{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:23:38Z","timestamp":1785435818114,"version":"3.56.0"},"reference-count":25,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018786","name":"Al-Zaytoonah University of Jordan","doi-asserted-by":"publisher","award":["2026-2025\/09\/07"],"award-info":[{"award-number":["2026-2025\/09\/07"]}],"id":[{"id":"10.13039\/501100018786","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2026-2025\/09\/07"],"award-info":[{"award-number":["2026-2025\/09\/07"]}],"id":[{"id":"https:\/\/ror.org\/04a5b0p13","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Diabetes mellitus type 2 (T2DM) is often associated with hypertension, necessitating treatment with combinations of medications that address both glycemic control and blood pressure. Whether commonly co-prescribed antihypertensives modify the glycemic efficacy of a sulfonylurea remains insufficiently characterized in controlled preclinical models. Methods: One hundred adult male Wistar rats were allocated to ten parallel groups (n = 10): healthy and diabetic untreated controls; glimepiride, bisoprolol or amlodipine monotherapy (in healthy and diabetic animals); and the diabetic combinations glimepiride+bisoprolol and glimepiride+amlodipine. T2DM was induced with a high-fat diet plus low-dose streptozotocin (35 mg\/kg, i.p.) and confirmed by fasting blood glucose \u2265 200 mg\/dL. Glycated hemoglobin (HbA1c) was measured weekly for 11 weeks. Non-parametric inference (Kruskal\u2013Wallis, Dunn\u2019s with Bonferroni correction, Mann\u2013Whitney U, Wilcoxon signed-rank) was complemented by Random Forest regression and PCA\/K-means clustering. Results: Week-11 HbA1c differed markedly across groups (Kruskal\u2013Wallis H = 94.3, p &lt; 0.001). Glimepiride + bisoprolol achieved near-normal control (4.37% \u00b1 0.15), statistically indistinguishable from healthy groups (p \u2265 0.33), and was the only diabetic regimen with a declining trajectory (\u22120.66 percentage points; Wilcoxon p = 0.004). Adding either antihypertensive to glimepiride did not worsen glycemic control. Amlodipine monotherapy did not attenuate hyperglycemia (8.47% \u00b1 0.20), approaching that of untreated diabetic controls (9.31% \u00b1 0.18), consistent with the absence of intrinsic glucose-lowering activity. All agents showed pronounced disease-state dependence (healthy\u2013diabetic divergence 2.33\u20133.13 points). Random Forest prediction was accurate (R2 = 0.985), and unsupervised clustering separated effective from ineffective regimens, corroborating the statistical findings. Conclusions: In this model, bisoprolol co-administration enhanced and amlodipine co-administration preserved glimepiride-mediated glycemic control. Glimepiride+bisoprolol emerged as the most effective regimen, supporting cardioselective \u03b2-blockade as a metabolically favorable antihypertensive partner for sulfonylurea therapy and warranting clinical confirmation. More broadly, these results provide a preclinical, evidence-based rationale for selecting metabolically favorable antihypertensives in patients with coexisting T2DM and hypertension, with the potential to improve glycemic outcomes and reduce the risk of adverse drug\u2013disease interactions during combination therapy.<\/jats:p>","DOI":"10.3390\/ph19071064","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T09:46:47Z","timestamp":1783676807000},"page":"1064","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bisoprolol and Amlodipine Co-Administration with Glimepiride in a Diabetic Rat Model: A Statistical and Machine Learning Analysis"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4263-0134","authenticated-orcid":false,"given":"Mohammad","family":"Hailat","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6330-766X","authenticated-orcid":false,"given":"Zeyad","family":"Hailat","sequence":"additional","affiliation":[{"name":"Department of Information Systems, Yarmouk University, Irbid 21163, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mo\u2019ath","family":"Ifraitekh","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3691-9759","authenticated-orcid":false,"given":"Zainab","family":"Zakaraya","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Al-Ahliyyah Amman University, Amman 11931, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwan","family":"Shalash","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Zarqa University, Zarqa 13111, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israa","family":"Al-Ani","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmacy, Middle East University, Amman 11831, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5832-7247","authenticated-orcid":false,"given":"Wael","family":"Abu Dayyih","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mutah University, Al Karak 61710, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/s11883-012-0227-2","article-title":"Diabetes and hypertension: Is there a common metabolic pathway?","volume":"14","author":"Cheung","year":"2012","journal-title":"Curr. 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