ACE Inhibitor Use Is Associated With Hospitalization for Severe Hypoglycemia in Patients With Diabetes

Morris, Andrew D.; Boyle, Douglas; McMahon, AD; Pearce, Hilary M.; Evans, Josie; Newton, R. W.; Jung, R. T.; MacDonald, Thomas M.

doi:10.2337/diacare.20.9.1363

Cited by 102 publications

(54 citation statements)

References 12 publications

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“…In contrast with our findings, an association between treatment for severe hypoglycaemia and use of ACE inhibitors has been indicated in a few registry based studies [23,24]. These studies are, however, hampered by important clinical differences between cases and control group (e.g.…”

Section: Discussioncontrasting

confidence: 99%

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

et al. 2003

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Aims/hypothesis. We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACE gene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess this relationship prospectively. Methods. We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor antagonists.Results. There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times higher rate in fourth quartile compared to first quartile; p=0.048). The impact of serum ACE activity was most pronounced in C-peptide negative subjects (4.2 times higher rate in fourth quartile compared to first quartile; p=0.003), and in this subgroup carriers of the D allele of the ACE gene had higher rates of severe hypoglycaemia compared to the group homozygous for the insertion (I) allele. In a multiple regression analysis high serum ACE activity and impaired awareness of hypoglycaemia were identified as the only significant predictors of severe hypoglycemia. To avoid progression of these frequent episodes into severe hypoglycaemia patients rely on maintenance of performance capacity [3] until hypoglycaemic symptoms are recognised and self-treated or until the next pre-scheduled meal is ingested.Risk of severe hypoglycaemia is a major limiting factor for the achievement of good metabolic control [4] rendering prediction of individual risk of severe hypoglycaemia increasingly important. Loss of hypoglycaemic warning symptoms and blunted hormonal counterregulatory response are the most important known predictors of severe hypoglycaemia [4,5]. However, even patients at high risk according to these paFollowing the Diabetes Control and Complications Trial [1] a growing demand for strict glycaemic control has emerged to avoid late diabetic complications in Type 1 diabetes. As a consequence the majority of patients with Type 1 diabetes experience mild hypoglycaemia on a regular basis and recent studies applying continuous glucose monitoring indicate that pa-

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Section: Discussioncontrasting

confidence: 99%

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

et al. 2003

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“…Some evidence has been presented to suggest that predisposition to severe hypoglycaemia may also have some genetic basis. Herings et al [9] and Morris et al [10] have shown that the use of ACE inhibitors increased the risk of having a severe hypoglycaemic event in adults, but these studies were retrospective in design and the findings remain controversial [11][12][13][14]. The fact that a small proportion of patients experiences severe hypoglycaemia whereas other patients with similar glycaemic control remain spared indicates that genetic factors may contribute to an increased risk, and studies conducted in Denmark and Sweden have supported this notion [8,20,21].…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that genetic factors may predispose to a susceptibility to severe hypoglycaemia. Studies have shown that the use of ACE inhibitors may be a factor in the incidence of hypoglycaemia in adults [9,10], but this still remains controversial [11][12][13][14], as these studies were retrospective in design and were unable to adjust for some important confounding variables.…”

Section: Introductionmentioning

confidence: 99%

The relationship between ACE genotype and risk of severe hypoglycaemia in a large population-based cohort of children and adolescents with type 1 diabetes

et al. 2007

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Aims/hypothesis Genetic factors may account for familial clustering related to diabetes complications. Studies have shown a significant relationship between the presence of the deletion (D) allele of the gene encoding ACE and risk of severe hypoglycaemia. This large prospective cohort study assesses this relationship in a large sample of children and adolescents with type 1 diabetes. Subjects and methods We studied 585 children and adolescents (mean age 11.9±4 years, 48.4% males). The frequency of severe hypoglycaemia (an event leading to loss of consciousness or seizure) was prospectively assessed over the 13-year period 1992-2004. Patients were seen with their parents every 3 months and data recorded at each visit. The ACE gene was detected using PCR. Results In our cohort of 585 children, 186 (31.8%) had at least one episode of severe hypoglycaemia, and of these 28.0% had the II genotype, 48.9% had the ID genotype and 23.1% had the DD genotype. This was in agreement with the Hardy-Weinberg proportion. A total of 477 severe hypoglycaemic episodes was recorded with a total of 3,404 person-years of follow-up, giving a total incidence of 14 per 100 patient-years. No significant increase in risk for DD genotype (incidence rate ratio=0.97, 95% CI 0.61-1.55) relative to II genotype was observed. Conclusions/interpretation This large prospective study concludes that the presence of the D allele of the ACE gene does not predict a significantly higher risk of severe hypoglycaemia in type 1 diabetic children and adolescents.

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“…In the 1990s, sporadic reports raised the hypothesis that angiotensin converting enzyme inhibitors (ACEIs) might cause hypoglycaemia [1][2][3][4], seemingly confirmed by several studies [5,6]. Safety signals mentioning the risk of hypoglycaemia with ACEIs were promulgated.…”

Section: Introductionmentioning

confidence: 99%

A signal of increased risk of hypoglycaemia with angiotensin receptor blockers caused by confounding

Gregoire

Pariente

Fourrier‐Réglat

et al. 2008

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Spontaneous reporting is a valuable way to provide early detection for safety signals related to drug use. • Due to the increasing size of pharmacovigilance databases, data-mining and other automated methods for signal generation are more and more often used.• Even if these methods are very useful, they do not allow, for every particular association, an automated exploration of the multiple sources of confounding. WHAT THIS STUDY ADDS• An association between angiotensin receptor blockers use and hypoglycaemia was found in the French pharmacovigilance database.• This signal disappeared after stratification on antidiabetic drug use, suggesting confounding by indication.• The association between hypoglycaemia and angiotensin receptor blocker use was actually less than expected in concomitant antidiabetic drug users. AIMSTo study reporting of hypoglycaemia in angiotensin receptor blocker (ARB) users, and to investigate the possibility of confounding. METHODSThe French pharmacovigilance database was examined for an association between hypoglycaemia and ARBs or other drugs using reports notified between 1996 and 2005. This association was also tested in patients taking or not taking antidiabetic agents (ADAs) using reporting odds ratios (ROR). RESULTSHypoglycaemia was mentioned in 807 of the 174 595 reports entered during the study period. Overall hypoglycaemia was associated with the use of ARBs [ROR 2, 95% confidence interval (CI) 1, 3] and with the use of ADAs (ROR 32, 95% CI 27, 37). Moreover, the use of ARBs was associated with the use of ADAs (OR 7, 95% CI 6,8). Considering separately reports with and without ADA, the association of ARB use with a higher risk of hypoglycaemia disappeared (OR 0.4, 95% CI 0.2, 0.8 and OR 2, 95% CI 1, 3, respectively). CONCLUSIONA signal indicating an association between ARB use and hypoglycaemia was found in the French pharmacovigilance database. This signal disappeared after stratification on ADA use, thus suggesting confounding by indication. Moreover, the association between ARB use and hypoglycaemia was negative in ADA users.

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ACE Inhibitor Use Is Associated With Hospitalization for Severe Hypoglycemia in Patients With Diabetes

Cited by 102 publications

References 12 publications

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

The relationship between ACE genotype and risk of severe hypoglycaemia in a large population-based cohort of children and adolescents with type 1 diabetes

A signal of increased risk of hypoglycaemia with angiotensin receptor blockers caused by confounding

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