Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins, ATC code: A10BJ05

Mechanism of action

Dulaglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist. The molecule consists of 2 identical disulfide-linked chains, each containing a modified human GLP-1 analogue sequence covalently linked to a modified human immunoglobulin G4 (IgG4) heavy chain fragment (Fc) by a small peptide linker. The GLP-1 analog portion of dulaglutide is approximately 90% homologous to native human GLP-1 (7-37). Native GLP-1 has a half-life of 1.5 - 2 minutes due to degradation by DPP-4 and renal clearance. In contrast to native GLP-1, dulaglutide is resistant to degradation by DPP-4, and has a large size that slows absorption and reduces renal clearance. These engineering features result in a soluble formulation and a prolonged half-life of 4.7 days, which makes it suitable for once-weekly subcutaneous administration. In addition, the dulaglutide molecule was engineered to prevent the Fcγ receptor-dependent immune response and to reduce its immunogenic potential.

Dulaglutide exhibits several antihyperglycaemic actions of GLP-1. In the presence of elevated glucose concentrations, dulaglutide increases intracellular cyclic AMP (cAMP) in pancreatic beta cells leading to insulin release. Dulaglutide suppresses glucagon secretion which is known to be inappropriately elevated  in patients with type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output.
Dulaglutide also slows gastric emptying.

Pharmacodynamic effects
Dulaglutide improves glycaemic control through the sustained effects of lowering fasting, pre-meal and postprandial glucose concentrations in patients with type 2 diabetes starting after the first dulaglutide administration and is sustained throughout the once weekly dosing interval.

A pharmacodynamic study with dulaglutide demonstrated, in patients with type 2 diabetes, a restoration of first phase insulin secretion to a level that exceeded levels observed in healthy subjects on placebo, and improved second phase insulin secretion in response to an intravenous bolus of glucose. In the same study, a single 1.5 mg dose of dulaglutide appeared to increase maximal insulin secretion from the β-cells, and to enhance β-cell function in subjects with type 2 diabetes mellitus as compared with placebo.

Consistent with the pharmacokinetic profile, dulaglutide has a pharmacodynamic profile suitable for once weekly administration (see section 5.2).

Clinical efficacy and safety

Glycaemic control
The safety and efficacy of dulaglutide were evaluated in nine randomised, controlled, phase 3 trials involving 6,193 patients with type 2 diabetes. Of these, 1,206 were ≥ 65 years of which 119 were ≥ 75 years. These studies included 3,808 dulaglutide-treated patients, of whom 1,558 were treated with Trulicity 0.75 mg weekly and 2,250 were treated with Trulicity 1.5 mg weekly. In all studies, dulaglutide produced clinically significant improvements in glycaemic control as measured by glycosylated haemoglobin A1c (HbA1c).

Monotherapy
Dulaglutide was studied in a 52-week active controlled monotherapy study in comparison to metformin.
Trulicity 1.5 mg and 0.75 mg were superior to metformin (1500-2000 mg/day) in the reduction in HbA1c and a significantly greater proportion of patients reached an HbA1c target of < 7.0% and ≤ 6.5% with Trulicity 1.5 mg and Trulicity 0.75 mg compared to metformin at 26 weeks.



Table 2. Results of a 52-week active controlled monotherapy study with two doses of dulaglutide in comparison to metformin

