1 other CV risk factor.[372]Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. 2021 Sep 2;385(10):896-907.
https://www.nejm.org/doi/10.1056/NEJMoa2108269
http://www.ncbi.nlm.nih.gov/pubmed/34215025?tool=bestpractice.com
Data suggest that this benefit may be dose-dependent.[373]Gerstein HC, Li Z, Ramasundarahettige C, et al. Exploring the relationship between efpeglenatide dose and cardiovascular outcomes in type 2 diabetes: insights from the AMPLITUDE-O trial. Circulation. 2023 Mar 28;147(13):1004-13.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.063716
http://www.ncbi.nlm.nih.gov/pubmed/36802715?tool=bestpractice.com
The most common adverse events with efpeglenatide treatment were gastrointestinal.[372]Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. 2021 Sep 2;385(10):896-907.
https://www.nejm.org/doi/10.1056/NEJMoa2108269
http://www.ncbi.nlm.nih.gov/pubmed/34215025?tool=bestpractice.com
An exploratory analysis of AMPLITUDE-O found that the beneficial effect of efpeglenatide on CV outcomes was independent of baseline SGLT2 inhibitor use.[374]Lam CSP, Ramasundarahettige C, Branch KRH, et al. Efpeglenatide and clinical outcomes with and without concomitant sodium-glucose cotransporter-2 inhibition use in type 2 diabetes: exploratory analysis of the AMPLITUDE-O trial. Circulation. 2022 Feb 22;145(8):565-74.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.121.057934
http://www.ncbi.nlm.nih.gov/pubmed/34775781?tool=bestpractice.com
Moreover, a post-hoc analysis of earlier phase 2 data showed that efpeglenatide may be able to prevent patients with prediabetes from developing type 2 diabetes.[375]Pratley RE, Jacob S, Baek S, et al. Efficacy and safety of efpeglenatide in key patient subgroups from the BALANCE randomized trial, stratified by pre-diabetes status, BMI, and age at baseline. BMJ Open Diabetes Res Care. 2022 Jan;10(1):e002207.
https://drc.bmj.com/content/10/1/e002207.long
http://www.ncbi.nlm.nih.gov/pubmed/35042751?tool=bestpractice.com
Efpeglenatide has yet to be submitted for regulatory approval.
Oral semaglutide
Both the oral and subcutaneous formulations of the GLP-1 receptor agonist semaglutide are approved for the treatment of type 2 diabetes. While the CV benefit of subcutaneous semaglutide has been well established in randomized controlled trials (RCTs), oral semaglutide failed to significantly improve major adverse CV events compared with placebo, and therefore only demonstrated noninferiority.[281]Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019 Aug 29;381(9):841-51.
https://www.nejm.org/doi/10.1056/NEJMoa1901118
http://www.ncbi.nlm.nih.gov/pubmed/31185157?tool=bestpractice.com
Further evidence is required to recommend the oral formulation of semaglutide for CV risk reduction in patients with type 2 diabetes at high risk for or with established atherosclerotic cardiovascular disease (CVD). A long-term CV outcomes trial comparing oral semaglutide to placebo in people with type 2 diabetes and a history of heart disease is ongoing (SOUL; NCT03914326).
Retatrutide
Retatrutide is an investigational novel single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon (GCGR) receptors. It is administered as a subcutaneous injection. Retatrutide demonstrated clinically meaningful glucose- and weight-lowering efficacy in people with type 2 diabetes in a 12-week phase 1 study.[376]Urva S, Coskun T, Loh MT, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet. 2022 Nov 26;400(10366):1869-81.
http://www.ncbi.nlm.nih.gov/pubmed/36354040?tool=bestpractice.com
One phase 2 RCT aimed to assess the safety and efficacy of retatrutide versus dulaglutide and placebo in individuals with type 2 diabetes.[377]Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023 Aug 12;402(10401):529-44.
http://www.ncbi.nlm.nih.gov/pubmed/37385280?tool=bestpractice.com
The primary outcome of this study was mean change in hemoglobin A1c (HbA1c) at 24 weeks, while a key secondary outcome included mean change in body weight at 36 weeks. Retatrutide resulted in significant reductions in glycemic control and body weight compared to dulaglutide and placebo. Furthermore, there were improvements in lipid profile and blood pressure. The majority of adverse effects were gastrointestinal and mild-to-moderate in nature with no reported deaths.[377]Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023 Aug 12;402(10401):529-44.
