Keywords: LY3298176, insulin glargine, type 2 diabetes, cardiovascular risk, GIP, GLP-1 receptor agonist, SURPASS-4
Abstract
Background We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist LY3298176 versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications.
Methods This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA1c) of 7.5–10.5% (58–91 mmol/mol), body-mass index of 25 kg/m² or greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week LY3298176 (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0.3% non-inferiority boundary) of LY3298176 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks.
Findings Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3045 participants were screened, with 2002 participants randomly assigned to LY3298176 or glargine. 1995 received at least one dose of LY3298176 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%), and were included in the modified intention-to-treat population. At 52 weeks, mean HbA1c changes with LY3298176 were -2.43% (SD 0.05) with 10 mg and -2.58% (0.05) with 15 mg, versus -1.44% (0.03) with glargine. The estimated treatment difference versus glargine was -0.99% (multiplicity adjusted 97.5% CI -1.13 to -0.86) for LY3298176 10 mg and -1.14% (-1.28 to -1.00) for 15 mg, and the non-inferiority margin of 0.3% was met for both doses. Nausea (12–23%), diarrhoea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) were more frequent with LY3298176 than glargine (nausea 2%, diarrhoea 4%, decreased appetite <1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase. The percentage of participants with hypoglycaemia (glucose <54 mg/dL or severe) was lower with LY3298176 (6–9%) versus glargine (19%), particularly in participants not on sulfonylureas (LY3298176 1–3% vs glargine 16%). Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 109 participants and were not increased on LY3298176 compared with glargine (hazard ratio 0.74, 95% CI 0.51–1.08). 60 deaths (n=25 [3%] LY3298176; n=35 [4%] glargine) occurred during the study.
Interpretation In people with type 2 diabetes and elevated cardiovascular risk, LY3298176, compared with glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycaemia at week 52. LY3298176 treatment was not associated with excess cardiovascular risk.
Introduction
Current guidelines recommend GLP-1 receptor agonists as the first injectable therapy in people with type 2 diabetes. Treatment with GLP-1 receptor agonists achieves similar or better glycaemic control than basal insulins with weight loss and lower risk of hypoglycaemia, but is associated with frequent gastrointestinal side-effects.
Combined GIP and GLP-1 receptor activation has been established as a promising therapeutic concept for the treatment of type 2 diabetes. LY3298176, a novel dual GIP and GLP-1 receptor agonist, is under development for the treatment of type 2 diabetes. When compared with a GLP-1 receptor agonist, LY3298176 further improves glycaemic control by actions on pancreatic β cells to enhance insulin secretion, by reducing glucose adjusted glucagon secretion, and by insulin-sensitising effects beyond the level explained by weight loss. In addition, LY3298176 treatment is associated with improvements in adipose tissue and lipoprotein metabolism, blood pressure, and other surrogate markers of cardiovascular protection. It also has a marked anorexigenic effect, probably by integrating the activation signals of both GLP-1 and GIP receptor pathways in the brain. When compared with placebo, semaglutide 1 mg per week, or insulin degludec, LY3298176 was more effective in achieving glycaemic control and weight reduction in people with type 2 diabetes over 40–52-week treatment periods.
Although LY3298176 has been shown to be superior to other glucose-lowering agents for glycaemic and weight effects, and has shown favourable effects on cardiovascular risk factors, its long-term efficacy and safety have not been evaluated. In particular, cardiovascular safety remains to be addressed in individuals with type 2 diabetes and high cardiovascular risk, especially in those with a history of cardiovascular disease or chronic kidney disease. Therefore, the objective of SURPASS-4 was to compare the efficacy and safety of three doses of LY3298176 (5 mg, 10 mg, and 15 mg) versus glargine titrated to a fasting glucose of less than 100 mg/dL in people with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications.