Baseline       Mean             Patients at target    Change in     Change in HbA1c        change in               HbA1c              FBG           body HbA1c                                                  weight
(%)           (%)           < 7.0%        ≤ 6.5%    (mmol/L)         (kg) (%)a          (%)b
26 weeks
Dulaglutide 1.5 mg once weekly              7.63       -0.78††          61.5#         46.0##     -1.61         -2.29 (n=269)
Dulaglutide 0.75 mg once weekly              7.58       -0.71††          62.6#         40.0#      -1.46         -1.36# (n=270)
Metformin
1500-2000 mg/day         7.60        -0.56           53.6           29.8      -1.34         -2.22 (n=268)
52 weeks
Dulaglutide 1.5 mg once weekly              7.63       -0.70††          60.0#         42.3##     -1.56#        -1.93 (n = 269)
Dulaglutide 0.75 mg once weekly              7.58       -0.55†           53.2           34.7      -1.00         -1.09# (n = 270)
Metformin
1500-2000 mg/day         7.60        -0.51           48.3           28.3      -1.15         -2.20 (n = 268)
† multiplicity adjusted 1-sided p-value < 0.025, for noninferiority; †† multiplicity adjusted 1-sided p-value < 0.025, for superiority of dulaglutide to metformin, assessed for HbA1c only # p < 0.05, ## p < 0.001 dulaglutide treatment group compared to metformin a
HbA1c value of 7.0% (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose: 8.6 mmol/L) b
HbA1c value of 6.5% (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose: 7.8 mmol/L)
FBG = fasting blood glucose; DCCT = Diabetes Control and Complications Trial; IFCC = International Federation of Clinical Chemistry and Laboratory Medicine

The rate of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and 0.75 mg, and metformin were 0.62, 0.15, and 0.09 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed.

Combination therapy with metformin
The safety and efficacy of dulaglutide was investigated in a placebo and active controlled (sitagliptin 100 mg daily) study of 104 weeks duration, all in combination with metformin. Treatment with Trulicity 1.5 mg and 0.75 mg resulted in a superior reduction in HbA1c compared to sitagliptin at 52 weeks, accompanied by a significantly greater proportion of patients achieving HbA1c targets of < 7.0% and ≤ 6.5%. These effects were sustained to the end of the study (104 weeks).



Table 3. Results of a 104-week placebo and active controlled study with two doses of dulaglutide in comparison to sitagliptin

Baseline       Mean                Patients at target     Change in    Change in HbA1c        change in                  HbA1c               FBG          body HbA1c                                                     weight
(%)            (%)              < 7.0%       ≤ 6.5%     (mmol/L)       (kg) (%)a         (%)b
26 weeks
Dulaglutide 1.5 mg once weekly               8.12        -1.22‡‡,##        60.9**,##    46.7**,##   -2.38**,##   -3.18**,## (n = 304)
Dulaglutide 0.75 mg once weekly               8.19        -1.01‡‡,##        55.2**,##    31.0**,##   -1.97**,##   -2.63**,## (n = 302)
Placebo (n = 177)         8.10          0.03              21.0          12.5       -0.49        -1.47 Sitagliptin
100 mg once daily         8.09          -0.61             37.8          21.8                    -1.46 (n = 315)                                                                          -0.97 52 weeks
Dulaglutide 1.5 mg once weekly               8.12         -1.10††           57.6##        41.7##     -2.38##      -3.03## (n = 304)
Dulaglutide 0.75 mg once weekly               8.19         -0.87††           48.8##        29.0##     -1.63##      -2.60## (n = 302)
Sitagliptin 100 mg once daily (n = 315)
8.09          -0.39             33.0          19.2       -0.90        -1.53 104 weeks
Dulaglutide 1.5 mg once weekly               8.12         -0.99††           54.3##        39.1##     -1.99##      -2.88## (n = 304)
Dulaglutide 0.75 mg once weekly               8.19         -0.71††           44.8##        24.2##     -1.39##       -2.39 (n = 302)
Sitagliptin 100 mg once daily (n = 315)
8.09          -0.32             31.1          14.1       -0.47        -1.75 †† multiplicity adjusted 1-sided p-value < 0.025, for superiority of dulaglutide compared to sitagliptin, assessed only for HbA1c at 52 and 104 weeks
‡‡ multiplicity adjusted 1-sided p-value < 0.001 for superiority of dulaglutide compared to placebo, assessed for HbA1c only
** p < 0.001 dulaglutide treatment group compared to placebo
## p < 0.001 dulaglutide treatment group compared to sitagliptin a
HbA1c value of 7.0% (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose: 8.6 mmol/L) b
HbA1c value of 6.5% (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose: 7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and 0.75 mg, and sitagliptin were 0.19, 0.18, and 0.17 episodes/patient/year, respectively. No cases of severe hypoglycaemia with dulaglutide were observed.