http://www.ncbi.nlm.nih.gov/pubmed/37385280?tool=bestpractice.com
A phase 3 study is currently underway.[378]ClinicalTrials.gov. A study of retatrutide (LY3437943) in participants with type 2 diabetes mellitus who have obesity or overweight (TRIUMPH-2). ClinicalTrials.gov Identifier: NCT05929079. Dec 2024 [internet publication].
https://clinicaltrials.gov/study/NCT05929079
Orforglipron
Orforglipron is an investigational oral nonpeptide GLP-1 receptor agonist that is in development for type 2 diabetes and obesity. One phase 2 study evaluated orforglipron at varying doses for the treatment of type 2 diabetes compared to placebo and dulaglutide.[379]Frias JP, Hsia S, Eyde S, et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. Lancet. 2023 Aug 5;402(10400):472-83.
http://www.ncbi.nlm.nih.gov/pubmed/37369232?tool=bestpractice.com
Orforglipron achieved meaningful reductions in HbA1c and body weight at 26 weeks with an adverse events profile consistent with other GLP-1 receptor agonists. Mean reduction in HbA1c (from a mean baseline of 8.1%) with orforglipron at 26 weeks was up to 2.1%, compared to 0.4% with placebo and 1.1% with dulaglutide. Orforglipron also demonstrated weight reductions up to 10.1 kg in adults with type 2 diabetes (from a mean baseline of 100.3 kg) compared to 2.2 kg with placebo and 3.9 kg for dulaglutide. With orforglipron, 65% to 96% of participants achieved an HbA1c of less than 7.0% at 26 weeks versus 64% in the dulaglutide group and 24% in the placebo group. Similar to other GLP-1 receptor agonists, orforglipron produced improvements in the blood pressure and levels of circulating lipids.[379]Frias JP, Hsia S, Eyde S, et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. Lancet. 2023 Aug 5;402(10400):472-83.
http://www.ncbi.nlm.nih.gov/pubmed/37369232?tool=bestpractice.com
Phase 3 trials are in progress.[380]ClinicalTrials.gov. A study of orforglipron in adult participants with obesity or overweight and type 2 diabetes (ATTAIN-2). ClinicalTrials.gov Identifier: NCT05872620. Oct 2024 [internet publication].
https://classic.clinicaltrials.gov/ct2/show/NCT05872620
[381]ClinicalTrials.gov. A study of daily oral orforglipron (LY3502970) compared with insulin glargine in participants with type 2 diabetes and obesity or overweight at increased cardiovascular risk (ACHIEVE-4). ClinicalTrials.gov Identifier: NCT05803421. Dec 2024 [internet publication].
https://clinicaltrials.gov/study/NCT05803421
[382]ClinicalTrials.gov. A long-term safety study of orforglipron (LY3502970) in participants with type 2 diabetes (ACHIEVE-J). ClinicalTrials.gov Identifier: NCT06010004. Oct 2024 [internet publication].
https://clinicaltrials.gov/study/NCT06010004
[383]ClinicalTrials.gov. A study of orforglipron (LY3502970) in adult participants with type 2 diabetes and inadequate glycemic control with diet and exercise alone (ACHIEVE-1). ClinicalTrials.gov Identifier: NCT05971940. Oct 2024 [internet publication].
https://clinicaltrials.gov/study/NCT05971940
[384]ClinicalTrials.gov. A study of orforglipron (LY3502970) compared with semaglutide in participants with type 2 diabetes inadequately controlled with metformin (ACHIEVE-3). ClinicalTrials.gov Identifier: NCT06045221. Oct 2024 [internet publication].
https://www.clinicaltrials.gov/study/NCT06045221
Cagrilintide/semaglutide
A subcutaneous combination drug formulation containing semaglutide (a GLP-1 receptor agonist) and cagrilintide (an investigational long-acting amylin analog). In one network meta-analysis, cagrilintide/semaglutide was found to be the most effective GLP-1 receptor agonist for lowering body weight in adults with type 2 diabetes (mean loss 14.03 kg).[385]Yao H, Zhang A, Li D, et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ. 2024 Jan 29;384:e076410.