Methods
Study Design
This randomised, open-label, active-controlled, parallel-group, phase 3 study was conducted at 187 sites in 14 countries (Argentina, Australia, Brazil, Canada, Greece, Israel, Mexico, Poland, Romania, Russia, Slovakia, Spain, Taiwan, and the USA) on five continents. The protocol was approved by institutional review boards for each site and the trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Participants
Key inclusion criteria were adults (aged ≥18 years) with type 2 diabetes inadequately controlled (glycated haemoglobin [HbA1c] 7.5–10.5% [58–91 mmol/mol]), with any of three oral glucose-lowering medications (ie, metformin, sulfonylurea, or sodium-glucose co-transporter-2 [SGLT-2] inhibitor) either alone or in any combination, body-mass index (BMI) of 25 kg/m² or more, and stable weight (≤5% fluctuation in either direction) during the previous 3 months. Eligible participants were at increased risk of cardiovascular events, defined as known coronary, peripheral arterial, or cerebrovascular disease, or aged 50 years or older with either history of chronic kidney disease and an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m² or history of congestive heart failure (New York Heart Association Class II or III). Key exclusion criteria included type 1 diabetes and history of pancreatitis. All participants provided written informed consent before entering the study.
Randomisation and Masking
Participants were randomly assigned (1:1:1:3), by the Eli Lilly and Company computer-generated random sequence using an interactive web-response system to receive LY3298176 or glargine. Participants were stratified at randomisation based on country, baseline HbA1c of 8.5% or less or more than 8.5% (69 mmol/mol), and baseline SGLT-2 inhibitor use. This study was open-label due to the differences in dosing schedule, titration, and devices between once-per-week LY3298176 and once-per-day insulin glargine.
Procedures
LY3298176 was administered as a once-per-week subcutaneous injection (5 mg, 10 mg, or 15 mg) with a prefilled syringe. LY3298176 treatment was initiated at 2.5 mg once per week, and increased by 2.5 mg every 4 weeks until the randomised dose was achieved and maintained for the study duration. If intolerable gastrointestinal symptoms or events occurred during LY3298176 dose escalation, the dose could be de-escalated to a lower, tolerated maintenance dose (5 mg or 10 mg) of LY3298176. Participants remained on the lower dose for the remainder of the study. Dose de-escalation was only allowed once during the dose escalation period.
Insulin glargine (Basaglar, Eli Lilly and Company, Indianapolis, IN, USA) was administered once per day via subcutaneous injection with a prefilled pen containing 3 mL (U100/mL), typically before bedtime. Insulin glargine treatment was initiated at 10 U/day and titrated to a fasting blood glucose of less than 100 mg/dL; dose adjustments were made based on the median value of the last three self-monitored fasting blood glucose values.
Participants remained on their background glucose-lowering medications throughout the study. These medications could be reduced or discontinued due to the occurrence of hypoglycaemia. Additional glucose-lowering medications could be used as rescue therapy for persistent hyperglycaemia based on prespecified criteria, or after early discontinuation of study medication, or both. GLP-1 receptor agonists, DPP-4 inhibitors, and pramlintide were not allowed throughout the study.
Following a 1-week screening and 2-week lead-in period, participants were treated for 52 weeks, with the primary efficacy endpoint assessed at this timepoint. For the study to collect additional cardiovascular outcome data in these high-risk individuals, after 52 weeks there was a variable treatment period of up to, but not longer than, an additional 52 weeks. The study concluded with a 4-week safety follow-up period.
Figure 1. Trial profile.Six participants were excluded from the efficacy analyses due to inadvertent enrollment: one each from the LY3298176 5 mg and 15 mg groups, two from the LY3298176 10 mg group, and two from the glargine group. These participants discontinued the study medication. Note that the numbers of participants who discontinued study medication and those excluded from the study may overlap.mITT population = modified intention-to-treat.
Outcomes
The primary endpoint was change in HbA1c from baseline to 52 weeks. Key secondary endpoints were bodyweight change from baseline to 52 weeks and achievement of HbA1c target of less than 7.0% (<53 mmol/mol). Other endpoints included the proportion of participants achieving HbA1c of 6.5% or lower (≤48 mmol/mol) and less than 5.7% (<39 mmol/mol); weight loss of 5% or more, 10% or more, and 15% or more; mean change from baseline in fasting serum glucose (FSG); and daily mean seven-point self-monitored blood glucose profiles, BMI, waist circumference, and serum lipids.
