Trulicity ® (dulaglutide)

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What is the incidence of hypoglycemia with Trulicity® (dulaglutide) use?

Events of severe hypoglycemia with dulaglutide were rare and generally related to the type of concomitant therapies used.

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Incidence of hypoglycemia in the pivotal clinical studies

Hypoglycemia in the AWARD studies

How was hypoglycemia defined 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

Studies without concomitant 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.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

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).1-5

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 <3.0 mmol/L (<54 mg/dL)11,d 

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)4,11b

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 <3.0 mmol/L (<54 mg/dL)11,d

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 <3.0 mmol/L (<54 mg/dL)11,d

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; 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.

Dulaglutide 3.0 mg and 4.5 mg (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 type 2 diabets mellitus (T2DM) on concomitant metformin therapy.12,13

Patients were treated for 52 weeks, which included a 12-week dose-escalation phase (Dulaglutide Dose Escalation Design in AWARD-11).11

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.11

In the clinical trial with patients receiving dulaglutide as add-on therapy to metformin, 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.11

There was a consistent pattern of dose-related improvement in 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.12-14

Hypoglycemia findings through 52 weeks from the AWARD-11 study is provided in Hypoglycemia Through 52 Weeks in AWARD-11.

Hypoglycemia Through 52 Weeks in AWARD-1111,15

Hypoglycemiaa

DULA 1.5 mg
(n=612)

DULA 3.0 mg
(n=616)

DULA 4.5 mg
(n=614)

Documented symptomaticb

8 (1.3)

2 (0.3)

7 (1.1)

Severec

1 (0.2)

0 (0.0)

1 (0.2)

Abbreviations: AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes; 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 event requiring the assistance of another person to actively administer rescue medication.

Studies with concomitant 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.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

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 (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).7,9,10

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.16

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.16

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. 16

References

1Umpierrez 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

2Weinstock 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

3Dungan 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

4Wysham 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

5Ludvik 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

6Dungan 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

7Giorgino 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

8Pozzilli 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

9Blonde 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

10Tuttle 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

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

12Frias 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

13Frias 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

14Frias 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

15Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36(5):1384-1395. https://doi.org/10.2337/dc12-2480

16Trulicity [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

Date of Last Review: 13 April 2021


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