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Trulicity ® (dulaglutide)
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What is the incidence of hypoglycemia with Trulicity® (dulaglutide) use?
Episodes of hypoglycemia have been reported in clinical trials of dulaglutide. Concomitant use of dulaglutide with an insulin secretagogue (eg, sulfonylurea) or insulin may increase the risk of hypoglycemia.
Content overview
Important Recommendations from the Summary of Product Characteristics
Patients receiving dulaglutide in combination with sulphonylurea or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemia may be lowered by a reduction in the dose of sulphonylurea or insulin.1
The use of dulaglutide does not require blood glucose self‑monitoring. Blood glucose self-monitoring is necessary to adjust the dose of sulphonylurea or insulin, particularly when dulaglutide therapy is started and insulin is reduced. A stepwise approach to insulin dose reduction is recommended.1
When dulaglutide is added to existing
- metformin and/or pioglitazone therapy, or
- metformin and/or sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy
the current dose of metformin and/or pioglitazone or SGLT2i, respectively, can be continued. 1
Use of Dulaglutide With Medications Known to Cause Hypoglycemia
Patients receiving dulaglutide in combination with an insulin secretagogue, like sulfonylureas, or insulin may have an increased risk of hypoglycemia. The risk of hypoglycemia may be lowered by a reduction in the dose of
- insulin secretagogue, or
- insulin.2
Hypoglycemia With Dulaglutide Use in Adults
Hypoglycemia in the AWARD Studies
Across the AWARD studies, documented symptomatic hypoglycemia was defined as a plasma glucose (PG) ≤3.9 mmol/L (≤70 mg/dL) with or without signs or symptoms associated with hypoglycemia while severe hypoglycemia was defined as a hypoglycemic event that required the assistance of another person for treatment. Hypoglycemic events that occurred between bedtime and waking were designated as nocturnal.3-12
AWARD Studies in Which Patients Received Dulaglutide Without Concomitant Treatment With a Sulfonylurea or Insulin
Across the 5 AWARD studies, the incidence of documented symptomatic hypoglycemia ranged from
- 1.4% to 10.9% in the dulaglutide 1.5 mg treatment groups, and
- 2.1% to 6.3% in the dulaglutide 0.75 mg treatment groups.2-7
Of the patients treated with dulaglutide, severe hypoglycemia was only reported in 1 patient who received dulaglutide 0.75 mg.7
In the 5 AWARD studies in which dulaglutide was not used concomitantly with a sulfonylurea or insulin, the duration of the studies ranged from 24 to 104 weeks. The incidence and mean rate, defined as episodes/patient/year, of documented symptomatic and severe hypoglycemia were similar across treatment groups (Incidence and Rate of Documented Symptomatic and Severe Hypoglycemia Through Final Study Endpoint in AWARD Studies in Which Patients Received Dulaglutide Without concomitant Treatment With a Sulfonylurea or Insulin).3-7
Hypoglycemiaa |
Dulaglutide |
Dulaglutide |
Comparator |
n=269 |
n=270 |
Metformin |
|
Documented symptomatic, PG ≤3.9 mmol/L (≤70 mg/dL) |
6.3 (0.62) |
5.9 (0.15) |
4.9 (0.09) |
Severe |
0 (0.0) |
0 (0.0) |
0 (0.0) |
n=304 |
n=302 |
Sitagliptin |
|
Documented symptomatic, PG ≤3.9 mmol/L (≤70 mg/dL) |
10.9 (0.19) |
6.3 (0.18) |
5.7 (0.17) |
0.7 |
0.3 |
0 |
|
Severe |
0 (0.0) |
0 (0.0) |
0 (0.0) |
n=299 |
NA |
Liraglutide |
|
Documented symptomatic, PG ≤3.9 mmol/L (≤70 mg/dL) |
2.7 (0.12) |
NA |
2.7 (0.29) |
Severe |
0 (0.0) |
NA |
0 (0.0) |
n=279 |
n=280 |
Exenatide Twice Daily |
|
Documented symptomatic, PG ≤3.9 mmol/L (≤70 mg/dL) |
6.5 (0.19) |
6.1 (0.14) |
13.4 (0.75) |
1.4 |
2.1 |
0 |
|
Severe |
0 (0.0) |
0 (0.0) |
0.7 (0.01) |
n=142 |
n=141 |
Placebo |
|
Documented symptomatic, PG ≤3.9 mmol/L (≤70 mg/dL) |
1.4 (0.16) |
2.1 (0.15) |
2.1 (0.12) |
0.7 |
0.7 |
0.7 |
|
Severe |
0 (0.0) |
0.7 (0.02) |
0 (0.0) |
Abbreviations: NA = not applicable; PG = plasma glucose; SGLT-2 = sodium-glucose cotransporter-2.