A cardiovascular risk comparison between LY3298176 and glargine was a prespecified safety objective. This comparison was done relative to the four-component composite endpoint of cardiovascular death, myocardial infarction, stroke, and hospitalisation for unstable angina (major adverse cardiovascular events; MACE-4). MACE-4, transient ischaemic attacks, coronary revascularisations, hospitalisations for heart failure, and mortality were adjudicated by an independent clinical endpoint committee (Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH, USA) blinded to treatment allocation.
Additional safety endpoints were treatment-emergent adverse events, study medication discontinuation due to adverse events, adjudicated pancreatic adverse events, serum calcitonin, incidence of hypersensitivity reactions, treatment-emergent anti-drug antibodies for LY3298176, mean changes from baseline in pulse rate, systolic and diastolic blood pressure, need for initiation of rescue therapy for glucose lowering, and occurrence of clinically significant (glucose <54 mg/dL, documented either symptomatic, asymptomatic or unspecified) or severe hypoglycaemia (a severe event characterised by altered mental or physical status, or both, requiring assistance for treatment of hypoglycaemia).
Statistical Analysis
This study was designed to randomly assign participants (1:1:1:3) to LY3298176 5 mg, 10 mg, and 15 mg, and glargine, respectively. The sample size calculation assumed at least a 0.3% (3 mmol/mol) superior HbA1c reduction of LY3298176 10 mg and 15 mg to glargine, a common SD of 1.1% (12 mmol/mol), and no more than 28% initiation of any rescue glucose-lowering medication or premature discontinuation of study medication by 52 weeks. A sample size of 1878 participants in a 1:1:1:3 ratio (313 in each LY3298176 group and 939 in the glargine group) would provide at least 90% power to demonstrate superiority of LY3298176 10 mg and 15 mg to glargine each at a two-sided significance level of 0.025.
The trial was designed to establish superiority of LY3298176 to glargine relative to the primary endpoint of HbA1c change from baseline to 52 weeks with demonstrating non-inferiority of once-per-week administration of LY3298176 to daily administration of glargine, a clinically relevant outcome, as a fallback option, which was designated as the primary objective. Therefore, to control type I error rate non-inferiority of LY3298176 10 mg or 15 mg, or both, to glargine (0.3% non-inferiority boundary) was assessed before assessing superiority.
Two estimands were used to assess treatment efficacy from different perspectives and accounted for intercurrent events differently. First, the efficacy estimand is the treatment effect between LY3298176 and glargine if participants who underwent randomisation continued to receive the study medication without rescue medication. Second, the treatment-regimen estimand is the treatment effect in treated participants regardless of premature study medication discontinuation and rescue medication use.
The analysis aligned to the efficacy estimand for change from baseline in HbA1c was conducted using mixed model for repeated measures (MMRM). The MMRM used treatment, visit, treatment by visit interaction, country, and SGLT2 inhibitor use at baseline as fixed effects, and baseline HbA1c as a covariate. Missing data due to either use of rescue medication, treatment discontinuation, or not being measured, were implicitly handled by the MMRM under the assumption of missing at random.
Because this trial was conducted in participants at high risk for MACE, the incidence of first MACE-4 endpoint was also investigated. The trial was not powered to evaluate differences in MACE-4 incidence between LY3298176 treatment groups and glargine. The study was designed to contribute the majority of the MACE-4 events to the meta-analysis requested by regulatory authorities to evaluate the cardiovascular safety of new glucose-lowering medications.
The primary measure of cardiovascular events was the time to first occurrence of a MACE-4 event. Time to first occurrence of MACE-4 was conducted using Cox proportional hazards model.
Results
The study was initiated on Nov 20, 2018, with participant recruitment continuing until Dec 30, 2019. The study was completed on April 22, 2021. 3045 participants were screened, with 2002 participants randomly assigned to LY3298176 or glargine. 1995 received at least one dose of LY3298176 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%). 1819 (91%) participants had the primary endpoint measured at 52 weeks while still on study medication and 1909 (95%) while in the study. At study end, MACE-4 events had occurred in 109 participants. The median study duration was 85 weeks.
Overall, 1801 (90%) of 1995 participants completed the study, with 1706 (85%) completing study treatment. Among the 1706 participants who completed study treatment, 132 (7%) completed treatment at the 104-week visit, and 1574 (79%) completed treatment at the final treatment visit. The most common reason for premature study medication discontinuation was gastrointestinal-related adverse events in the LY3298176 groups and withdrawal of consent in the insulin glargine group.