The safety and efficacy of dulaglutide was also investigated in an active controlled study (liraglutide 1.8 mg daily) of 26 weeks duration, both in combination with metformin. Treatment with Trulicity 1.5 mg resulted in similar lowering of HbA1c and patients achieving HbA1c targets of < 7.0% and ≤ 6.5% compared to liraglutide.

Table 4. Results of a 26-week active controlled study of one dose of dulaglutide in comparison to liraglutide

Baseline     Mean             Patients at target     Change in     Change in HbA1c      change in               HbA1c               FBG           body HbA1c                                                   weight
(%)         (%)           < 7.0 %       ≤ 6.5 %   (mmol/L)          (kg) (%)a          (%)b
26 weeks
Dulaglutide 1.5 mg once weekly              8.06     -1.42‡           68.3           54.6       -1.93         -2.90# (n = 299)
Liraglutide+ 1.8 mg               -1.36 daily (n = 300)
8.05                      67.9           50.9       -1.90         -3.61 ‡
1-sided p-value p < 0.001, for noninferiority of dulaglutide compared to liraglutide, assessed only for HbA1c.
# p < 0.05 dulaglutide treatment group compared to liraglutide.
+
Patients randomised to liraglutide were initiated at a dose of 0.6 mg/day. After Week 1, patients were up-titrated to 1.2 mg/day and then at Week 2 to 1.8 mg/day.
a
HbA1c value of 7.0% (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose: 8.6 mmol/L) b
HbA1c value of 6.5% (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose: 7.8 mmol/L)

The rate of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg was 0.12 episodes/patient/year and with liraglutide was 0.29 episodes/patient/year. No cases of severe hypoglycaemia were observed.

Combination therapy with metformin and sulphonylurea
In an active controlled study of 78 weeks duration, dulaglutide was compared to insulin glargine, both on a background of metformin and a sulphonylurea. At 52 weeks, Trulicity 1.5 mg demonstrated superior lowering in HbA1c to insulin glargine which was maintained at 78 weeks; whereas lowering in HbA1c with Trulicity 0.75 mg was non-inferior to insulin glargine. With Trulicity 1.5 mg a significantly higher percentage of patients reached a target HbA1c of < 7.0% or ≤ 6.5% at 52 and 78 weeks compared to insulin glargine.



Table 5. Results of a 78-week active controlled study with two doses of dulaglutide in comparison to insulin glargine

Baseline       Mean             Patients at target    Change in     Change in HbA1c        change in               HbA1c              FBG           body HbA1c                                                  weight
(%)          (%)            < 7.0%        ≤ 6.5%    (mmol/L)         (kg) (%)a          (%)b
52 weeks
Dulaglutide 1.5 mg once weekly               8.18      -1.08††          53.2##         27.0##     -1.50         -1.87## (n = 273)
Dulaglutide 0.75 mg once weekly               8.13       -0.76†           37.1          22.5#      -0.87##       -1.33## (n = 272)
Insulin glargine+ once daily (n = 262)
8.10       -0.63            30.9           13.5      -1.76          1.44 78 weeks
Dulaglutide 1.5 mg once weekly               8.18      -0.90††          49.0##         28.1##     -1.10#        -1.96## (n = 273)
Dulaglutide 0.75 mg once weekly               8.13       -0.62†           34.1           22.1      -0.58##       -1.54## (n = 272)
Insulin glargine+ once daily (n = 262)
8.10       -0.59            30.5           16.6      -1.58          1.28 † multiplicity adjusted 1-sided p-value < 0.025, for noninferiority; †† multiplicity adjusted 1-sided p-value < 0.025, for superiority of dulaglutide to insulin glargine, assessed for HbA1c only # p < 0.05, ## p < 0.001 dulaglutide treatment group compared to insulin glargine +
Insulin glargine doses were adjusted utilising an algorithm with a fasting plasma glucose target of < 5.6 mmol/L a
HbA1c value of 7.0% (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose: 8.6 mmol/L) b
HbA1c value of 6.5% (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose: 7.8 mmol/L)
The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and 0.75 mg, and insulin glargine were 1.67, 1.67, and 3.02 episodes/patient/year, respectively. Two cases of severe hypoglycaemia were observed with dulaglutide 1.5 mg and two cases of severe hypoglycaemia were observed with insulin glargine.