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/38286487
http://www.ncbi.nlm.nih.gov/pubmed/38286487?tool=bestpractice.com
The efficacy and safety of cagrilintide/semaglutide was assessed in a 32-week, multicenter, double-blind, phase 2 trial.[386]Frias JP, Deenadayalan S, Erichsen L, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2023 Aug 26;402(10403):720-30.
http://www.ncbi.nlm.nih.gov/pubmed/37364590?tool=bestpractice.com
Adults with type 2 diabetes and a body mass index (BMI) ≥27 kg/m² on metformin, with or without an SGLT2 inhibitor, were randomly assigned to cagrilintide/semaglutide , semaglutide alone, or cagrilintide alone. The primary endpoint was change from baseline in HbA1c; secondary endpoints were bodyweight, fasting plasma glucose, continuous glucose monitoring (CGM) parameters, and safety. Treatment with cagrilintide/semaglutide resulted in clinically relevant improvements in glycemic control (including CGM parameters). The mean change in HbA1c with cagrilintide/semaglutide was greater versus cagrilintide alone, but not versus semaglutide alone. Treatment with cagrilintide/semaglutide resulted in significantly greater weight loss versus semaglutide alone and cagrilintide alone and was well tolerated. Adverse events were reported by 68% of participants in the cagrilintide/semaglutide group, 71% in the semaglutide alone group, and 80% in the cagrilintide alone group. Mild or moderate gastrointestinal adverse events were most common; no fatal adverse events were reported.[386]Frias JP, Deenadayalan S, Erichsen L, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2023 Aug 26;402(10403):720-30.
http://www.ncbi.nlm.nih.gov/pubmed/37364590?tool=bestpractice.com
Longer and larger phase 3 studies are needed.
Colchicine
Colchicine is an anti-inflammatory drug that has been in use for many decades for indications such as gout. More recently, it has been approved for risk reduction in atherosclerotic CVD. In one randomized, double-blinded, placebo-controlled trial of patients with type 2 diabetes and recent MI (COLCOT; Colchicine Cardiovascular Outcomes Trial), colchicine led to a large reduction in CV events compared with placebo.[387]Roubille F, Bouabdallaoui N, Kouz S, et al. Low-dose colchicine in patients with type 2 diabetes and recent myocardial infarction in the colchicine cardiovascular outcomes trial (COLCOT). Diabetes Care. 2024 Mar 1;47(3):467-70.
http://www.ncbi.nlm.nih.gov/pubmed/38181203?tool=bestpractice.com
The COLCOT-T2D study is currently recruiting 10,000 patients in Canada with type 2 diabetes and no history of CVD; it will evaluate whether low-dose colchicine in addition to standard treatment is effective in reducing the risk of CV events in this population, with the aim of establishing whether colchicine could have a role in primary prevention of CVD in patients with type 2 diabetes.[388]Montreal Heart Institute. Clinical study COLCOT-T2D: prevention of heart disease in people with type 2 diabetes. 2022 [internet publication].
https://colcot-t2d.org/en
Mazdutide
An investigational synthetic peptide analog of mammalian oxyntomodulin which acts as a dual GLP-1 and glucagon receptor (GCGR) agonist. It is administered as a subcutaneous injection. Mazdutide has shown promise for the treatment of type 2 diabetes and obesity in phase 1 trials.[389]Jiang H, Pang S, Zhang Y, et al. A phase 1b randomised controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in chinese patients with type 2 diabetes. Nat Commun. 2022 Jun 24;13(1):3613.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232612
http://www.ncbi.nlm.nih.gov/pubmed/35750681?tool=bestpractice.com
[390]Benson C, Tham LS, Du YU, et al. 333-OR: oxyntomodulin analog LY3305677 (LY) improves glycemic control and weight loss in healthy volunteers and subjects with type 2 diabetes (T2D). Diabetes. 2022 Jun 1;71(1 suppl):333.
https://diabetesjournals.org/diabetes/article/71/Supplement_1/333-OR/146313/333-OR-Oxyntomodulin-Analog-LY3305677-LY-Improves
In a phase 2 trial in Chinese patients with diabetes, treatment with mazdutide for 20 weeks showed significant improvement in glycemic control and weight loss compared with placebo. The drug appears to be safe with a similar adverse effect profile to GLP-1 receptor agonists (with gastrointestinal adverse effects most frequently reported).[391]Zhang B, Cheng Z, Chen J, et al. Efficacy and safety of mazdutide in chinese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial. Diabetes Care. 2024 Jan 1;47(1):160-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10733643
http://www.ncbi.nlm.nih.gov/pubmed/37943529?tool=bestpractice.com
Phase 3 trials are in progress.
