Purpose <p>β-blockers (BB) are a heterogeneous class of medications guideline-recommended for heart failure (HF) and diabetes mellitus (DM). However, physicians may be reluctant to prescribe BBs due to concerns regarding negative metabolic effects. The primary objective was to assess the short-term change in glucose control in PwT2DM (patients with T2DM) who initiated bisoprolol versus the reference cohorts. Secondary objectives were to assess change in lipid control, and proportion of patients with hypoglycemic events during follow-up in PwT2DM who initiated bisoprolol.</p> Methods <p>We performed a retrospective cohort study of T2DM patients on bisoprolol compared to no treatment, carvedilol, other selective BBs, or nonselective BBs. Anonymized data was collected from the Maccabi Health Services (MHS) database between 2003 and 2023.</p> Results <p>A total of 12,981 records were analyzed. The reduction in HbA1C (difference of −0.05 [−0.09, −0.01]), fasting plasma glucose (FPG) (difference of −1.72 [−3.35, −0.1]), and cholesterol measures (total, HDL, LDL differences of −9.12 [−10.94, −7.31], −0.94 [−1.24, −0.65], and −7.89 [−9.53, −6.26], respectively) was significantly greater in the bisoprolol cohort compared to reference cohort 1 (no treatment). In cohort 2, the reduction in HbA1C was significantly greater with carvedilol users compared to bisoprolol users (difference of 0.34 [0.04, 0.63]). The reduction in total cholesterol and LDL was significantly greater in the bisoprolol cohort compared to reference cohort 4 (nonselective BB users, differences of −5.86 [−9.46, −2.25] and −7.08 [−10.25, −3.92], respectively).</p> Conclusion <p>Bisoprolol had a neutral effect on the glycemic profile with a statistically beneficial impact on the lipid profile, comparable to carvedilol.</p>