Combination therapy with sulphonylurea
The safety and efficacy of dulaglutide as add-on to a sulphonylurea was investigated in a placebo controlled study of 24 weeks duration. Treatment with Trulicity 1.5 mg in combination with glimepiride resulted in a statistically significant reduction in HbA1c compared to placebo with glimepiride at 24 weeks. With Trulicity 1.5 mg, a significantly higher percentage of patients reached a target HbA1c of < 7.0% and ≤ 6.5% at 24 weeks compared to placebo.



Table 6. Results of a 24-week placebo controlled study of dulaglutide as add-on to glimepiride 
Baseline        Mean             Patients at target     Change in     Change in HbA1c         change in               HbA1c               FBG           body HbA1c                                                   weight
(%)            (%)           < 7.0%        ≤ 6.5%     (mmol/L)         (kg) (%)a          (%)b
24 weeks
Dulaglutide 1.5 mg once weekly              8.39        -1.38‡‡         55.3‡‡         40.0**      -1.70‡‡        -0.91 (n=239)
Placebo (n=60)           8.39         -0.11           18.9           9.4         0.16          -0.24 ‡‡ p < 0.001 for superiority of dulaglutide compared to placebo, with overall type I error controlled ** p < 0.001 for dulaglutide treatment group compared to placebo a
HbA1c value of 7.0% (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose: 8.6 mmol/L) b
HbA1c value of 6.5% (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose: 7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and placebo were 0.90 and 0.04 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed for dulaglutide or placebo.

Combination therapy with SGLT2 inhibitor with or without metformin
The safety and efficacy of dulaglutide as add-on to sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy (96% with and 4% without metformin) were investigated in a placebo controlled study of 24 weeks duration. Treatment with Trulicity 0.75 mg or Trulicity 1.5 mg in combination with SGLT2i therapy resulted in a statistically significant reduction in HbA1c compared to placebo with SGLT2i therapy at 24 weeks. With both Trulicity 0.75 mg and 1.5 mg, a significantly higher percentage of patients reached a target HbA1c of < 7.0% and ≤ 6.5% at 24 weeks compared to placebo.

Table 7. Results of a 24-week placebo controlled study of dulaglutide as add-on to SGLT2i therapy 
Baseline        Mean             Patients at target     Change in     Change in HbA1c         change in               HbA1c               FBG           body HbA1c                                                   weight
(%)            (%)           < 7.0%^       ≤ 6.5%     (mmol/L)         (kg) (%)a         (%)b
24 weeks
Dulaglutide 0.75 mg once weekly              8.05        -1.19‡‡         58.8‡‡         38.9**       -1.44          -2.6 (n = 141)
Dulaglutide 1.5 mg once weekly              8.04        -1.33‡‡         67.4‡‡         50.8**       -1.77          -3.1 (n = 142)
Placebo (n=140)          8.05         -0.51           31.2           14.6        -0.29          -2.3 ‡‡ p < 0.001 for superiority of dulaglutide compared to placebo, with overall type I error controlled ** p < 0.001 for dulaglutide treatment group compared to placebo
^ Patients who withdrew from randomised treatment before 24 weeks were considered as not meeting the target
a
HbA1c value of 7.0% (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose: 8.6 mmol/L) b
HbA1c value of 6.5% (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose: 7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 0.75 mg, dulaglutide 1.5 mg, and placebo were 0.15, 0.16 and 0.12 episodes/patient/year, respectively. One patient reported severe hypoglycaemia with dulaglutide 0.75 mg in combination with SGLT2i therapy and none with dulaglutide 1.5 mg or placebo.