Bexagliflozin
Bexagliflozin, an oral SGLT2 inhibitor, is approved in the US as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is not available in Europe. Phase 3 clinical trials have studied bexagliflozin as monotherapy and in combination with metformin in adults with type 2 diabetes; it has also been studied in phase 3 trials in adults with type 2 diabetes and moderate renal impairment, and in adults with type 2 diabetes and established or increased risk of CVD.[392]ClinicalTrials.gov. Safety and efficacy of bexagliflozin as monotherapy in patients with type 2 diabetes. ClinicalTrials.gov Identifier: NCT02715258. Jun 2021 [internet publication].
https://clinicaltrials.gov/study/NCT02715258
[393]ClinicalTrials.gov. Safety and efficacy of bexagliflozin compared to placebo as add-on therapy to metformin in type 2 diabetes subjects. ClinicalTrials.gov Identifier: NCT03259789. Jul 2021 [internet publication].
https://clinicaltrials.gov/study/NCT03259789
[394]ClinicalTrials.gov. Safety and efficacy of bexagliflozin compared to glimepiride as add-on therapy to metformin in type 2 diabetes subjects. ClinicalTrials.gov Identifier: NCT02769481. May 2021 [internet publication].
https://clinicaltrials.gov/study/NCT02769481
[395]ClinicalTrials.gov. Safety and efficacy of bexagliflozin compared to sitagliptin as add-on therapy to metformin in type 2 diabetes subjects. ClinicalTrials.gov Identifier: NCT03115112. Jun 2021 [internet publication].
https://clinicaltrials.gov/study/NCT03115112
[396]ClinicalTrials.gov. Safety and efficacy of bexagliflozin in type 2 diabetes mellitus patients with moderate renal impairment. ClinicalTrials.gov Identifier: NCT02836873. Jun 2021 [internet publication].
https://clinicaltrials.gov/study/NCT02836873
[397]ClinicalTrials.gov. Bexagliflozin efficacy and safety trial (BEST). ClinicalTrials.gov Identifier: NCT02558296. Jul 2021 [internet publication].
https://clinicaltrials.gov/study/NCT02558296
[398]Allegretti AS, Zhang W, Zhou W, et al. Safety and effectiveness of bexagliflozin in patients with type 2 diabetes mellitus and stage 3a/3b CKD. Am J Kidney Dis. 2019 Sep;74(3):328-37.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10077840
http://www.ncbi.nlm.nih.gov/pubmed/31101403?tool=bestpractice.com
[399]Halvorsen YD, Conery AL, Lock JP, et al. Bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes in adults: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2023 Oct;25(10):2954-62.
https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15192
http://www.ncbi.nlm.nih.gov/pubmed/37409573?tool=bestpractice.com
Treatment with bexagliflozin reduced HbA1c compared to placebo and efficacy was noninferior to glimepiride and sitagliptin, with reduction in HbA1c being shown across subgroups of age, sex, race, and geographic region. It also showed clinically meaningful improvement in weight, eGFR, and systolic blood pressure. A head-to-head double-blind RCT demonstrated that bexagliflozin was noninferior to dapagliflozin as an adjunct to metformin in Chinese patients with type 2 diabetes mellitus, where the primary endpoint was reduction in HbA1c.[400]Xie L, Han J, Cheng Z, et al. Efficacy and safety of bexagliflozin compared with dapagliflozin as an adjunct to metformin in Chinese patients with type 2 diabetes mellitus: a 24-week, randomized, double-blind, active-controlled, phase 3 trial. J Diabetes. 2024 Apr;16(4):e13526.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10999497
http://www.ncbi.nlm.nih.gov/pubmed/38584148?tool=bestpractice.com
Secondary efficacy endpoint analyses showed results in both groups consistent with previous clinical trials, including a reduction in body weight and systolic blood pressure.