aData presented as percentage of patients (mean rate); rate = episodes/patient/year. Documented symptomatic hypoglycemia was defined as a PG ≤3.9 mmol/L (≤70 mg/dL) with or without signs or symptoms associated with hypoglycemia. Severe hypoglycemia was defined as a hypoglycemic event that required the assistance of another person for treatment.
bEndpoint 52 weeks.
cEndpoint 104 weeks.
dData presented as mean rate percentage.
eEndpoint 26 weeks.
fCanagliflozin, dapagliflozin, or empagliflozin.
gEndpoint 24 weeks.
Hypoglycemia in the AWARD-11 Study
The AWARD-11 trial was a phase 3, randomized, double-blind, active-controlled, parallel-arm study that assessed the efficacy and safety of dulaglutide 3.0 mg and dulaglutide 4.5 mg compared to dulaglutide 1.5 mg in adults with inadequately controlled type 2 diabetes on concomitant metformin therapy.14,15
Patients were treated for 52 weeks, which included a 12-week dose-escalation phase (Dulaglutide Dose Escalation Design in AWARD-11).2
Figure 1 description: The AWARD-11 study consisted of 3 phases. The first was a 2-week screening and lead-in period. This was followed by a 52-week treatment period, with primary efficacy endpoint at 36 weeks, and a 4-week safety follow-up period. At the end of the lead-in period, patients were randomized in a 1:1:1 ratio into 3 groups: Dulaglutide 1.5 mg, 3.0 mg, and 4.5 mg once weekly. Dose escalation took place over a 12-week period. All 3 treatment arms began with dulaglutide 0.75 mg for 4 weeks, then dulaglutide 1.5 mg for 4 weeks, then either dulaglutide 1.5 mg or 3.0 mg for another 4 weeks before finally reaching the study dose of 1.5 mg, 3.0 mg, or 4.5 mg once weekly. All patients received concomitant metformin throughout the lead-in, treatment, and safety follow-up periods.
Abbreviation: DU = dulaglutide.
From baseline through 36 weeks, hypoglycemia, identified as a glucose level <3 mmol/L (<54 mg/dL), was reported by
- 7 of 612 (1.1%) patients on dulaglutide 1.5 mg,
- 2 of 616 (0.3%) patients on dulaglutide 3 mg, and
- 7 of 614 (1.1%) patients on dulaglutide 4.5 mg.2
From baseline through 36 weeks, severe hypoglycemia was experienced by
- 1 of 612 (0.2%) patient on dulaglutide 1.5 mg,
- 0 of 616 (0%) patients on dulaglutide 3 mg, and
- 1 of 614 (0.2%) patient on dulaglutide 4.5 mg.2
There was a consistent pattern of dose-related improvement in glycated hemoglobin (HbA1c), body weight, and proportion of patients achieving glycemic target of HbA1c <7% at 36 and 52 weeks in patients escalated to dulaglutide 3.0 mg and 4.5 mg compared to patients maintained on dulaglutide 1.5 mg.14-16
Hypoglycemia findings through 52 weeks from the AWARD-11 study is provided in Hypoglycemia Through 52 Weeks in AWARD-11.
Hypoglycemiaa |
DULA 1.5 mg |
DULA 3.0 mg |
DULA 4.5 mg |
Documented symptomaticb |
8 (1.3) |
2 (0.3) |
7 (1.1) |
Severec |
1 (0.2) |
0 (0.0) |
1 (0.2) |
Abbreviations: DULA = dulaglutide; PG = plasma glucose.
aAll values presented as n (%); AEs presented as number of patients with ≥1 event.
bPG <3 mmol/L (<54 mg/dL).