Combination therapy with metformin and pioglitazone
In a placebo and active (exenatide twice daily) controlled study, both in combination with metformin and pioglitazone, Trulicity 1.5 mg and 0.75 mg demonstrated superiority for HbA1c reduction in comparison to placebo and exenatide, accompanied by a significantly a greater percentage of patients achieving HbA1c targets of < 7.0% or ≤ 6.5%

Table 8. Results of a 52-week active controlled study with two doses of dulaglutide in comparison to exenatide

Baseline     Mean               Patients at target      Change in    Change in HbA1c      change in                 HbA1c                FBG          body HbA1c                                                     weight
(%)         (%)             < 7.0%        ≤ 6.5%      (mmol/L)        (kg) (%)a          (%)b
26 weeks
Dulaglutide 1.5 mg once weekly              8.10     -1.51‡‡,††        78.2**,##    62.7**,##    -2.36**,##    -1.30** (n = 279)
Dulaglutide 0.75 mg once weekly              8.05     -1.30‡‡/††        65.8**/##     53.2**/##   -1.90**/##    0.20 */## (n = 280)
Placebo (n = 141)        8.06       -0.46             42.9          24.4        -0.26        1.24 Exenatide+
10 mcg twice daily       8.07       -0.99             52.3          38.0        -1.35        -1.07 (n = 276)
52 weeks
Dulaglutide 1.5 mg once weekly              8.10       -1.36††          70.8##        57.2##      -2.04##       -1.10 (n = 279)
Dulaglutide 0.75 mg once weekly              8.05       -1.07††           59.1#        48.3##      -1.58#        0.44# (n = 280)
Exenatide+
10 mcg twice daily       8.07       -0.80             49.2          34.6        -1.03        -0.80 (n = 276)
†† multiplicity adjusted 1-sided p-value < 0.025, for superiority of dulaglutide to exenatide, assessed for HbA1c only
‡‡ multiplicity adjusted 1-sided p-value < 0.001 for superiority of dulaglutide compared to placebo, assessed for HbA1c only
* p < 0.05, **p < 0.001 dulaglutide treatment group compared to placebo # p < 0.05, ##p < 0.001 dulaglutide treatment group compared to exenatide +
Exenatide dose was 5 mcg twice daily for first 4 weeks and 10 mcg twice daily thereafter a
HbA1c value of 7.0% (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose: 8.6 mmol/L) b
HbA1c value of 6.5% (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose: 7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and 0.75 mg, and exenatide twice daily were 0.19, 0.14, and 0.75 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed for dulaglutide and two cases of severe hypoglycaemia were observed with exenatide twice daily.

Combination therapy with titrated basal insulin, with or without metformin In a 28-week placebo controlled study, Trulicity 1.5 mg was compared to placebo as add-on to titrated basal insulin glargine (88% with and 12% without metformin) to evaluate the effect on glycaemic control and safety. To optimise the insulin glargine dose, both groups were titrated to a target fasting serum glucose of < 5.6 mmol/L. The mean baseline dose of insulin glargine was 37 units/day for patients receiving placebo and 41 units/day for patients receiving Trulicity 1.5 mg. The initial insulin glargine doses in patients with HbA1c < 8.0% were reduced by 20%. At the end of the 28-week treatment period the dose was 65 units/day and 51 units/day, for patients receiving placebo and Trulicity 1.5 mg, respectively. At 28 weeks, treatment with once weekly Trulicity 1.5 mg resulted in a statistically significant reduction in HbA1c compared to placebo and a significantly greater percentage of patients achieving HbA1c targets of < 7.0% and ≤ 6.5% (Table 9).


Table 9. Results of a 28-week study of dulaglutide compared to placebo as add-on to titrated insulin glargine

Baseline     Mean             Patients at target    Change in    Change in HbA1c      change in               HbA1c              FBG          body HbA1c                                                 weight
(%)        (%)            < 7.0%        ≤ 6.5%    (mmol/L)        (kg) (%)a          (%)b
28 weeks
Dulaglutide 1.5 mg once weekly and
8.41     -1.44‡‡          66.7‡‡        50.0**    -2.48‡‡       -1.91‡‡ insulin glargine
(n = 150)
Placebo once weekly and insulin glargine      8.32      -0.67            33.3          16.7      -1.55         0.50 (n = 150)
‡‡ p < 0.001 for superiority of dulaglutide compared to placebo, overall type I error controlled ** p < 0.001 dulaglutide treatment group compared to placebo a
HbA1c value of 7.0% (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose: 8.6 mmol/L) b
HbA1c value of 6.5% (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose: 7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and insulin glargine were 3.38 episodes/patient/year compared to placebo and insulin glargine 4.38 episodes/patient/year. One patient reported severe hypoglycaemia with dulaglutide 1.5 mg in combination with insulin glargine and none with placebo.


