Long-Term Effectiveness and Safety of Once Weekly Dulaglutide as Add-on to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes

Aim of this monocentric retrospective observational study was to evaluate the 18-month effectiveness and safety of once weekly 1.5 mg GLP-1 receptor agonist (GLP-1 RA) dulaglutide (DU) as add-on to metformin (MET) or MET plus conventional insulin secretagogues (SFU/glinide) in a study cohort with excess body weight (BW) and type 2 diabetes (T2D). Comparative efficacy versus once daily 1.2/1.8 mg liraglutide (LIRA) in a study sample naïve to GLP-1 RAs, matching for age, gender, BMI, T2D duration, cardiovascular comorbidities and medications, was addressed as a secondary aim. Clinical and biochemical data for efficacy outcomes and information on drug discontinuation due to adverse events (AEs) were collected from digital records. Initial analysis included 126 overweight and obese T2D patients (48.4% females). Out of these, 13 discontinued DU due to moderate-severe gastrointestinal AEs after a median follow-up of 6 (3 to 8) months, while 65 completed 18 months of continuous therapy. At 6 months, there was a significant median HbA1c reduction of -0.9 (-1.50 to -0.20) % with respect to baseline values (p<0.001), which remained stable during 18 months of follow-up. These results were accompanied by a moderate BW loss sustained over time, with a median reduction of -1.16 (-4,29 to 0.45) % at 6 months and -1.47 (-4.2 to 0.72) % at 18 months (p=0.048). At univariate Spearman analysis, a negative correlation between baseline BMI and risk of drug discontinuation due to gastrointestinal AEs was observed. The protective effect of obesity (BMI ≥ 30kg/m(2)) against drug discontinuation was confirmed by an exploratory logistic regression analysis, while adjusting for confounders [OR 0.211 (95%CI 0.058–0.771), p=0.019]. Neither gender, nor age, nor T2D duration, nor concomitant SUF/glinide use, nor shifting to DU from other GLP-1 RAs influenced its long-term effectiveness. However, higher baseline HbA1c values emerged as predictors of clinically relevant efficacy outcomes, either in form of HbA1c reduction ≥ 0.5% [OR 2.961 (95%CI 1.394–6.290), p=0.005] or BW loss ≥ 5% [OR 2.571 (95%CI 1.171–5.644), p=0.019]. The efficacy outcomes were corroborated by head-to-head comparison with LIRA, a GLP-1 RA with durable beneficial effects on glycemic control and BW in real word scenarios (1). With the advantage of once weekly administration, at 18-month follow-up, a significant larger fraction of patients on DU therapy reached glycemic targets (HbA1c ≤ 7.0%) when compared to those on LIRA: from 14.8% at baseline (both groups) to 64.8% with DU and 42.6% with LIRA (p=0.033). Although limited by a retrospective design and lack of constant up-titration for LIRA to the highest dose, these findings indicate that the beneficial glycometabolic responses to DU on a background of MET or MET plus SFU/glinide are durable, especially in presence of obesity and greater HbA1c impairment. (1) Ref: Mirabelli et al. IJERPH. 2019;17(1):207.