cAn episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
AWARD Studies in Which Patients Received Dulaglutide and Concomitant Treatment With a Sulfonylurea or Insulin
Across the 5 AWARD studies, the incidence of documented symptomatic hypoglycemia ranged from
- 11.3% to 80.8% in the dulaglutide 1.5 mg treatment groups, and
- 39% to 85.6% in the dulaglutide 0.75 mg treatment groups.8-12
The incidence of nocturnal hypoglycemia ranged from
- 6.7% to 54.3% in the dulaglutide 1.5 mg treatment groups, and
- 23.2% to 53.8% in the dulaglutide 0.75 mg treatment groups.8-12
The incidence of severe hypoglycemia ranged from
- 0% to 3.4% in the dulaglutide 1.5 mg treatment groups, and
- 0% to 3% in the dulaglutide 0.75 mg treatment groups.8-12
AWARD Studies With Insulin Glargine as Comparator
Hypoglycemia in the REWIND Study
REWIND was an event-driven, randomized, double-blind, placebo-controlled study of dulaglutide.17
The study evaluated the effect on major adverse cardiovascular events (death due to cardiovascular causes or unknown causes, nonfatal myocardial infarction, or nonfatal stroke) (MACE-3) and other serious outcomes with once-weekly dulaglutide 1.5 mg treatment compared with placebo when added to standard of care in participants 50 years of age and older with type 2 diabetes and established CV disease and/or risk factors.18
The median follow-up time in REWIND was 5.4 years.18
In REWIND, hypoglycemia was reported as a TEAE by
- 459 of 4949 (9.27%) patients receiving dulaglutide 1.5 mg, and
- 411 of 4952 (8.30%) patients receiving placebo.2
Additionally, hypoglycemia led to permanent discontinuation of study drug in
- 5 of 4949 (0.10%) patients receiving dulaglutide 1.5 mg, and
- 0 of 4952 (0%) patients receiving placebo.2
Higher proportion of patients permanently discontinued the study drug in dulaglutide 1.5 mg group than placebo group (p=.031).2
In REWIND, severe hypoglycemia was captured as a prespecified adverse event of special interest.18
During REWIND, severe hypoglycemia was reported in
- 64 of 4949 (1.3%) patients who received dulaglutide 1.5 mg, and
- 74 of 4952 (1.5%) patients who received placebo.18
Dulaglutide did not differ significantly from placebo in frequencies of prespecified adverse events of special interest including severe hypoglycemia.18
Hypoglycemia With Dulaglutide Use in Pediatric Population
Hypoglycemia in the AWARD-PEDS Study
AWARD-PEDS was a phase 3, randomized, placebo-controlled study that assessed the efficacy and safety of dulaglutide 0.75 mg and 1.5 mg in pediatric patients, ages 10 to less than 18 years old, with inadequately controlled type 2 diabetes despite diet and exercise, with or without metformin and/or basal insulin.19
The study included a 26-week double-blinded period, followed by a 26-week open-label period.19
During the 26-week open-label period, patients previously randomized to placebo were initiated on dulaglutide 0.75 mg. Patients previously randomized to 0.75 mg and 1.5 mg remained on their assigned doses through 52 weeks (if tolerated).19
The primary endpoint of AWARD-PEDS was to show superiority of dulaglutide (0.75 mg and 1.5 mg, pooled doses) versus placebo for change in glycated hemoglobin (HbA1c) at 26 weeks.19
Overall, the safety findings from AWARD-PEDS were consistent with the safety profile observed in adults.19
Incidences of hypoglycemic episodes during the AWARD-PEDS study through 26 weeks and 52 weeks are presented inIncidence of Hypoglycemia During the 26-Week Placebo-Controlled Trial Period in AWARD-PEDS and Incidence of Hypoglycemia Through 52 Weeks in AWARD-PEDS, respectively.
Parametera |
Pooled DULA |
DULA 1.5 mg |
DULA 0.75 mg |
PBO |
Documented symptomatic hypoglycemiab |
8 (8) |
3 (6) |
5 (10) |
6 (12) |
Plasma glucose <3 mmol/L (<54 mg/dL) |
4 (4) |
2 (4) |
2 (4) |
1 (2) |
Severe hypoglycemiac |
0 |
0 |
0 |
0 |
Abbreviations: DULA = dulaglutide; PBO = placebo.
aData presented as n (%).
bPlasma glucose <3.9 mmol/L (<70 mg/dL).