Combination therapy with prandial insulin with or without metformin
In this study, patients on 1 or 2 insulin injections per day prior to study entry, discontinued their prestudy insulin regimen and were randomised to dulaglutide once weekly or insulin glargine once daily, both in combination with prandial insulin lispro three times daily, with or without metformin. At 26 weeks, both Trulicity 1.5 mg and 0.75 mg were superior to insulin glargine in lowering of HbA1c and this effect was sustained at 52 weeks. A greater percentage of patients achieved HbA1c targets of < 7.0% or ≤ 6.5% at 26 weeks and < 7.0% at 52 weeks than with insulin glargine.

Table 10. Results of a 52-week active controlled study with two doses of dulaglutide in comparison to insulin glargine

Baseline        Mean             Patients at target       Change in     Change in HbA1c         change in               HbA1c                 FBG           body HbA1c                                                     weight
(%)            (%)           < 7.0%        ≤ 6.5%       (mmol/L)          (kg) (%)a          (%)b
26 weeks
Dulaglutide 1.5 mg once weekly               8.46         -1.64††          67.6#        48.0#        -0.27##        -0.87## (n = 295)
Dulaglutide 0.75 mg once weekly               8.40         -1.59††          69.0#         43.0         0.22##         0.18## (n = 293)
Insulin glargine+ once daily (n = 296)
8.53          -1.41           56.8          37.5         -1.58           2.33 52 weeks
Dulaglutide 1.5 mg once weekly               8.46         -1.48††          58.5#         36.7         0.08##        -0.35## (n = 295)
Dulaglutide 0.75 mg once weekly               8.40         -1.42††          56.3          34.7         0.41##         0.86## (n = 293)
Insulin glargine+ once daily (n = 296)
8.53          -1.23           49.3          30.4         -1.01           2.89 †† multiplicity adjusted 1-sided p-value < 0.025, for superiority of dulaglutide to insulin glargine, assessed for HbA1c only
# p < 0.05, ## p < 0.001 dulaglutide treatment group compared to insulin glargine +
Insulin glargine doses were adjusted utilizing an algorithm with a fasting plasma glucose target of < 5.6 mmol/L a
HbA1c value of 7.0% (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose: 8.6 mmol/L) b
HbA1c value of 6.5% (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose: 7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and 0.75 mg, and insulin glargine were 31.06, 35.66, and 40.95 episodes/patient/year, respectively. Ten patients reported severe hypoglycaemia with dulaglutide 1.5 mg, seven with dulaglutide 0.75 mg, and fifteen with insulin glargine.



Fasting blood glucose
Treatment with dulaglutide resulted in significant reductions from baseline in fasting blood glucose. The majority of the effect on fasting blood glucose concentrations occurred by 2 weeks. The improvement in fasting glucose was sustained through the longest study duration of 104 weeks.

Postprandial glucose
Treatment with dulaglutide resulted in significant reductions in mean post prandial glucose from baseline (changes from baseline to primary time point -1.95 mmol/L to -4.23 mmol/L).

Beta-cell function
Clinical studies with dulaglutide have indicated enhanced beta-cell function as measured by homeostasis model assessment (HOMA2-%B). The durability of effect on beta-cell function was maintained through the longest study duration of 104 weeks.

Body weight
Trulicity 1.5 mg was associated with sustained weight reduction over the duration of studies (from baseline to final time point -0.35 kg to -2.90 kg). Changes in body weight with Trulicity 0.75 mg ranged from 0.86 kg to -2.63 kg. Reduction in body weight was observed in patients treated with dulaglutide irrespective of nausea, though the reduction was numerically larger in the group with nausea.

Patient reported outcomes
Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily. In addition, there was significantly lower perceived frequency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily.

