key: cord-0022186-jasasn9z
authors: Frias, Juan P.; Bonora, Enzo; Nevárez Ruiz, Luis; Hsia, Stanley H.; Jung, Heike; Raha, Sohini; Cox, David A.; Bethel, M. Angelyn; Konig, Manige
title: Efficacy and safety of dulaglutide 3.0 and 4.5 mg in patients aged younger than 65 and 65 years or older: Post hoc analysis of the AWARD‐11 trial
date: 2021-07-08
journal: Diabetes Obes Metab
DOI: 10.1111/dom.14469
sha: f80c947b07c8ff5172668e3da8ba9beee37393e0
doc_id: 22186
cord_uid: jasasn9z

AIM: To evaluate the efficacy and safety of dulaglutide 3.0 and 4.5 mg versus 1.5 mg when used as an add‐on to metformin in subgroups defined by age (<65 and ≥65 years). MATERIALS AND METHODS: Of 1842 patients included in this post hoc analysis, 438 were aged 65 years or older and 1404 were younger than 65 years. The intent‐to‐treat (ITT) population, while on treatment without rescue medication, was used for all efficacy analyses; the ITT population without rescue medication was used for hypoglycaemia analyses; all other safety analyses used the ITT population. RESULTS: Patients aged 65 years or older and those younger than 65 years had a mean age of 69.5 and 53.2 years, respectively. In each age subgroup, the reduction from baseline in HbA1c and body weight (BW), and the proportion of patients achieving a composite endpoint of HbA1c of less than 7% (<53 mmol/mol) with no weight gain and no documented symptomatic or severe hypoglycaemia, were larger for dulaglutide 3.0 and 4.5 mg compared with dulaglutide 1.5 mg, but the treatment‐by‐age interactions were not significant. The safety profile for the additional dulaglutide doses was consistent with that of dulaglutide 1.5 mg and was similar between the age subgroups. CONCLUSION: Dulaglutide doses of 3.0 or 4.5 mg provided clinically relevant, dose‐related improvements in HbA1c and BW with no significant treatment‐by‐age interactions, and with a similar safety profile across age subgroups.

Type 2 diabetes (T2D), which accounts for more than 90% of patients with diabetes, 1 is a health condition increasing in prevalence among the ageing population. 2 Approximately 40% of the adult population with diabetes in the United States is older than 65 years, 3 and the number of older adults living with this condition is expected to increase rapidly in the coming decades. 4 Older patients with T2D have an increased risk of many co-morbidities, including cognitive dysfunction, cardiovascular disease (CVD), frailty, chronic kidney disease, retinopathy and peripheral neuropathy, affecting manual dexterity and physical ability. [5] [6] [7] These may predispose this patient population to an increased risk of recurring hypoglycaemia and hypoglycaemiaassociated morbidity, particularly in patients treated with insulin.

Co-morbidities may affect accurate insulin dosing and insulin clearance, and hypoglycaemic events increase the risk of falls and/or additional cardiovascular-related morbidity. Therefore, the use of insulin therapy, particularly in elderly patients with T2D diabetes, is limited by the risk of hypoglycaemia. 8, 9 Guideline changes by the American Diabetes Association (ADA) now recommend personalizing treatment for older patients with T2D

based on their functional status and co-morbidities. Less stringent glycaemic treatment goals are recommended for frail elderly patients to keep the risk of hypoglycaemia low while also taking co-morbid illness and/or limited life expectancy into consideration. 4 Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are recommended as first-line therapy in combination with metformin, irrespective of the HbA1c level, in patients who either are at high risk or have pre-existing atherosclerotic cardiovascular disease (ASCVD), heart failure or chronic kidney disease. Additionally, GLP-1 RAs and SGLT-2is are the preferred second treatment option after metformin for patients who would benefit from weight loss, while GLP-1 RAs, SGLT-2is, dipeptidyl peptidase-4 inhibitors and thiazolidinedione are recommended after metformin for patients with increased hypoglycaemic risk. 10, 11 These guidelines also pertain to older adults, particularly those with pre-existing CVD and increased risk of hypoglycaemia 4 ; however, as with any other pharmacotherapy, they need to be used cautiously according to a patient's history, profile and individualized needs.

Prior Assessment of Weekly AdministRation of LY2189265 in Diabetes (AWARD) studies have shown that dulaglutide at 0.75 and 1.5 mg once-weekly is effective for glycaemic control and well tolerated in elderly patients with T2D. 9, 12 In the AWARD-11 study, dulaglutide 3.0 and 4.5 mg once-weekly provided clinically relevant, dose-related improvements in glycaemic control and body weight (BW) in patients with T2D inadequately controlled with metformin monotherapy. 13 The safety profile was comparable with the 1.5 mg dose through 52 weeks and consistent with prior dulaglutide studies in the AWARD trial programme. The AWARD-11 study enrolled nearly one quarter of patients aged 65 years or older. We conducted a post hoc analysis to examine the efficacy and safety of these additional dulaglutide doses in this elderly population.