cDefined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
Parametera |
Pooled DULA |
DULA 1.5 mg |
DULA 0.75 mg |
PBO/DULA 0.75 mgb |
Documented symptomatic hypoglycemiac |
12 (11.7) |
5 (9.6) |
7 (13.7) |
6 (11.8) |
Plasma glucose <3 mmol/L (<54 mg/dL) |
4 (3.9) |
2 (3.9) |
2 (3.9) |
1 (1.0) |
Severe hypoglycemiad |
0 |
0 |
0 |
0 |
Abbreviations: DULA = dulaglutide; PBO = placebo.
aData presented as n (%).
bAt the end of week 26, participants who were receiving placebo started receiving dulaglutide 0.75 mg.
cPlasma glucose <3.9 mmol/L (<70 mg/dL).
dDefined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
References
1Trulicity [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2Data on file, Eli Lilly and Company and/or one of its subsidiaries.
3Umpierrez G, Povedano ST, Manghi FP, et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care. 2014;37(8):2168-2176. https://doi.org/10.2337/dc13-2759
4Weinstock RS, Guerci B, Umpierrez G, et al. Safety and efficacy of once-weekly dulaglutide versus sitagliptin after 2 years in metformin-treated patients with type 2 diabetes (AWARD-5): a randomized, phase III study. Diabetes Obes Metab. 2015;17(9):849-858. http://dx.doi.org/10.1111/dom.12479
5Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384(9951):1349-1357. https://doi.org/10.1016/S0140-6736(14)60976-4
6Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care. 2014;37(8):2159-2167. https://doi.org/10.2337/dc13-2760
7Ludvik B, Frías JP, Tinahones FJ, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6(5):370-381. https://doi.org/10.1016/S2213-8587(18)30023-8
8Dungan KM, Weitgasser R, Perez Manghi F, et al. A 24-week study to evaluate the efficacy and safety of once-weekly dulaglutide added on to glimepiride in type 2 diabetes (AWARD-8). Diabetes Obes Metab. 2016;18(5):475-482. http://dx.doi.org/10.1111/dom.12634
9Giorgino F, Benroubi M, Sun JH, et al. Efficacy and safety of once-weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and glimepiride (AWARD-2). Diabetes Care. 2015;38(12):2241-2249. https://doi.org/10.2337/dc14-1625
10Pozzilli P, Norwood P, Jódar E, et al. Placebo-controlled, randomized trial of the addition of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes (AWARD-9). Diabetes Obes Metab. 2017;19(7):1024-1031. http://dx.doi.org/10.1111/dom.12937
11Blonde L, Jendle J, Gross J, et al. Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study. Lancet. 2015;385(9982):2057-2066. https://doi.org/10.1016/S0140-6736(15)60936-9
12Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 2018;6(8):605-617. https://doi.org/10.1016/S2213-8587(18)30104-9
13Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Company; 2022.
14Frias JP, Nevárez Ruiz L, Li YG, et al. Efficacy and safety of higher dulaglutide doses (3.0 mg and 4.5 mg) when added to metformin in patients with type 2 diabetes: a phase 3, randomized, double-blind, parallel arm study (AWARD-11). J Endocr Soc. 2020;4(suppl 1):A1036. Endocrine Society abstract OR26-08. https://doi.org/10.1210/jendso/bvaa046.2057
15Frias JP, Bonora E, Nevarez Ruiz L, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care. 2021;44(3):765-773. https://doi.org/10.2337/dc20-1473
16Frias JP, Bonora E, Nevarez Ruiz LA, et al. Efficacy and safety of dulaglutide 3mg and 4.5mg vs. dulaglutide 1.5mg: 52-week results from AWARD-11. Diabetes. 2020;69(suppl 1). American Diabetes Association abstract 357-OR. https://doi.org/10.2337/db20-357-OR
17Gerstein HC, Colhoun HM, Dagenais GR, et al; REWIND Trial Investigators. Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obes Metab. 2018;20(1):42-49. https://doi.org/10.1111/dom.13028
18Gerstein HC, Colhoun HM, Dagenais GR, et al; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130. https://doi.org/10.1016/S0140-6736(19)31149-3
19Arslanian SA, Hannon T, Zeitler P, et al; AWARD-PEDS Investigators. Once-weekly dulaglutide for the treatment of youths with type 2 diabetes. N Engl J Med. 2022;387(5):433-443. https://doi.org/10.1056/NEJMoa2204601
Date of Last Review: 26 December 2023