Blood pressure
The effect of dulaglutide on blood pressure as assessed by Ambulatory Blood Pressure Monitoring was evaluated in a study of 755 patients with type 2 diabetes. Treatment with dulaglutide provided reductions in systolic blood pressure (SBP) (-2.8 mmHg difference compared to placebo) at 16 weeks. There was no difference in diastolic blood pressure (DBP). Similar results for SBP and DBP were demonstrated at the final 26 week time point of the study.

Cardiovascular Evaluation

Meta-analysis of phase 2 and 3 studies
In a meta-analysis of phase 2 and 3 registration studies, a total of 51 patients (dulaglutide: 26 [N = 3,885]; all comparators: 25 [N = 2,125]) experienced at least one cardiovascular (CV) event (death due to CV causes, nonfatal MI, nonfatal stroke, or hospitalisation for unstable angina). The results showed that there was no increase in CV risk with dulaglutide compared with control therapies (HR: 0.57; CI: [0.30, 1.10]).

Cardiovascular outcome study
The Trulicity long-term cardiovascular outcome study was a placebo-controlled, double-blind clinical trial. Type 2 diabetes patients were randomly allocated to either Trulicity 1.5 mg (4,949) or placebo (4,952) both in addition to standards of care for type 2 diabetes (the 0.75 mg dose was not administered in this study). The median study follow-up time was 5.4 years.

The mean age was 66.2 years, the mean BMI was 32.3 kg/m², and 46.3% of patients were female. There were 3,114 (31.5%) patients with established CV disease. The median baseline HbA1c was 7.2%. The Trulicity treatment arm included patients ≥ 65 years (n = 2,619) and ≥ 75 years (n = 484), and patients with mild (n = 2,435), moderate (n = 1,031) or severe (n = 50) renal impairment.


The primary endpoint was the time from randomisation to first occurrence of any major adverse cardiovascular events (MACE): CV death, non-fatal myocardial infarction, or non-fatal stroke. Trulicity was superior in preventing MACE compared to placebo (Figure 1). Each MACE component contributed to the reduction of MACE, as shown in Figure 2.



Figure 1. Kaplan-Meier plot of time to first occurrence of the composite outcome: CV death, non-fatal myocardial infarction or non-fatal stroke, in the dulaglutide long-term cardiovascular outcome study 



Figure 2. Forest plot of analyses of individual cardiovascular event types, all cause death, and consistency of effect across subgroups for the primary endpoint

A significant and sustained reduction in HbA1c levels from baseline to month 60 was observed with Trulicity vs placebo, in addition to standard of care (-0.29% vs 0.22%; estimated treatment difference -0.51% [-0.57; -0.45]; p < 0.001). There were significantly fewer patients in the Trulicity group who received an additional glycaemic intervention compared to placebo (Trulicity: 2,086 [42.2%]; placebo: 2,825 [57.0%]; p < 0.001).


Special populations

Use in patients with renal impairment
In a 52 week study, Trulicity 1.5 mg and 0.75 mg were compared to titrated insulin glargine as add-on to prandial insulin lispro to evaluate the effect on glycaemic control and safety of patients with moderate to severe chronic kidney disease (eGFR [by CKD-EPI] < 60 and ≥ 15 mL/min/1.73 m2). Patients discontinued their pre-study insulin regimen at randomisation. At baseline, overall mean eGFR was 38 mL/min/1.73 m2, 30% of patients had eGFR < 30 mL/min/1.73 m2.

At 26 weeks, both Trulicity 1.5 mg and 0.75 mg were non-inferior to insulin glargine in lowering of HbA1c and this effect was sustained at 52 weeks. A similar percentage of patients achieved HbA1c targets of < 8.0% at 26 and 52 weeks with both dulaglutide doses as well as insulin glargine.

