Trulicity ® (dulaglutid) injektion

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Kan jag föreskrive Trulicity® (dulaglutid) till patienter med nedsatt njurfunktion?

Dulaglutid har liknande effekt och säkerhet hos patienter med varierande njurfunktionsnivåer vid baslinjen.

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Can I prescribe Trulicity® (dulaglutide) to patients with renal impairment?

Dulaglutide has similar efficacy and safety in patients with varying levels of baseline kidney function.

  • No dose adjustment is required in patients with mild, moderate or severe renal impairment (eGFR < 90 to ≥ 15 mL/min/1.73 m2).1
  • There is very limited experience in patients with end stage renal disease (< 15 mL/min/1.73 m2), therefore dulaglutide can not be recommended in this population.1
  • In a phase 1, pharmacokinetic (PK) study that evaluated a single dose of dulaglutide 1.5 mg in patients with renal impairment, including end-stage renal disease (ESRD), no clinically relevant changes were noted in the PK parameters of dulaglutide.2
  • The AWARD-7 study showed, that dulaglutide has similar efficacy and safety compared with insulin glargine in patients with chronic kidney disease.3
  • The AWARD-11 post hoc analysis suggests that the effect of dulaglutide (with doses 1.5, 3.0 and 4.5 mg) was consistent regardless of baseline renal function level.4
  • Eli Lilly and Company has not studied the use of dulaglutide in patients with a history of kidney transplant or nephrectomy.

Further information on the clinical studies

AWARD-7 Study

The AWARD-7 study was a randomized, multicenter, open-label (blinded for the dose of dulaglutide), 52-week study.

This study compared the efficacy and safety of once-weekly dulaglutide 1.5 and 0.75 mg with daily insulin glargine in the treatment of patients with

  • Type 2 diabetes (T2DM) and
  • Moderate to severe chronic kidney disease (CKD).3

HbA1c - LSM change from baseline across treatment groups

HbA1c improved significantly from baseline to 26 and 52 weeks in all treatment groups (p<0.0001).3 

The least squares mean (LSM) change in HbA1c from baseline to 26 weeks was similar across treatment groups, thus demonstrating noninferiority of treatment with dulaglutide 1.5 mg and dulaglutide 0.75 mg compared with insulin glargine treatment (Change in HbA1c From Baseline to 26 and 52 Weeks in Patients Treated With Dulaglutide 1.5 mg, Dulaglutide 0.75 mg, or Insulin Glargine).3

Change in HbA1c From Baseline to 26 and 52 Weeks in Patients Treated With Dulaglutide 1.5 mg, Dulaglutide 0.75 mg, or Insulin Glargine3

HbA1c, %a

Dulaglutide 1.5 mg
(n=183)

Dulaglutide 0.75 mg
(n=180) 

Insulin Glargine
(n=186) 

Change from baseline to 26 weeks

-1.2 (0.1)b

-1.1 (0.1)b 

-1.1 (0.1)b

LSM difference (95% CI)

-0.05 (-0.26, 0.15)c

0.02 (-0.18, 0.22)d

N/A

Change from baseline to 52 weeks

-1.1 (0.1)b

-1.1 (0.1)b

-1.0 (0.1)b

LSM difference (95% CI)

-0.10 (-0.34, 0.14)c

-0.10 (-0.33, 0.13)e

N/A

Abbreviations: HbA1c = glycated hemoglobin; LSM = least squares mean; mITT = modified intention-to-treat; N/A = not applicable.

aData presented as LSM (SE) unless otherwise indicated and based on mITT population, defined as all randomized patients who received ≥1 dose of treatment and who had ≥1 postrandomization HbA1c measurement.

bp<0.0001 vs baseline.

cp<0.0001 for noninferiority vs insulin glargine with a 0.4% margin; p<.05 for noninferiority vs insulin glargine with a 0.3% margin.

dp<0.05 for noninferiority vs insulin glargine with a 0.4% margin.

ep<0.0001 for noninferiority vs insulin glargine with a 0.4% margin.

eGFR - LSM change from baseline across treatment groups

The LSM reduction in the estimated glomerular filtration rate (eGFR) from baseline to 26 weeks was significantly smaller in the dulaglutide 1.5 mg and dulaglutide 0.75 mg treatment groups compared with the insulin glargine treatment group (p<0.05).3 

The LSM reduction in eGFR from baseline to 52 weeks was less in the dulaglutide 1.5 mg and dulaglutide 0.75 mg treatment groups compared with the insulin glargine treatment group and reached significance when calculated based on cystatin C (p<0.05) (Change in eGFR From Baseline to 26 and 52 Weeks in Patients Treated With Dulaglutide 1.5 mg, Dulaglutide 0.75 mg, or Insulin Glargine).3

Change in eGFR From Baseline to 26 and 52 Weeks in Patients Treated With Dulaglutide 1.5 mg, Dulaglutide 0.75 mg, or Insulin Glargine3

eGFR, mL/min/1.73m2a 

Dulaglutide 1.5 mg
(n=192)

