Trulicity (Page 7 of 14)

14.4 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus and Moderate to Severe Chronic Kidney Disease

In this open-label comparator trial (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26 weeks, a total of 576 adult patients with type 2 diabetes were randomized and treated to compare TRULICITY 0.75 mg and 1.5 mg with insulin glargine (NCT01621178).

Patients on insulin and other antidiabetic therapy (e.g., oral antidiabetic drugs, pramlintide) had non-insulin therapies discontinued and had their insulin dose adjusted for 12 weeks prior to randomization. Patients on insulin therapy alone maintained a stable insulin dose for 3 weeks prior to randomization. At randomization, patients discontinued their pre-trial insulin regimen and patients were randomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro. For patients randomized to insulin glargine, the initial insulin glargine dose was based on the basal insulin dose prior to randomization. Insulin glargine was allowed to be titrated with a fasting plasma glucose goal of ≤150 mg/dL. Insulin lispro was allowed to be titrated with a preprandial and bedtime glucose goal of ≤180 mg/dL.

Patients had a mean age of 65 years; a mean duration of type 2 diabetes of 18 years; 52% were male; race: White, Black, and Asian were 69%, 16%, and 3%, respectively; and 32% of the trial population were in the US. At baseline, overall mean eGFR was 38 mL/min/1.73 m2 , 30% of patients had eGFR <30 mL/min/1.73 m2 , and 45% of patients had macroalbuminuria. Patients on over 70 units/day of basal insulin were excluded from the trial.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c at 26-weeks from baseline. The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%. Mean fasting plasma glucose increased in the TRULICITY arms (Table 13).

Mean baseline body weight was 90.9 kg, 88.1 kg, and 88.2 kg in the TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine arms, respectively. The mean changes from baseline at Week 26 were -1.1, -2, and 1.9 kg in the TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine arms, respectively.

Table 13: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lispro, in Patients with Moderate to Severe Chronic Kidney Disease in Adult Patients with Type 2 Diabetes Mellitusa

Abbreviation: HbA1c = hemoglobin A1c

a Intent-to-treat population (all randomized and treated patients) was used in the analysis regardless of discontinuation of study drug or initiation of rescue therapy. At Week 26, primary efficacy was missing for 12%, 15%, and 9% of individuals randomized to and treated with TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine, respectively. Missing data were imputed using multiple imputation within treatment group.

b Least-squares (LS) mean from ANCOVA pattern mixture model adjusted for baseline value and other stratification factors.

26-Week Primary Time Point
TRULICITY0.75 mg TRULICITY1.5 mg Insulin Glargine
Intent-to-Treat Population (N) 190 192 194
HbA1c (%) (Mean)
Baseline 8.6 8.6 8.6
Change from baselineb -0.9 -1.0 -1.0
Difference from insulin glargineb (95% CI) 0.0 (-0.2, 0.3) -0.1 (-0.3, 0.2)
Percentage of patients HbA1c <8.0% 73 75 74
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 167 161 170
Change from baselineb 6 14 -23
Difference from insulin glargineb (95% CI) 30 (16, 43) 37 (24, 50)

14.5 Cardiovascular Outcomes Trial in Adults with Type 2 Diabetes Mellitus and Cardiovascular Disease or Multiple Cardiovascular Risk Factors

The REWIND trial (NCT01394952) was a multi-national, multi-center, randomized, placebo-controlled, double-blind trial. In this trial, 9901 adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors were randomized to TRULICITY 1.5 mg or placebo both added to standard of care. The median follow-up duration was 5.4 years. The primary endpoint was the time to the first occurrence of a composite 3-component Major Adverse Cardiovascular Events (MACE) outcome, which included CV death, non-fatal myocardial infarction (MI), and non-fatal stroke.

Patients eligible to enter the trial were 50 years of age or older who had type 2 diabetes mellitus, had an HbA1c value ≤9.5% with no lower limit at screening, and had either established CV disease, or did not have established CV disease but had multiple CV risk factors. Patients who were confirmed to have established CV disease (31.5% of randomized patients) had a history of at least one of the following: MI (16.2%); myocardial ischemia by a stress test or with cardiac imaging (9.3%); ischemic stroke (5.3%); coronary, carotid, or peripheral artery revascularization (18.0%); unstable angina (5.9%); or hospitalization for unstable angina with at least one of the following: ECG changes, myocardial ischemia on imaging, or a need for percutaneous coronary intervention (12.0%). Patients confirmed to be without established CV disease, but with multiple CV risk factors, comprised 62.8% of the randomized trial population.