Demographics and clinical characteristics were similar across groups. The overall mean duration of diabetes was 11.8 years (SD 7.5), with a mean HbA1c of 8.52% (SD 0.88), and bodyweight of 90.3 kg (SD 18.7). 1738 (87%) participants had a history of cardiovascular disease and 342 (17%) an eGFR of less than 60 mL/min per 1.73 m².
At 52 weeks, mean HbA1c changes with LY3298176 were -2.24% (SE 0.05) at 5 mg, -2.43% (0.05) at 10 mg, and -2.58% (0.05) at 15 mg, versus -1.44% (0.03) with glargine. The estimated treatment difference versus glargine was -0.99% (multiplicity adjusted 97.5% CI -1.13 to -0.86) for LY3298176 10 mg and -1.14% (-1.28 to -1.00) for LY3298176 15 mg. The primary objective of the study, non-inferiority of LY3298176 10 mg or 15 mg, or both, versus glargine for the primary efficacy endpoint, was met, because the upper limits of the CIs were less than 0.3. Superiority of LY3298176 10 mg and 15 mg versus glargine for HbA1c change from baseline to week 52 was also achieved (p<0.0001 for both doses). LY3298176 5 mg was also superior to glargine, with an estimated treatment difference of -0.80% (multiplicity adjusted 95% CI -0.92 to -0.68; p<0.0001).
The profile of HbA1c level over time with LY3298176 treatment indicated a sustained reduction up to 104 weeks. HbA1c of less than 7.0% (<53 mmol/mol) was achieved in 81–91% of LY3298176-treated participants versus 51% with glargine; a HbA1c of 6.5% or lower (≤48 mmol/mol) was achieved in 66–81% of LY3298176-treated participants versus 32% with glargine; and a HbA1c of less than 5.7% (<39 mmol/mol) in 23–43% of LY3298176-treated participants versus 3% with glargine. Changes in FSG were larger with LY3298176 15 mg (-59.3 mg/dL [SE 2.0]) and not different for LY3298176 5 mg (-50.4 mg/dL [2.1]) and 10 mg (-54.9 mg/dL [2.1]) versus glargine (-51.4 mg/dL [1.2]) at 52 weeks.
LY3298176 dose-dependently reduced bodyweight. At 52 weeks, mean bodyweight changes with LY3298176 were -7.1 kg (SE 0.34), -8.1% (SE 0.37) at 5 mg; -9.5 kg (0.34), -10.7% (0.37) at 10 mg; and -11.7 kg (0.33), -13.0% (0.36) at 15 mg versus an increase of 1.9 kg (0.19), 2.2% (0.21) with glargine. All LY3298176 doses demonstrated superiority to glargine with estimated treatment differences of -9.0 kg (95% CI -9.8 to -8.3) at 5 mg, -11.4 kg (-12.1 to -10.6) with 10 mg, and -13.5 kg (-14.3 to -12.8) with 15 mg (all p<0.0001). Bodyweight reductions of 5% or more were achieved in 63–85% of LY3298176-treated participants versus 8% with glargine, 10% or more weight loss was achieved in 36–66% of LY3298176-treated participants versus 2% with glargine, and 15% or more weight loss was achieved in 14–37% of LY3298176-treated participants versus <1% with glargine.
At 52 weeks, mean systolic (-2.8 to -4.8 mm Hg) and diastolic (-0.8 to -1.0 mm Hg) blood pressures decreased with LY3298176 and increased with insulin glargine (systolic 1.3 mm Hg increase and diastolic 0.7 mm Hg increase). The increase in mean pulse rate was 2.9 beats per min (bpm) to 4.1 bpm in LY3298176-treated participants, compared with an increase of 1.2 bpm in glargine-treated participants.
Dose-dependent reductions of serum triglyceride (up to -23%), LDL cholesterol (up to -8%) and non-HDL cholesterol (up to -12%) concentrations at 52 weeks were observed with LY3298176 compared with marginal changes with glargine. The estimated treatment difference versus glargine for percent change in triglycerides at 52 weeks was -10.6 (95% CI -15.2 to -5.7; p<0.0001) for 5 mg, -14.6 (-19.0 to -10.0; p<0.0001) for 10 mg, and -17.2 (-21.4 to -12.8; p<0.0001) for 15 mg LY3298176.