Dulaglutide 0.75 mg
(n=190)

Insulin Glargine
(n=194)

CKD-EPI creatinine

Baseline, mean (SD)

38.1 (13.2)

38.3 (12.3)

38.5 (13.0)

Change from baseline to 26 weeks

-0.1 (-1.2, 1.0)b

-0.4 (-1.4, 0.7)b

-1.9 (-3.0, -0.9)c

Change from baseline to 52 weeks

-1.1 (-2.4, 0.2)

-1.5 (-2.8, -0.2)c

-2.9 (-4.2, -1.6)d

CKD-EPI cystatin C

Baseline, mean (SD)

37.3 (14.2)

37.7 (13.7)

38.3 (14.8)

Change from baseline to 26 weeks

0.8 (-0.7, 2.3)b

1.1 (-0.4, 2.5)e

-3.0 (-4.4, -1.5)d

Change from baseline to 52 weeks

-0.7 (-2.5, 1.0)b

-0.7 (-2.4, 1.1)b

-3.3 (-5.1, -1.6)c

Abbreviations: CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; eGFR = estimated glomerular filtration rate; LSM = least squares mean.

aData presented as LSM (95% CI) unless otherwise indicated and based on safety population, defined as all patients who received ≥1 dose of treatment and who had any postdose data.

bp<0.05 vs insulin glargine.

cp<0.05 vs baseline.

dp<0.0001 vs baseline.

ep<0.0001 vs insulin glargine.

Urine Albumin-to-Creatinine Ratio (UACR)

In patients with baseline macroalbuminuria, there was a significant decrease in the LSM UACR from baseline to

  • 26 and 52 weeks in patients treated with dulaglutide 1.5 mg (26 weeks, p<0.0001; 52 weeks, p=0.0024), and
  • 26 weeks in patients treated with dulaglutide 0.75 mg (p=0.0102).3

The decrease in the LSM UACR from baseline to 26 and 52 weeks was significantly greater in patients treated with dulaglutide 1.5 mg compared with those treated with insulin glargine (26 weeks, p=0.0076; 52 weeks, p=0.0205).

The decrease was numerically greater in patients treated with dulaglutide 0.75 mg compared with those treated with insulin glargine.3

AWARD-11 Study

AWARD-11 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 with dulaglutide 1.5 mg when added to metformin in patients with T2DM.5,6

A post hoc analysis evaluated the safety and efficacy of dulaglutide 1.5, 3.0, and 4.5 mg across patients with varying baseline renal function.4

Renal function was categorized into 3 subgroups by baseline eGFR

  • ≥90 mL/min/1.73m2
  • ≥60 to <90 mL/min/1.73 m2, and
  • ≥30  to <60 mL/min/1.73 m2.4

The AWARD-11 post hoc analysis suggests that the effect of dulaglutide was consistent regardless of baseline renal function level.4

Change in HbA1c and body weight from baseline to week 52 across eGFR subgroups

The effect of dulaglutide on change from baseline to week 52 in HbA1c was not significantly affected (p= 0.128) across baseline renal function subgroups (Change in HbA1c From Baseline to 52 Weeks - Stratified by Renal Function).4

Change in HbA1c From Baseline to 52 Weeks - Stratified by Renal Function4

Abbreviations: CFB = change from baseline; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; LS = least squares.

Note: The test for different treatment effects across renal function subgroup resulted in p= 0.128.

Baseline renal function had no significant effect (p= 0.607) on change from baseline to week 52 in body weight (Change in Body Weight From Baseline to 52 Weeks – Stratified by Renal Function).4

Change in Body Weight From Baseline to 52 Weeks – Stratified by Renal Function4

Abbreviations: CFB = change from baseline; eGFR = estimated glomerular filtration rate; LS = least squares.

Note: The test for different treatment effects across renal function subgroup resulted in p= 0.607.

Common TEAEs and CV effects across baseline renal function subgroups 

Common TEAEs of Dulaglutide by Baseline Renal Function Subgroup at Week 524

Safety Outcomes According to Renal Function Levela

Dulaglutide 1.5 mg
(N=612)

Dulaglutide 3.0 mg
(N=616)

Dulaglutide 4.5 mg
(N=614)

Test for Different Treatment Effects Across Renal Function Subgroup (p-value)b

Number of patients with events, n/N (%)

Gastrointestinal eventsc


0.657

   Baseline eGFR ≥90

87/408 (21.3)

99/393 (25.2)

111/397 (28.0)

   60≤ baseline eGFR <90

35/171 (20.5)

52/198 (26.3)

50/184 (27.2)

   30≤ baseline eGFR  <60

6/33 (18.2)

3/25 (12.0)

10/33 (30.3)

Hypoglycemiad


0.188

   Baseline eGFR ≥90

6/408 (1.5%)