The study design of the AWARD-11 trial was previously described in detail. 13 Briefly, this randomized, phase 3, double-blind, multicentre, parallel-arm study (ClinicalTrials.gov identifier: NCT03495102) included a 2-week lead-in period, followed by a 52-week treatment period (with primary efficacy endpoint at 36 weeks), and a 4-week safety follow-up period. Patients initiated treatment with dulaglutide 0.75 mg for 4 weeks, followed by stepwise dose escalation every 4 weeks to the randomized dose of 1.5, 3.0 or 4.5 mg ( Figure S1 ).

The key eligibility criteria of the AWARD-11 trial were age 18 years or older, HbA1c of 7.5% or higher (≥58 mmol/mol) and 11.0% or less (≤97 mmol/mol), body mass index (BMI) of 25 kg/m 2 or higher, and patients were taking commercially available metformin.

For this post hoc exploratory analysis, the primary efficacy measure was the change in HbA1c from baseline to 36 weeks in subgroups defined by age (<65 and ≥65 years). Secondary efficacy measures (all assessed at 36 weeks) were the change from baseline in BW and the proportion of patients achieving an HbA1c of less than 7.0% (<53 mmol/mol). Patients performed fasting plasma glucose measurements once-daily, four-point self-monitored blood glucose (SMBG) measurements once-weekly, and six-point SMBG during the week preceding clinic visits. Safety assessments at 52 weeks included incidence of treatment-emergent adverse events (TEAEs), discontinuation of study drug because of adverse events (AEs), adjudicated and confirmed cardiovascular (CV) and pancreatic AEs, and occurrence of hypoglycaemic episodes. Hypoglycaemic episodes were collected on a dedicated case report form, including cases where SMBG was 70 mg/dL or less (≤3.9 mmol/L), regardless of whether symptoms were experienced. As defined by the ADA, events were categorized as documented symptomatic hypoglycaemia any time patients felt they were experiencing symptoms and/or signs associated with hypoglycaemia and had a plasma glucose level of 70 mg/dL or less (≤3.9 mmol/L). Severe hypoglycaemia was defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. Total hypoglycaemic events were defined as an episode with a plasma glucose level below the defined threshold, regardless of symptoms, an episode of symptomatic hypoglycaemia where the plasma glucose level was not measured, and all severe hypoglycaemia episodes. 14, 15 Although 65 years is the most common age cut point used for subgroup analyses reported in clinical trials, [16] [17] [18] [19] [20] [21] some studies define 70 years as the cut point for elderly patients. 22 Thus, we also compared the effects of dulaglutide dose escalation on change in HbA1c and BW from baseline and the proportion of patients achieving an HbA1c of less than 7.0% (<53 mmol/mol) at 36 weeks using a cut point of 70 years. Safety assessments were also carried out in these subgroups of patients aged less than 70 and 70 years or older.

The safety and efficacy analyses were performed using the intent-totreat (ITT) population, defined as all patients randomized who received at least one dose of study drug. Efficacy analyses excluded measurements collected after discontinuation of study drug or initiation of another antihyperglycaemic medication ('on-treatment without rescue analysis'). The analysis for hypoglycaemia was performed using the ITT population excluding observations after rescue medication. All tests of treatment effects were conducted at a two-sided alpha level of .05, unless otherwise specified. All tests of interactions between treatments and factors of interest were conducted at a two-sided alpha level of .10. were younger than 65 years of age.

At baseline, in the subgroup aged 65 years or older, the average age was 69.5 years, with a mean HbA1c of 8.4% (68.3 mmol/mol), mean BW of 90.0 kg and mean BMI of 32.9 kg/m 2 . The mean duration of disease was 9.9 years, and females comprised 48.4% of patients. In the subgroup younger than 65 years of age, the average age was 53.2 years, with a mean HbA1c of 8.7% (71.6 mmol/mol), mean BW of 97.5 kg and mean BMI of 34.7 kg/m 2 . The mean duration of disease was 6.9 years, and females comprised 48.9% of patients. Baseline data for fasting serum glucose, systolic blood pressure, diastolic blood pressure, mean baseline estimated glomerular filtration rate (eGFR), eGFR categories and patient CV risk factors are also presented in Table 1 . Within each age subgroup, these baseline characteristics were comparable among treatment groups ( Table 1) .

As expected, patients aged 65 years or older had a longer duration of T2D and a higher prevalence of renal impairment, hypertension, dyslipidaemia, history of CVD and atrial fibrillation.

In patients younger than 65 years, the least-squares mean (LSM) change in HbA1c from baseline to week 36 was À1.74% and À1.94% with dulaglutide 3.0 and 4.5 mg, respectively, compared with À1.59% for dulaglutide 1.5 mg ( Figure 1A ). In the subgroup aged 65 years or older, similar results were observed, as the LSM change in HbA1c from baseline to week 36 was À1.58% and À1.65% with dulaglutide 3.0 and 4.5 mg, respectively, compared with À1.33% for dulaglutide 1.5 mg ( Figure 1A ). The results for both age subgroups were in line with those seen in the overall study population ( Figure 1A) , with no statistically significant treatment-by-age subgroup interaction for HbA1c reduction (interaction P = .591).