Table 11. Results of a 52-week active controlled study with two doses of dulaglutide in comparison to insulin glargine (in patients with moderate to severe chronic kidney disease) 
Baseline     Mean change       Patients at    Change in      Change in HbA1c         in HbA1c           target         FBG         body weight HbA1c
(%)             (%)         < 8.0% (%)a     (mmol/L)          (kg)
26 weeks
Dulaglutide 1.5 mg once weekly                8.60           -1.19†               78.3      1.28##         -2.81## (n = 192)
Dulaglutide 0.75 mg once weekly                8.58           -1.12†               72.6      0.98##         -2.02## (n = 190)
Insulin glargine+
8.56           -1.13                75.3      -1.06           1.11 once daily (n = 194)
52 weeks
Dulaglutide 1.5 mg once weekly                8.60           -1.10†               69.1      1.57##         -2.66## (n = 192)
Dulaglutide 0.75 mg once weekly                8.58           -1.10†               69.5      1.15##         -1.71## (n = 190)
Insulin glargine+
8.56           -1.00                70.3      -0.35           1.57 once daily (n = 194)
†
1-sided p-value < 0.025, for non-inferiority of dulaglutide to insulin glargine ## p < 0.001 dulaglutide treatment group compared to insulin glargine
+
Insulin glargine doses were adjusted utilizing an algorithm with a fasting plasma glucose target of ≤ 8.3 mmol/L a
HbA1c value of 8.0% (DCCT) corresponds to 63.9 mmol/mol (IFCC) (average blood glucose: 10.1 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and dulaglutide 0.75 mg, and insulin glargine were 4.44, 4.34, and 9.62 episodes/patient/year, respectively. No patients reported cases of severe hypoglycaemia with dulaglutide 1.5 mg, six with dulaglutide 0.75 mg, and seventeen with insulin glargine. The safety profile of dulaglutide in patients with renal impairment was similar to that observed in other studies with dulaglutide.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

Following subcutaneous administration to patients with type 2 diabetes, dulaglutide reaches peak plasma concentrations in 48 hours. The mean peak (Cmax) and total (AUC) exposures were approximately 114 ng/ml and 14,000 ngh/ml, respectively, after multiple subcutaneous 1.5 mg doses of dulaglutide in patients with type 2 diabetes. Steady-state plasma concentrations were achieved between 2 to 4 weeks of once-weekly administration of dulaglutide (1.5 mg). Exposures after subcutaneous administration of single dulaglutide (1.5 mg) doses in the abdomen, thigh, or upper arm were comparable. The mean absolute bioavailability of dulaglutide following single-dose subcutaneous administration of single 1.5 mg and 0.75 mg doses was 47% and 65%, respectively.

Distribution

The apparent population mean central volume of distribution was 3.09 L and the apparent population mean peripheral volume of distribution was 5.98 L.

Biotransformation

Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways.

Elimination

Apparent population mean clearance of dulaglutide was 0.142 L/h. and the elimination half-life was approximately 5 days.

Special populations

Elderly
Age had no clinically relevant effect on the pharmacokinetic and pharmacodynamic properties of dulaglutide.

Gender and race
Gender and race had no clinically meaningful effect on the pharmacokinetics of dulaglutide.

Body weight or body mass index
Pharmacokinetic analyses have demonstrated a statistically significant inverse relationship between body weight or body mass index (BMI) and dulaglutide exposure, although there was no clinically relevant impact of weight or BMI on glycaemic control.

Renal impairment
The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study and were generally similar between healthy subjects and patients with mild to severe renal impairment (CrCl < 30 ml/min), including end stage renal disease (requiring dialysis). Additionally, in a 52-week clinical study in patients with type 2 diabetes and moderate to severe renal impairment (eGFR [by CKD-EPI] < 60 and ≥ 15 mL/min/1.73 m2), the pharmacokinetic profile of Trulicity 0.75 mg and 1.5 mg once weekly was similar to that demonstrated in previous clinical studies. This clinical study did not include patients with end stage renal disease.


Hepatic impairment
The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study, where subjects with hepatic impairment had statistically significant decreases in dulaglutide exposure of up to 30% to 33% for mean Cmax and AUC, respectively, compared to healthy controls. There was a general increase in tmax of dulaglutide with increased hepatic impairment. However, no trend in dulaglutide exposure was observed relative to the degree of hepatic impairment. These effects were not considered to be clinically relevant.

Paediatric population
Studies characterising the pharmacokinetics of dulaglutide in paediatric patients have not been performed.