alogliptin and Hypertension

Background Blood pressure ( BP ) treatment goals in patients with diabetes mellitus and increased cardiovascular risk remain controversial. Our study objective was to determine cardiovascular outcomes according to achieved BP s over the average follow-up period in the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) trial. Methods and Results EXAMINE was a cardiovascular outcomes trial in 5380 patients with type 2 diabetes mellitus and recent acute coronary syndromes. Risks of major adverse cardiac events and cardiovascular death or heart failure were analyzed using a Cox proportional hazards model with adjustment for baseline covariates in 10-mm Hg increments of clinician-measured systolic BP from ≤100 to >160 mm Hg and diastolic BP from ≤60 to >100 mm Hg averaged during the 24 months after randomization. Based on 2015 guidelines from the American College of Cardiology, the American Heart Association and the American Society of Hypertension and 2017 American Diabetes Association guidelines, systolic BP s of 131 to 140 mm Hg and diastolic BP s of 81 to 90 mm Hg were the reference groups. A U-shaped relationship between cardiovascular outcomes and BP s was observed. Importantly, compared with the systolic BP reference group, adjusted hazard ratios for major adverse cardiac events and cardiovascular death or heart failure were significantly higher in patients with systolic BP s <130 mm Hg. Similarly, compared with the diastolic BP reference group, adjusted hazard ratios for major adverse cardiac events and for cardiovascular death or heart failure were significantly higher for diastolic BP s <80 mm Hg. Conclusions In patients with type 2 diabetes mellitus and recent acute coronary syndrome, average BP s <130/80 mm Hg were associated with worsened cardiovascular outcomes. These data suggest that intensive control of BP in patients with type 2 diabetes mellitus and ischemic heart disease should be evaluated in a prospective randomized trial. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00968708.

Topics: Aged; Analysis of Variance; Blood Pressure Determination; Cause of Death; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Myocardial Ischemia; Piperidines; Prognosis; Prospective Studies; United States; Uracil

Glucagon-like peptide-1 (GLP-1), a novel type of glucose-lowering agent, has been reported to exert cardioprotective effects. However, the cardioprotective mechanism of GLP-1 on spontaneous hypertension-induced cardiac hypertrophy has not been fully elucidated. In this study, we revealed that liraglutide or alogliptin treatment ameliorated spontaneous hypertension-induced cardiac hypertrophy, as evidenced by decreased levels of cardiac hypertrophic markers (atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain), as well as systolic blood pressure, diastolic blood pressure, mean arterial pressure, and histological changes. Both drugs significantly reduced the levels of angiotensin II (AngII) and AngII type 1 receptor (AT1R) and upregulated the levels of AngII type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2), as indicated by a reduced AT1R/AT2R ratio. Simultaneously, treatment with liraglutide or alogliptin significantly increased GLP-1 receptor expression and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and downregulated the phosphorylation of mammalian target of rapamycin (mTOR), p70 ribosomal S6 protein kinase, and eukaryotic translation initiation factor 4E binding protein 1 in spontaneous hypertension rats. Furthermore, our data demonstrated that the AMPK inhibitor compound C or mTOR activator MHY1485 inhibited the anti-hypertrophic effect of GLP-1. In summary, our study suggests that liraglutide or alogliptin protects the heart against cardiac hypertrophy by regulating the expression of AngII/AT1R/ACE2 and activating the AMPK/mTOR pathway, and GLP-1 agonist can be used in the treatment of patients with cardiac hypertrophy.

Topics: Adenylate Kinase; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Cardiomegaly; Cardiotonic Agents; Cell Line; Disease Models, Animal; Glucagon-Like Peptide 1; Hypertension; Liraglutide; Male; Morpholines; Myocytes, Cardiac; Piperidines; Rats; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Triazines; Uracil

In addition to serving as an incretin-based treatment of type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 (GLP-1) can also reverse cardiovascular diseases caused by vascular remodelling. However, a detailed mechanism underlying how GLP-1 reverses vascular remodelling remains unclear. Here, Spontaneous hypertension rats (SHR) were used as an in vivo model of vascular remodelling. Treatment with a GLP-1 receptor (GLP-1R) agonist Liraglutide or dipeptidyl peptidase 4 (DPP4) inhibitor Alogliptin decreased systolic blood pressure (SBP), diastolic blood pressure (DBP), thickness of vascular wall, and overall collagen levels in SHR. In vitro vascular remodelling can be induced by exposing rat aortic smooth muscle cells (RASMC) to angiotensin II (Ang II); GLP-1 treatment attenuated AngII induction of RASMC proliferation, migration, and excessive extracellular matrix (ECM) degradation. Downregulation of matrix metalloproteinase 1 (MMP1) enhanced the inhibitory effects of GLP-1, and extracellular regulated protein kinase 1/2 (ERK1/2) and nuclear factor kappa-B (NF-κB) signalling participated in these processes. These results provide a new mechanistic understanding of key therapeutic strategies for the treatment of vascular remodelling-related diseases.

Topics: Animals; Blood Pressure; Cells, Cultured; Dipeptidyl-Peptidase IV Inhibitors; Down-Regulation; Gene Expression Regulation, Enzymologic; Glucagon-Like Peptide 1; Hypertension; Liraglutide; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 1; Myocytes, Smooth Muscle; NF-kappa B; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Uracil; Vascular Remodeling

The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors on blood pressure in patients with diabetes mellitus (DM) are controversial. There is no information on the effect of DPP-4 inhibitors on blood pressure and arterial stiffness in hypertensive patients with DM. We evaluated the effects of alogliptin on blood pressure and arterial stiffness in hypertensive patients with type 2 diabetes mellitus (T2DM).. Blood pressure and brachial-ankle pulse wave velocity (baPWV) were measured before and after 3, 6, and 12 months of treatment with alogliptin in 22 hypertensive patients with T2DM.. After 3, 6, and 12 months, alogliptin treatment decreased hemoglobin A1c from 7.0 ± 0.97% to 6.4 ± 0.61%, 6.3 ± 0.58%, and 6.3 ± 0.75% (P < 0.01, respectively), glucose from 8.6 ± 4.39 mmol/l to 7.05 ± 2.16, 7.05 ± 2.28, and 6.44 ± 1.50 mmol/l (P < 0.01, respectively), systolic blood pressure from 137 ± 18 mm Hg to 127 ± 13, 125 ± 15, and 120 ± 17 mm Hg (P < 0.01, respectively), diastolic blood pressure from 79 ± 13 mm Hg to 74 ± 8, 74 ± 10, and 70 ± 8 mm Hg (P < 0.01, respectively) and baPWV from 1,947 ± 349 cm/second to 1,774 ± 259, 1,856 ± 361, and 1,756 ± 286 cm/second (P < 0.01, respectively). A baseline baPWV value of 1,643 cm/second was the optimal cut-off value for patients who had reduced blood pressure after treatment with alogliptin (sensitivity of 83.3% and specificity of 75.0%).. Alogliptin was associated with improvements not only in glucose metabolism but also in blood pressure and arterial stiffness in hypertensive patients with T2DM. The cut-off value of baPWV may enable identification of responders of decrease in blood pressure by alogliptin in hypertensive patients with T2DM.. Registration Number for Clinical Trial: UMIN000007722.

Topics: Aged; Arterial Pressure; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Prospective Studies; Time Factors; Treatment Outcome; Uracil; Vascular Stiffness