In patients younger than 65 years, the LSM change in BW from baseline to week 36 was À3.9 and À4.8 kg with dulaglutide 3.0 and 4.5 mg, respectively, compared with À3.1 kg for dulaglutide 1.5 mg ( Figure 1B ). Comparing these results with patients in the 65 years or older subgroup, a similar trend was observed. The LSM change in BW from baseline was À4.3 and À4.5 kg with dulaglutide 3.0 and 4.5 mg, respectively, compared with À3.1 kg for dulaglutide 1.5 mg at 36 weeks ( Figure 1B ). The results for both age subgroups were in line with those seen in the overall study population ( Figure 1B) , with no statistically significant treatment-by-age subgroup interaction for change in BW (interaction P = .510).

In both age subgroups, the proportion of patients achieving the HbA1c target of less than 7% with no weight gain or documented symptomatic or severe hypoglycaemia at the primary endpoint of 36 weeks was significantly higher (P ≤ .034) for the additional dulaglutide doses (3.0 and 4.5 mg) in comparison with dulaglutide 1.5 mg ( Figure 1C ). The proportions of patients achieving this composite target in both age subgroups were in line with those seen in the overall study population ( Figure 1C ), with no statistically significant treatment-by-age subgroup interaction (interaction P = .506).

Similar results were obtained for patients younger than 70 and those aged 70 years or older, with no statistically significant treatment-by-age subgroup interaction for HbA1c reduction from baseline (interaction P = .937), weight change from baseline (interaction P = .376), or the proportion of patients reaching the HbA1c target of less than 7% with no weight gain or documented symptomatic or severe hypoglycaemia (interaction P = .717) ( 

The most frequent TEAE experienced in both age subgroups was nausea, which ranged from 12.1% to 18.7%, followed by diarrhoea (range, 7.5% to 12.7%), vomiting (range, 6.4% to 10.7%), dyspepsia (range, 2.3% to 8.7%) and nasopharyngitis (range, 4.2% to 8.3%) ( Table 2 ). There was no statistically significant treatment-by-age subgroup interaction for any of these TEAEs (interaction P = .383). The incidence of TEAEs related to a composite of supraventricular arrythmias, conduction disorders and adjudicated CV events was low and was similar across dose groups, with no significant treatment-byage subgroup interaction (interaction P = .963).

The incidence of all AEs reported as serious (serious adverse events [SAEs]) was low across dose groups in each age subgroup ( .904

Atrial fibrillation Incidence of documented symptomatic hypoglycaemia (<70 mg/ dL) was not different between treatment groups, and the treatmentby-age subgroup interaction was not significant (interaction P = .293).

Similarly, no difference was observed between treatment groups with a non-significant treatment-by-age subgroup interaction (interaction P = .422) for total hypoglycaemia incidence ( Similar safety results were obtained for patients younger than 70 and those aged 70 years or older with non-statistically significant treatment-by-age subgroup interactions for safety assessments, except for nausea, which was higher in the 70 years or older subgroup (interaction P = .054) ( Table 3) . This was probably driven by the small number of patients in the 70 years or older subgroup in combination with the higher incidence in the lowest dulaglutide dose group (1.5 mg) relative to the higher dose groups (3.0 and 4.5 mg). No statistically significant treatment-by-age subgroup interactions were observed for discontinuation of study drug because of AEs, SAEs or incidences of hypoglycaemia (Table 3 ).

The AWARD-11 trial showed that dulaglutide 3.0 or 4.5 mg versus The tolerability profile of dulaglutide across all three dose groups was comparable between age groups. As expected, the most common TEAEs reported across all doses in AWARD-11 were nausea, vomiting and diarrhoea. In the overall study population, the incidence of nausea was similar across dose groups, whereas diarrhoea and vomiting were more frequently reported in the 3.0 and 4.5 mg groups. 13 In the current subgroup analysis, there was no dose relationship between reports of common gastrointestinal (GI) events in the older age subgroup compared with the younger age subgroup, and the overall incidences of these events among older patients was generally similar to those reported in the younger age group. Cardiac complications (arrythmias, conduction disorders and CV events) were also similar across doses and age subgroups. Discontinuations of study drug as a result of any AE or specifically because of nausea, vomiting or diarrhoea were not significantly different among older versus younger patients, further supporting the conclusion that overall and GI tolerability of dulaglutide across the dose range studied in AWARD-11 are similar between age groups, consistent with prior studies with lower doses of dulaglutide. 9, 12 The dulaglutide safety profile related to SAEs was also comparable between age groups across all doses. The incidence of SAEs was not dose-related in either age subgroup.

This analysis has certain limitations that may influence the interpretation and generalizability of the results. With no evidence of treatment-by-age interaction, the most appropriate estimate of the effect size for any of the endpoints is that observed in the overall population of the trial; however, it is reassuring that further exploratory subgroup analysis by age remains consistent with the overall results for the 

The peer review history for this article is available at https://publons. com/publon/10.1111/dom.14469.

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Efficacy and safety of dulaglutide 3.0 and 4.5 mg in patients aged younger than 65 and 65 years or older: Post hoc analysis of the AWARD-11 trial