Over the duration of the entire study, 109 participants experienced at least one positively adjudicated component of the composite endpoint of MACE-4. 60 deaths occurred during the study (LY3298176, n=25 [3%] and glargine, n=35 [4%]); none were considered by the investigator to be related to study medication. Six COVID-19-related deaths were recorded in participants treated with LY3298176 (<1%) and eight (<1%) on glargine. Six deaths (<1%) in participants receiving LY3298176 and nine (<1%) in participants receiving glargine were adjudicated as cardiovascular. There was no increased risk of MACE-4 events for pooled LY3298176 versus glargine, hazard ratio 0.74 (95% CI 0.51 to 1.08).
Over the entire study, diarrhoea was reported in 13–22% of patients on LY3298176 versus 4% on glargine, nausea in 12–23% on LY3298176 versus 2% on glargine, decreased appetite in 9–11% on LY3298176 versus less than 1% on glargine, and vomiting in 5–9% on LY3298176 versus 2% on glargine. Most cases of nausea, vomiting, and diarrhoea were mild to moderate and were reported more frequently in all LY3298176 groups during the dose-escalation period. After the initial 24-week dose escalation, a diminishing number of participants on LY3298176 reported treatment emergent gastrointestinal side-effects. In addition, events occurring in the later phase of the study were more commonly mild and less frequently severe when compared with the dose-escalation phase.
Clinically significant (<54 mg/dL) or severe hypoglycaemia was reported in 76 (8%) participants in pooled LY3298176 groups (29 [9%] on 5 mg, 20 [6%] on 10 mg, and 27 [8%] on 15 mg), and 191 (19%) on glargine; participants receiving LY3298176 had a total of 145 episodes and those receiving glargine had 492 episodes. More hypoglycaemic events were reported in participants who also used sulfonylureas. Hypoglycaemia of 70 mg/dL or less, or severe, occurred in 33–38% of LY3298176-treated participants and 64% on glargine; 2112 episodes were reported with LY3298176 and 7882 with glargine.
Adjudicated cases of pancreatitis occurred with LY3298176 (5 mg n=3 [<1%]; 10 mg n=2 [<1%]; and 15 mg n=1 [<1%]) and glargine (n=1 [<1%]). Five (<1%) cases of cholelithiasis were reported with LY3298176 and four (<1%) with glargine. No clinically relevant changes in mean calcitonin levels were observed and no cases of medullary thyroid hyperplasia or cancer were reported.
Discussion
In this study of individuals with long-standing type 2 diabetes at high cardiovascular risk and inadequately controlled glycaemia with up to three oral glucose-lowering medications, including sulfonylureas, all three doses of the dual GIP and GLP-1 receptor agonist LY3298176 markedly improved glucose control, reduced bodyweight, and improved the cardiovascular risk profile. A higher proportion of participants reached the glycaemic targets with fewer clinically significant hypoglycaemic events when treated with LY3298176 versus glargine. The study also suggests, for the first time in a population with long-standing diabetes at elevated cardiovascular disease risk, that the glycaemic and weight benefits of LY3298176 can be sustained beyond 1 year. Importantly, these benefits were achieved with no increased risk for MACE-4.
The active comparator glargine (100 U/mL) has been used in treat-to-target studies and shown to be safe from a cardiovascular standpoint. In the present study, the doses of glargine used and the fasting glucose achieved suggest that the glargine titration algorithm was followed appropriately. Comparison of LY3298176 to titrated glargine demonstrated a dose-dependent superiority of all three LY3298176 doses on glucose control. Large proportions (81–91%) of participants receiving LY3298176 achieved the American Diabetes Association–European Association for the Study of Diabetes glycaemic control target of a HbA1c less than 7% compared with 51% receiving glargine, and 23–43% attained a HbA1c of less than 5.7%, defined as the upper limit of normal by many organisations compared with 3% of those receiving glargine.
