Trulicity Plateau & Non-Response Troubleshooting: A Clinical Guide

Two Different Stalls: Glucose and Weight

People usually mean one of two things by a plateau: an HbA1c that has stopped falling, or weight that has stopped falling. Trulicity is approved to improve glycemic control in adults and children 10 years and older with type 2 diabetes, and to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It has no weight-loss indication [1]. In AWARD-11, weight change was a secondary objective, so a weight stall and a glucose stall are different questions [2].

The Dose Check Comes First

The adult schedule in the label is 0.75 mg once weekly, increased to 1.5 mg after 4 weeks if more glycemic control is needed, then increased in 1.5 mg steps after at least 4 weeks on the current dose, to a maximum of 4.5 mg weekly [1]. That leaves three possible steps above the starting dose: 1.5, 3 and 4.5 mg. Someone who has never gone above 1.5 mg has not used the full adult range.

What AWARD-11 found at 3 and 4.5 mg

AWARD-11 randomized 1,842 adults with type 2 diabetes inadequately controlled on metformin to dulaglutide 1.5 mg, 3.0 mg or 4.5 mg weekly for 52 weeks, with the primary comparison at 36 weeks [2]. Mean baseline HbA1c was 8.6% [2]. At 36 weeks, 4.5 mg was superior to 1.5 mg: HbA1c fell 1.77 versus 1.54 percentage points on the treatment-regimen analysis (estimated difference -0.24, P<0.001), and 1.87 versus 1.53 points on the on-treatment analysis (difference -0.34, P<0.001) [2]. The 3.0 mg dose beat 1.5 mg on the on-treatment analysis only (difference -0.17, P=0.003; treatment-regimen analysis P=0.096) [2]. The 4.5 mg dose was also superior to 1.5 mg for weight loss at 36 weeks under both analyses [2]. The label reports HbA1c below 7.0% in 50%, 56% and 62% of patients on 1.5, 3 and 4.5 mg [1].

What the higher doses cost in side effects

In the same 36-week trial, nausea was reported by 13.4% on 1.5 mg, 15.6% on 3 mg and 16.4% on 4.5 mg; diarrhea by 7.0%, 11.4% and 10.7%; and vomiting by 5.6%, 8.3% and 9.3% [1]. In the adult placebo-controlled pool at the two lower doses, any gastrointestinal reaction occurred in 21% on placebo, 32% on 0.75 mg and 41% on 1.5 mg, and treatment was stopped for GI reasons in 0.2%, 1.3% and 3.5% respectively [1]. Severe gastrointestinal reactions were reported in 1.4% on placebo, 2.2% on 0.75 mg and 4.3% on 1.5 mg [1]. The label states that Trulicity is not recommended in patients with severe gastroparesis [1].

When 4.5 mg Is Already the Dose

The adult label stops at 4.5 mg weekly and gives no further escalation [1]. What it does address is combining with insulin or a sulfonylurea: when starting Trulicity, the label advises considering a reduction in the insulin or sulfonylurea dose to lower hypoglycemia risk [1]. The label's tables show hypoglycemia below 54 mg/dL in 14.7% of patients on Trulicity 1.5 mg with insulin glargine versus 9.3% on placebo with glargine, and 3.3% with glimepiride versus 0% [1].

Switching: What the Head-to-Head Trials Show

SUSTAIN-7 was an open-label trial in 1,201 adults with HbA1c 7.0 to 10.5% on metformin alone, run at 194 sites in 16 countries [4]. At 40 weeks, semaglutide 1.0 mg lowered HbA1c by 1.8 percentage points versus 1.4 with dulaglutide 1.5 mg, and semaglutide 0.5 mg lowered it by 1.5 points versus 1.1 with dulaglutide 0.75 mg (estimated difference -0.40, p<0.0001) [4]. Enrollment required inadequate control on metformin monotherapy, and neither dulaglutide 3 mg nor 4.5 mg was tested [4].

SURPASS-CVOT randomized adults with type 2 diabetes and atherosclerotic cardiovascular disease to tirzepatide up to 15 mg or dulaglutide 1.5 mg weekly; 13,165 patients were included in the modified intention-to-treat analysis. Cardiovascular death, myocardial infarction or stroke occurred in 12.2% on tirzepatide and 13.1% on dulaglutide (hazard ratio 0.92, 95.3% CI 0.83 to 1.01): noninferior, with superiority not met [5]. The dulaglutide arm in that trial was 1.5 mg, not the 4.5 mg adult maximum.

The Cardiovascular Result Was Shown at 1.5 mg

REWIND enrolled 9,901 adults aged 50 and older with type 2 diabetes and either a previous cardiovascular event or cardiovascular risk factors, at 371 sites in 24 countries [3]. Participants received dulaglutide 1.5 mg weekly or placebo and were followed for a median of 5.4 years [3]. The primary composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death occurred in 12.0% versus 13.4% (hazard ratio 0.88, 95% CI 0.79 to 0.99; p=0.026) [3]. All-cause death was 10.8% versus 12.0%, which was not significant [3]. The label reports fatal or non-fatal stroke at 3.2% versus 4.1% (hazard ratio 0.76) [1]. Gastrointestinal adverse events were reported by 47.4% of dulaglutide patients and 34.1% of placebo patients during follow-up [3].

REWIND tested only the 1.5 mg weekly dose [3].

Kidney Disease and Children

The label reports no clinically relevant effect of renal or hepatic impairment on dulaglutide pharmacokinetics [1]. AWARD-7 randomized 577 adults with type 2 diabetes and stage 3 to 4 chronic kidney disease to dulaglutide 1.5 mg, dulaglutide 0.75 mg or insulin glargine, all with insulin lispro, for 52 weeks; HbA1c change at 26 weeks on dulaglutide was non-inferior to glargine [6]. Only the 0.75 and 1.5 mg doses were studied in that trial [6].

Children have a lower ceiling. The maximum recommended pediatric dose is 1.5 mg once weekly, reached after at least 4 weeks at 0.75 mg [1]. In the 26-week trial of 154 patients aged 10 to under 18, HbA1c rose 0.6 points on placebo and fell 0.6 points on 0.75 mg and 0.9 points on 1.5 mg (P<0.001 for both comparisons). HbA1c below 7.0% was reached by 51% of pooled dulaglutide patients versus 14% on placebo, and there was no difference in BMI change [7]. For a pediatric patient on Trulicity, there is no higher labeled dose to move to.

What to Track

HbA1c was the primary endpoint at 36 weeks in AWARD-11 [2], and each labeled dose step is held for at least 4 weeks before the next one [1]. The label says to follow its dose escalation to reduce the risk of gastrointestinal adverse reactions [1]. In the adult placebo-controlled trials, 3.5% of patients taking 1.5 mg stopped treatment because of gastrointestinal reactions, and nausea, diarrhea and vomiting were among the most common adverse reactions [1]. If a dose is missed, the label says to take it if at least 3 days (72 hours) remain before the next scheduled dose, and otherwise to skip it and resume the usual day [1].