At baseline, demographic and disease characteristics were balanced between treatment groups. Patients had a mean age of 66 years; 46% were female; race: White, Black, and Asian were 76%, 7%, and 4%, respectively.

The median baseline HbA1c was 7.2%. The mean duration of type 2 diabetes was 10.5 years and the mean BMI was 32.3 kg/m2.

At baseline, 50.5% of patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73m2), 21.6% had moderate renal impairment (eGFR ≥30 but <60 mL/min/1.73m2), and 1.1% of patients had severe renal impairment (eGFR <30 mL/min/1.73m2) out of 9713 patients whose eGFR were available.

At baseline, 94.7% of patients were taking antidiabetic medication, with 10.5% of patients taking three or more antidiabetic drugs. The most common background antidiabetic drugs used at baseline were metformin (81.2%), sulfonylurea (46.0%), and insulin (23.9%). At baseline, CV disease and risk factors were managed with ACE inhibitors or angiotensin receptor blockers (81.5%), beta blockers (45.6%), calcium channel blockers (34.4%), diuretics (46.5%), statin therapy (66.1%), antithrombotic agents (58.7%), and aspirin (51.7%). During the trial, investigators were to modify anti-diabetic and cardiovascular medications to achieve local standard of care treatment targets with respect to blood glucose, lipids, and blood pressure, and manage patients recovering from an acute coronary syndrome or stroke event per local treatment guidelines.

For the primary analysis, a Cox proportional hazards model was used to test for superiority. Type I error was controlled across multiple tests. TRULICITY significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal MI, or non-fatal stroke (HR: 0.88, 95% CI 0.79, 0.99). Refer to Figure 6 and Table 14.

Vital status was available for 99.7% of patients in the trial. A total of 1128 deaths were recorded during the REWIND trial. A majority of the deaths in the trial were adjudicated as CV deaths, and non-CV deaths were comparable between the treatment groups (4.4% in patients treated with TRULICITY and 5.0% in patients treated with placebo). There were 536 all-cause deaths (10.8%) in the dulaglutide group compared to 592 deaths (12.0%) in the placebo group.

Figure 6
(click image for full-size original)
Number of patients at risk
Placebo495247914625443742753575742
Dulaglutide494948154670452143693686741

Figure 6. KAPLAN MEIER CURVE: Time to First Occurrence of MACE in the REWIND Trial

Table 14: Treatment Effect for MACE and the Individual Components in the REWIND Trial, Median Trial Observation Time of 5.4 years in Adult Patients with Type 2 Diabetes Mellitusa

a All randomized patients.

b Cox-proportional hazards model with treatment as a factor. Type I error was controlled for the primary and secondary endpoints.

c p=0.026 for superiority (2-sided).

d Number and percentage of patients with events.

e Results for components of MACE, fatal and non-fatal stroke, and fatal and non-fatal MI are listed descriptively for supportive purposes. No statistical significance should be inferred since these CIs are not adjusted for multiplicity.

Time to First Occurrence of: TRULICITY N=4949 Placebo N=4952 Hazard Ratio (95% CI) b
Composite of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death (MACE)d 594 (12.0%)663 (13.4%)0.88 (0.79, 0.99)c
Cardiovascular deathd,e 317 (6.4%)346 (7.0%)0.91 (0.78, 1.06)
Non-fatal myocardial infarctiond,e 205 (4.1%)212 (4.3%)0.96 (0.79, 1.16)
Non-fatal stroked,e 135 (2.7%)175 (3.5%)0.76 (0.61, 0.95)
Fatal or non-fatal myocardial infarctiond,e 223 (4.5%)231 (4.7%)0.96 (0.79, 1.15)
Fatal or non-fatal stroked,e 158 (3.2%)205 (4.1%)0.76 (0.62, 0.94)

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