enalapril and Hypoglycemia

Renin, angiotensin-II, and angiotensin-converting enzyme (ACE) have been found in the hypothalamus and pituitary in rats, and renin, angiotensinogen, and ACE have been found in human pituitary lactotrophs. To determine the physiological relevance of the renin-angiotensin system in the pituitary hormone response to stress in humans, we created significant inhibition of ACE by administering a clinically used dose (10 mg) of enalapril (E) 4 h before measuring the stress hormone responses to insulin-induced hypoglycemia. Eight fasting lean healthy males (aged 20-35 yr) were given either placebo (P) or E (10 mg, orally) in two studies separated by at least 5 days in a blinded study design. Glucose, ACTH, cortisol, PRL, and GH levels were measured before E or P and at 20-min intervals beginning 20 min before insulin administration. ACE levels were similar at baseline (E, 21.6 +/- 2.7; P, 22.4 +/- 2.4 mU/mL/min), but were significantly lower at the time of insulin injection with E treatment (E, 2.9 +/- 0.5; P, 20.9 +/- 2.5 mU/mL/min; P less than 0.001). The mean of the total area under the curve of PRL secretion was significantly lower for the E group (E, 3767.2 +/- 710.7; P, 4554.9 +/- 650.1 micrograms/L.min; P less than 0.05). Although the mean peak PRL levels were lower for the E group, this did not reach statistical significance (E, 53.0 +/- 9.7; P, 64.4 +/- 9.4 micrograms/L; 0.05 less than P less than 0.10). These differences in PRL responses appeared to be due primarily to substantial decreases in PRL responses with E in three of the eight subjects. No significant differences were found with ACTH, cortisol, or GH for basal levels, peak levels, or areas under the curve.

Topics: Adrenocorticotropic Hormone; Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Hypothalamo-Hypophyseal System; Hypothalamus; Insulin; Male; Peptidyl-Dipeptidase A; Pituitary Gland; Prolactin

In diabetic patients, it has been suggested that angiotensin converting enzyme inhibitors may be associated with unexplained hypoglycaemic episodes. Such a side effect may limit the use of these drugs in diabetic hypertensive patients. Ten insulin-dependent diabetic patients mean age 38.4 +/- 13.1 years, mean diabetes duration 10.3 +/- 6.6 years (m +/- SD) were selected on the basis of good glycaemic control: HbA1: 7.6 +/- 0.9 per cent (upper limit of normal value less than 7.5 per cent) on continuous subcutaneous insulin infusion. In a double blind study, they were randomly and successively allocated for a 3 months period to enalapril 20 mg daily or placebo. Before treatment, after enalapril and placebo, mean blood glucose values, HbA1, daily insulin dosage were recorded as well as the number of clinical and biological (less than 3 mmol/l) hypoglycaemic episodes. Peripheral insulin sensitivity was assessed by euglycaemic insulin clamp technique. Compared to placebo, enalapril did not induce any modification of daily insulin dosage, glycaemic control. The incidence of hypoglycaemic episodes was similar. Neither peripheral insulin sensitivity was modified by enalapril. In the conditions of this study, enalapril did not interfere with glycaemic control in insulin-dependent diabetics in good metabolic control.

Topics: Administration, Cutaneous; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 1; Double-Blind Method; Enalapril; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Insulin Infusion Systems; Male; Middle Aged; Random Allocation

Topics: Captopril; Enalapril; Humans; Hypoglycemia

Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes.. We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF.. Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Blood Glucose; Diabetes Mellitus; Enalapril; Glycated Hemoglobin; Heart Failure; Humans; Hypoglycemia; Insulins; Stroke Volume; Tetrazoles; Valsartan; Ventricular Function, Left