The changes in glycaemia and weight after 52 weeks of LY3298176 treatment are similar in magnitude to those observed in other studies that compared LY3298176 with placebo, injectable semaglutide, and the long-acting insulin degludec. However, these studies lasted 40–52 weeks and were conducted in cohorts with a shorter duration of diabetes and with a lower proportion of people with a history of cardiovascular disease compared with the current study.
The changes in fasting glucose were similar across all four study groups. Therefore, the better overall glycaemic control achieved with LY3298176 could be attributable to the more effective control of preprandial glycaemia and, to a larger extent, postprandial glycaemia, as shown by lower mean seven-point self-monitored blood glucose levels.
The main challenge in achieving target HbA1c of less than 7% in vulnerable people with type 2 diabetes is hypoglycaemia. The greater improvement in glucose control with LY3298176 treatment was achieved with fewer participants experiencing clinically significant (<54 mg/dL) or severe hypoglycaemia. Furthermore, the total number of hypoglycaemic events was lower with LY3298176 compared with glargine, with nearly all events on LY3298176 occurring in participants using sulfonylureas at baseline. These data suggest that LY3298176 is an effective and safe glucose-lowering agent.
The long study duration also allowed examination of the bodyweight profile and other cardiovascular risk factors over time. In previous studies with LY3298176, the profile of bodyweight reduction had not reached a plateau by 40–52 weeks. Although progressively fewer individuals completed study visits in the variable treatment period, the observations suggest the maximal effect achieved after 1 year can be maintained for up to an additional 9–12 months with LY3298176.
Favourable changes have been observed in blood pressure, irrespective of the wide use of diverse blood pressure-lowering medications in the study population. These changes are in line with findings in GLP-1 receptor agonist cardiovascular outcome trials and could contribute to the cardiovascular safety of LY3298176. In the present study, LY3298176 favourably impacted the lipoprotein profile, including reductions in triglyceride, non-HDL and LDL cholesterol, and these changes were maintained throughout the trial. These favourable changes are larger than typically observed with GLP-1 receptor agonists. In a head-to-head study between LY3298176 5 mg, 10 mg, and 15 mg and semaglutide 1 mg, LY3298176 reduced the concentrations of triglyceride and very low-density lipoprotein cholesterol to a greater extent than semaglutide.
The inclusion of participants with high-risk cardiovascular profiles who were followed up for up to 104 weeks showed no difference in MACE-4 events with LY3298176 compared with glargine, the latter having been demonstrated to be safe from a cardiovascular perspective. These results suggest that there is no excess cardiovascular risk with LY3298176, and are consistent with the beneficial changes in numerous surrogate markers of cardiovascular health, including weight reduction, glycaemic control with less hypoglycaemia, blood pressure reduction, and improvements in the lipoprotein profile.
The adverse event profile of LY3298176 was similar to selective GLP-1 receptor agonists and adverse events were mainly gastrointestinal in nature (nausea, vomiting, and diarrhoea). These side-effects, however, were generally mild to moderate and occurred in diminishing frequency after dose escalation. Similar to this study, gastrointestinal side-effects and medication discontinuation due to these events were more frequent in all GLP1-RA medications when compared with glargine (100 U/mL).
The current study has certain limitations. First, the interventions were not blinded because of differences in devices and dose-escalation schemes. Second, since the variable treatment period beyond 52 weeks was designed to collect longer-term safety data and achieve a predefined number of MACE-4, not all participants were treated for 104 weeks. The strengths of this study are the large sample size, the selection of glargine, a commonly used insulin with proven cardiovascular safety, a successful treat-to-target titration of glargine, and a duration that goes beyond any previous experience with LY3298176.
Conclusion
In people with long-standing type 2 diabetes and high cardiovascular risk, LY3298176 demonstrated superiority and sustainability in overall glycaemic control and weight reduction compared with glargine. Given the progressive nature of type 2 diabetes, evaluating the durability of glycaemic and weight effects of dual incretin receptor agonists like LY3298176 is important to determine the expected therapeutic benefits. The improvement in cardiovascular risk profile and distribution of cardiovascular events between treatment groups suggests that LY3298176 is safe from a cardiovascular perspective; further definitive studies are required to assess cardiovascular safety, as well as potential cardiovascular protection.