Safety and effectiveness of the dual GIP/GLP-1 receptor agonist Tirzepatide in people with type 2 diabetes in routine clinical care

Background: Type 2 diabetes (T2D) is a chronic, progressive disease that requires long-term treatment aimed at glycemic control, weight management and prevention of hypoglycemia and cardiovascular complications. Over the last decade, incretin-based therapies have progressively become a cornerstone of its management. Tirzepatide, the first dual GIP/GLP-1 receptor agonist, produced larger reductions in HbA1c and body weight than placebo and active comparators, including semaglutide 1 mg, in the SURPASS program, with the large majority of patients reaching an HbA1c <7% and a substantial proportion achieving a weight loss of 10% or more. However, randomized controlled trials enroll selected populations, and evidence from routine clinical practice is still limited, particularly in older patients with long-standing T2D, a complex glucose-lowering regimen, a high comorbidity burden and previous exposure to GLP-1 receptor agonists (GLP-1RA). Aim of the research: To evaluate the real-world effectiveness of tirzepatide in people with T2D, focusing on changes in HbA1c and body weight, on the achievement of glycemic and weight-loss targets, and on differences according to sex and previous GLP-1RA exposure. Methods: This retrospective, observational, single-center study included all consecutive patients with T2D who initiated tirzepatide at the Diabetology Unit of the Azienda Ospedale-Università di Padova between March 2025 and July 2026. Clinical and laboratory data were collected at baseline and at the first available follow-up. Changes were assessed with paired tests, differences by sex and GLP-1RA exposure with repeated-measures ANOVA, and factors associated with target achievement with logistic regression. Results: Of 495 patients (mean age 64.0 ± 11.1 years, 39.0% men, median diabetes duration 12 years, 74.1% already treated with a GLP-1RA), 357 (72.1%) had a follow-up assessment after a mean of 9.1 ± 3.5 months. HbA1c decreased by 0.91 ± 1.18 percentage points (from 7.70% to 6.90%, p < 0.001) and body weight by 4.65 kg (p < 0.001). Among patients with baseline HbA1c ≥7%, 42.0% reached HbA1c <7% and 20.7% <6.5%; weight loss of ≥5%, ≥10% and ≥15% was achieved by 41.5%, 16.3% and 6.3% of patients, and the combined targets of HbA1c <7% with ≥5% or ≥10% weight loss by 26.5% and 13.4%. Systolic and diastolic blood pressure decreased by a median of 8 and 4 mmHg, together with LDL cholesterol (−2.6 mg/dL), triglycerides (−9 mg/dL) and ALT (−1 U/L), whereas AST, HDL cholesterol and albuminuria did not change significantly. GLP-1RA-naïve patients had greater reductions than previously treated patients (HbA1c −1.66 vs −0.70 percentage points; weight −6.99 vs −4.00 kg), and naïve status was independently associated with reaching HbA1c <7% (OR 8.18) and ≥5% weight loss (OR 2.66), together with a lower baseline HbA1c, while no difference was found between sexes, either for HbA1c (p = 0.200) or for body weight (p = 0.682). Sulfonylureas/glinides were discontinued in 41.3% of users, and basal-bolus and basal insulin in 25.0% and 16.8%, respectively; among patients who continued basal-bolus insulin, the mean daily dose decreased from 70.9 to 60.3 U (median −2.5 U/day, p = 0.015). Conclusions: In routine clinical practice, tirzepatide was associated with clinically relevant improvements in glycemic control, body weight and cardiometabolic parameters, and with a reduction in the use of hypoglycemia-prone therapies, in a population older and more complex than those enrolled in randomized trials. The magnitude of the effects was smaller than in the SURPASS trials and similar to that reported in other real-world cohorts, and the response was greater in GLP-1RA-naïve patients; this is likely related to a lower baseline HbA1c and a very high proportion of previous GLP-1RA exposure.