Antihypertensive drugs are commonly prescribed for the treatment of patients with both diabetes and hypertension. However, the role of selected agents in the development of hypoglycemia remains controversial. The main objective of this study was to evaluate the effect of antihypertensive agents on the risk of hypoglycemia in diabetic patients receiving insulin or sulfonylurea therapy. A matched case-control study was conducted using Pennsylvania Medicaid data. Five control subjects, matched for sex and age, with no reported medical condition of hypoglycemia, were randomly selected for each case patient admitted for hypoglycemia in 1993, resulting in a total of 404 cases and 1375 controls. With these sample sizes, we were able to detect a difference of 10% (P < 0.05) for our primary outcome measure, hospitalization for hypoglycemia. The relative risk of hypoglycemia was estimated using an unconditional logistic regression. The risk of hypoglycemia was 5.5 times greater (95% confidence interval [CI], 4.0 to 7.6) in insulin versus sulfonylurea users and was not influenced by use of angiotensin-converting enzyme (ACE) inhibitors overall. However, use of the ACE inhibitor enalapril was associated with an increased risk of hypoglycemia (odds ratio, 2.4; 95% CI, 1.1 to 5.3) in sulfonylurea users, suggesting that analyzing the unintended side effects of a class of drugs can sometimes mask the adverse effects of individual drugs. Use of beta-blockers was not associated with an increased risk of hypoglycemia, providing further empiric evidence that beta-blockers are an appropriate treatment for persons with concomitant diabetes and hypertension. Per capita health care costs were approximately 3 times higher in patients hospitalized for hypoglycemia compared with controls (P < 0.05). Hospitalization for hypoglycemia is expensive and may be prevented with appropriate monitoring of diabetic patients taking selected antihypertensive agents such as enalapril.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Data Collection; Diabetes Mellitus; Drug Interactions; Enalapril; Female; Hospitalization; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Logistic Models; Male; Middle Aged; Monitoring, Physiologic; Retrospective Studies; Risk Factors; Sulfonylurea Compounds; Treatment Outcome

Angiotensin II facilitates epinephrine release during insulin-induced hypoglycemia, and this effect appears to be independent of type 1 angiotensin II (AT1) receptors in man. In the present study, we hypothesized that the action of angiotensin II on adrenomedullary epinephrine release is mediated by an AT2 receptor-dependent mechanism. In conscious chronically instrumented rats, we measured plasma concentrations of catecholamines during acute insulin-induced hypoglycemia in groups of rats pretreated with the AT1 receptor antagonist losartan (10 mg/kg i.v.), the AT2 receptor antagonist PD123319 (30 mg/kg i.v.), combined losartan + PD123319, the converting enzyme inhibitor enalapril (1 mg/kg i.v.), or vehicle. In vehicle-treated rats, the area under the curve for changes in plasma epinephrine concentration [AUC(plasma epinephrine)] during insulin-induced hypoglycemia was 111+/-8 nmolXh/L (+/-SEM). Pretreatment with losartan alone did not affect AUC(plasma epinephrine) (113+/-17 nmol x h/L), while pretreatment with PD123319 tended to reduce the response (87+/-10 nmol x h/L; P=.08 versus vehicle). However, AUC(plasma epinephrine) was significantly reduced in rats that were pretreated with combined losartan + PD123319 (68+/-5 nmol x h/L; P<.001 versus vehicle) or enalapril: 86+/-10 nmol x h/L (P<.05 versus vehicle). Thus, combined treatment with losartan + PD 123319 proved more effective in attenuating the reflex increase in plasma epinephrine concentration during hypoglycemia than either of the two AT receptor antagonists given alone. We speculate that angiotensin II through binding to both receptor subtypes facilitates the sympathoadrenal reflex response by actions at several anatomical levels of the neural pathways involved in the sympathoadrenal reflex response elicited during insulin-induced hypoglycemia.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalapril; Epinephrine; Heart Rate; Humans; Hypoglycemia; Imidazoles; Insulin; Kinetics; Losartan; Male; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2

Topics: Diabetes Mellitus, Type 2; Drug Interactions; Enalapril; Female; Glyburide; Humans; Hypertension; Hypoglycemia; Male; Middle Aged

Topics: Aged; Diabetes Mellitus, Type 2; Enalapril; Humans; Hypertension; Hypoglycemia; Insulin Resistance; Male

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Glomerular Filtration Rate; Humans; Hypoglycemia; Insulin Resistance

Topics: Adult; Captopril; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enalapril; Humans; Hypertension; Hypoglycemia; Male; Nifedipine

Topics: Captopril; Diabetes Mellitus, Type 2; Enalapril; Glyburide; Humans; Hypertension; Hypoglycemia; Male; Middle Aged