0/393 (0.0%)

4/397 (1.0)

   60≤ baseline eGFR  <90

3/171 (1.8%)

2/198 (1.0%)

3/184 (1.6)

   30≤ baseline eGFR <60

0/33 (0.0%)

0/25 (0.0%)

0/33 (0.0)

Incidence of new-onset albuminuriae


0.236

   Baseline eGFR ≥90

23/408 (5.6)

18/393 (4.6)

23/397 (5.8)

   60≤ baseline eGFR <90

9/171 (5.3)

7/198 (3.5)

16/184 (8.7)

   30≤ baseline eGFR <60

2/33 (6.1)

5/25 (20.0)

4/33 (12.1)

Incidence of new-onset macroalbuminuriaf





0.827

   Baseline eGFR ≥90

7/408 (1.7)

3/393 (0.8)

7/397 (1.8)

   60≤ baseline eGFR <90

4/171 (2.3)

1/198 (0.5)

3/184 (1.6)

   30≤ baseline eGFR <60

2/33 (6.1)

0/25 (0.0)

1/33 (3.0)

Abbreviations: eGFR = estimated glomerular filtration rate; UACR = urine albumin-to-creatinine ratio.

aRenal function level as measured by eGFR using cystatin C equation (in mL/min/1.73 m2).

bP value for test of homogeneity of odds ratios in treatment groups and renal subgroups is from a Breslow Day test.

cIncluded nausea, vomiting, and diarrhea.

dDefined as plasma glucose <54 mg/dL.

eDevelopment of UACR >3.39 mg/mmol (30 mg/g Cr).

fDevelopment of UACR >33.9 mg/mmol (300 mg/g Cr).

Cardiovascular Effects of Dulaglutide by Baseline Renal Function Subgroups at Week 524

Parametera

Dulaglutide 1.5 mg
(N=612)

Dulaglutide 3.0 mg
(N=616)

Dulaglutide 4.5 mg
(N=614)

Test for Different Treatment Effects Across Renal Function Subgroup
(p-value)b

Heart rate (bpm)





0.162

   Baseline eGFR ≥90

1.2 ± 0.43

2.1 ± 0.44

2.2 ± 0.44

   60≤ baseline eGFR <90

2.8 ± 0.67

1.3 ± 0.62

2.6 ± 0.64

   30≤ baseline eGFR <60

0.3 ± 1.82

2.4 ± 1.97

-0.1 ± 1.72

Diastolic blood pressure (mm Hg)





0.897

   Baseline eGFR ≥90

-0.9 ± 0.39

-1.0 ± 0.40

-1.1 ± 0.39

   60≤ baseline eGFR <90

-1.7 ± 0.60

-1.2 ± 0.55

-1.2 ± 0.58

   30≤ baseline eGFR <60

-0.5 ± 1.69

0.3 ± 1.90

-0.7 ± 1.65

PR interval (msec)





0.410

   Baseline eGFR ≥90

3.3 ± 0.63

4.3  ± 0.65

4.0 ± 0.64

   60≤ baseline eGFR <90

4.6 ± 1.17

5.8 ± 1.08

4.0 ± 1.11

   30≤ baseline eGFR <60

2.3 ± 2.66

2.1 ± 2.69

5.6 ± 2.50

Abbreviations: eGFR = estimated glomerular filtration rate; LSM = least squares mean.

aData presented as changes from baseline to week 52 (LSM change ± SE) unless otherwise stated.

bInteraction p values are from a mixed model for repeated measures to assess the change from baseline, which includes an interaction between the treatment groups and the renal subgroups.

Regardless of baseline renal function, the incidence of common TEAEs and CV effects was consistent across dulaglutide treatment groups (p>0.10 for all events).4

References

1Trulicity [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2Loghin C, de la Peña A, Cui X, et al. Pharmacokinetics of once weekly dulaglutide in special populations. Diabetes. 2014;63(suppl 1):A251. American Diabetes Association abstract 980-P. https://doi.org/10.2337/db14-833-1316

3Tuttle 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

4Garcia-Perez LE, Maldonado JM, Ranta KT, Raha S. Effect of once weekly dulaglutide 3.0 mg and 4.5 mg in patients with different baseline renal function: post-hoc analysis from the AWARD-11 Trial. Poster presented at: 81st Scientific Sessions of the American Diabetes Association (ADA 2021 Virtual); June 25-29, 2021. Accessed June 3, 2021. https://diabetes.diabetesjournals.org/content/70/Supplement_1/673-P

5Frias 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

6Frias 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

Glossary

AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes

CKD = chronic kidney disease

eGFR = estimated glomerular filtration rate

ESRD = end-stage renal disease

HbA1c = glycated hemoglobin

LSM = least squares mean

PK = pharmacokinetic

T2DM = type 2 diabetes mellitus

UACR = urine albumin to creatinine ratio

Datum fӧr senaste ӧversyn June 18, 2021


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