Trulicity® (dulaglutid): Hypoglykemi

Detailed Information

Hypoglycemia in the AWARD Studies

Across the AWARD studies, documented symptomatic hypoglycemia was defined as a 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.^1-10

AWARD Studies in Which Patients Received Dulaglutide Without Concomitant Treatment With a Sulfonylurea or Insulin

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 (Table 1).^1-5

Table 1. 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

Hypoglycemiaa	Dulaglutide 1.5 mg	Dulaglutide 0.75 mg	Comparator
Monotherapy  (AWARD-3)1,11,b	n=269	n=270	Metformin n=268
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)
Add-on to metformin  (AWARD-5)2,11,c	n=304	n=302	Sitagliptin n=315
Documented symptomatic, PG ≤3.9 mmol/L (70 mg/dL)	10.9 (0.19)	6.3 (0.18)	5.7 (0.17)
Documented symptomatic, PG <3mmol/L (54 mg/dL) 11d	0.7	0.3	0
Severe	0 (0.0)	0 (0.0)	0 (0.0)
Add-on to metformin  (AWARD-6)3,e	n=299	NA	Liraglutide n=300
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)
Add-on to metformin + pioglitazone (AWARD-1)4,11,b	n=279	n=280	Exenatide Twice Daily n=276
Documented symptomatic, PG ≤3.9 mmol/L (70 mg/dL)	6.5 (0.19)	6.1 (0.14)	13.4 (0.75)
Documented symptomatic, PG <3 mmol/L (54 mg/dL) 11d	1.4	2.1	0
Severe	0 (0.0)	0 (0.0)	0.7 (0.01)
Add-on to SGLT-2 inhibitorf ± metformin (AWARD-10)5,11,g	n=142	n=141	Placebo n=140
Documented symptomatic, PG ≤3.9 mmol/L (70 mg/dL)	1.4 (0.16)	2.1 (0.15)	2.1 (0.12)
Documented symptomatic, PG <3 mmol/L (54 mg/dL)11d	0.7	0.7	0.7
Severe	0 (0.0)	0.7 (0.02)	0 (0.0)

Abbreviations: AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes; N/A = not applicable; PG = plasma glucose; SGLT-2 = sodium-glucose cotransporter-2.

^a Data presented as percentage of patients (mean rate); rate = episodes/patient/year. Documented symptomatic hypoglycemia was defined as a PG ≤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.

^b Endpoint 52 weeks.

^c Endpoint 104 weeks.

^d Data presented as mean rate percentage

^e Endpoint 26 weeks.

^f Canagliflozin, dapagliflozin, or empagliflozin.

^g Endpoint 24 weeks.

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.^1-5,11

Of the patients treated with dulaglutide, severe hypoglycemia was only reported in 1 patient of whom received dulaglutide 0.75 mg.⁵

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 patients with inadequately controlled T2DM on concomitant metformin therapy.¹²

Patients were treated for 52 weeks, which included a 12-week dose-escalation phase (Figure 1).¹¹

Figure 1. Dulaglutide Dose Escalation Design in AWARD-11¹¹

Abbreviations: AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes; DBL = data base lock; Dula = dulaglutide.

In the clinical trial with patients receiving dulaglutide as add-on therapy to metformin, incidences of hypoglycemia, identified as a glucose level < 3 mmol/L (< 54 mg/dL), through 36 weeks were reported in 

• 7 patients, 1.1%, on dulaglutide 1.5 mg

• 2 patients, 0.3%, on dulaglutide 3 mg, and 

• 7 patients, 1.1%, on dulaglutide 4.5 mg.¹³

Incidences of severe hypoglycemia were experienced in 

• 1 patient, 0.2%, on dulaglutide 1.5 mg

• no patients on dulaglutide 3 mg, and 

• 1 patient, 0.2%, on dulaglutide 4.5 mg.¹³

There was a consistent pattern of dose-related improvement in HbA1c, BW, 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.^12,14

Hypoglycemia findings through 52 weeks from the AWARD-11 study is provided in Table 2.

Table 2. Hypoglycemia Through 52 Weeks in AWARD-11¹¹

Hypoglycemiaa	DULA 1.5 mg (n=612)	DULA 3.0 mg (n=616)	DULA 4.5 mg (n=614)
Documented symptomatic, PG < 3 mmol/L (<54 mg/dL)	8 (1.3)	2 (0.3)	7 (1.1)
Severe	1 (0.2)	0 (0.0)	1 (0.2)

Abbreviations: Assessment of Weekly AdministRation of LY2189265 in Diabetes; DULA = dulaglutide.

^a All values presented as n (%); AEs presented as number of patients with ≥1 event.

AWARD Studies in Which Patients Received Dulaglutide and Concomitant Treatment With a Sulfonylurea or Insulin

In the 5 AWARD studies in which dulaglutide was used concomitantly with a sulfonylurea or insulin, the duration of the studies ranged from 24 to 78 weeks.^6-10 Overall, the incidence and mean rate of documented symptomatic, nocturnal, and severe hypoglycemia were lower in patients treated with dulaglutide 1.5 mg or dulaglutide 0.75 mg compared with those treated with an active comparator along with a sulfonylurea or insulin.^7,9,10

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.^6-10

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.^6-10

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.^6-10

AWARD Studies With Insulin Glargine as Comparator

Overall, the incidence and mean rate of documented symptomatic, nocturnal, and severe hypoglycemia were lower in patients treated with dulaglutide 1.5 mg or dulaglutide 0.75 mg compared with those treated with the active comparator insulin glargine.^7,9,10

Use of Dulaglutide With Medications Known to Cause Hypoglycemia

The risk of hypoglycemia is increased when dulaglutide is used in combination with insulin secretagogues, such as sulfonylureas, or insulin. Patients may require a lower dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting.¹⁵

References

1. Umpierrez G, Tofé Povedano S, Pérez Manghi F, 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

2. Weinstock 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

3. Dungan 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

4. Wysham 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

5. Ludvik 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

6. Dungan 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

7. Giorgino 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

8. Pozzilli 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

9. Blonde 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

10. Tuttle 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

11. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

12. Frias 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

13. Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020.

14. Frias 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

15. Trulicity [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

Glossary

AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes

BW = body weight

HbA1c = glycated hemoglobin

PG = plasma glucose

T2DM = type 2 diabetes mellitus