Clinical Effectiveness and Safety of Once-Weekly GLP-1 Receptor Agonist Dulaglutide as Add-On to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes

Abstract

Aims and methods: The aim of this monocentric retrospective observational study was to evaluate the 18-month safety and effectiveness of GLP-1 receptor agonist (GLP-1 RA) dulaglutide (DU) 1.5 mg/once weekly as an add-on to metformin (MET) or MET plus conventional insulin secretagogues in a study cohort with excess body weight and type 2 diabetes (T2D). Comparative efficacy versus liraglutide (LIRA) 1.2–1.8 mg/once daily in a study sample naïve to GLP-1 RAs, frequency matching for age, gender, T2D duration, degree of glycemic impairment, 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. Results: 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 mean follow-up of 6 (4 standard deviations (SD)) months, while 65 completed 18 months of continuous therapy. At 6 months, there was a significant mean HbA1c reduction of −0.85% (1.17 SD) with respect to baseline values (p < 0.001), which remained stable during 18 months follow-up. These results were accompanied by a moderate weight loss sustained over time, with a mean reduction of −2.0% (4.3 SD) at 6 months and −1.3% (4.8 SD) at 18 months (p = 0.091). At univariate analysis, a negative correlation between baseline body mass index (BMI) and risk of drug discontinuation due to gastrointestinal AEs was observed. The protective effect of obesity against drug discontinuation was confirmed by logistic regression analysis. Neither gender, nor age, nor T2D duration, nor concomitant conventional insulin secretagogue use, nor switching 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 terms of HbA1c reduction ≥ 0.5% or body weight loss ≥ 5%. The efficacy outcomes were corroborated by head-to-head comparison with LIRA, a GLP-1 RA with durable beneficial effects on glycemic control and body weight in real-world experiences. With the advantage of once-weekly administration, at 18-month follow-up, a significantly 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). Conclusions: Although limited by a retrospective design and lack of constant up-titration for LIRA to the highest dose, these findings indicate that the beneficial responses to DU on a background of MET or MET plus insulin secretagogues are durable, especially in the presence of obesity and greater HbA1c impairment.

Insulin Resistance and Cancer: In Search for a Causal Link

“…Alongside nutrition therapies, pharmacological interventions for diabetes have been suggested to influence cancer risk in affected patients. However, if the use of insulin analogues and conventional insulin secretagogues, which lead to increased levels of circulating insulin [ 290 ], has been associated with increased risk of cancer [ 121 , 122 , 291 , 292 ], metformin and thiazolidinediones (TZDs) may have the potential to prevent tumor development.…”

Association of Glucagon-Like Peptide-1 Receptor Agonist vs Dipeptidyl Peptidase-4 Inhibitor Use With Mortality Among Patients With Type 2 Diabetes and Advanced Chronic Kidney Disease

“…5,6 Both glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are associated with better blood glucose control, greater body weight reduction, lower mortality, and lower incidence of cardiovascular events in the general population with diabetes. [7][8][9] According to the American Diabetes Association guideline, 10 GLP-1 receptor agonist treatment is recommended for patients with diabetes and CKD who have an estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 and are at risk for cardiovascular disease. According to the Kidney Disease: Improving Global Outcomes 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease, 11,12 GLP-1 receptor agonist treatment is suggested for individuals who are unable to use metformin or SGLT-2 inhibitors.…”

The Comparison of the Kidney Effects of Dipeptidyl Peptidase 4 Inhibitors and Glucagon-Like Peptide 1 Agonist-Administered Concomitant with Sodium-Glucose Cotransporter 2 Inhibitors in Japanese Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease

“…Among 408 patients with T2DM, 66 patients stopped SGLT2i because of chronic or recurring genital infections [ 24 ]. They also reported that 13 out of 126 participants with T2DM discontinued dulaglutide due to moderate-severe gastrointestinal AEs [ 25 ]. In the present survey, we showed the superiority of the concomitant use of GLP1Ra during the SGLT2i treatment compared with the concomitant use of DPP4i, especially on the change in eGFR; however, the use of GLP1Ra and SGLT2i may increase the frequency of AEs or the deterioration of eGFR.…”