Sulphonylurea-induced Hypoglycaemia Research Articles

Association of CYP2C9*2 Allele with Sulphonylurea-Induced Hypoglycaemia in Type 2 Diabetes Mellitus Patients: A Pharmacogenetic Study in Pakistani Pashtun Population.

Polymorphism in cytochrome P450 (CYP) 2C9 enzyme is known to cause significant inter-individual differences in drug response and occurrence of adverse drug reactions. Different alleles of the CYP2C9 gene have been identified, but the notable alleles responsible for reduced enzyme activity are CYP2C9*2 and CYP2C9*3. No pharmacogenetic data are available on CYP2C9*2 and CYP2C9*3 alleles in the Pakistani population. In Pakistan, pharmacogenetics, which examines the relationship between genetic factors and drug response, are in the early stages of development. We, for the first time, investigated the association between the CYP2C9 variant alleles CYP2C9*2 and CYP2C9*3 and the incidence of hypoglycaemia in patients with Type 2 diabetes mellitus (T2DM) receiving sulphonylurea medications. A total of n = 400 individuals of Pashtun ethnicity were recruited from 10 different districts of Khyber Pakhtunkhwa, Pakistan to participate in the study. The study participants were divided into two distinct groups: the case group (n = 200) and the control group (n = 200). The case group consisted of individuals with T2DM who were receiving sulphonylurea medications and experienced hypoglycaemia with it, whereas the control group included individuals with T2DM who were receiving sulphonylurea medication but did not experience sulphonylurea-induced hypoglycaemia (SIH). Blood samples were obtained from study participants following informed consent. DNA was isolated from whole blood samples using a Wiz-Prep DNA extraction kit. Following DNA isolation, CYP2C9 alleles were genotyped using MassARRAY sequencing platform at the Centre of Genomics at the Rehman Medical Institute (RMI). The frequency of CYP2C9*2 (low-activity allele) was more frequent in the diabetic patients with SIH compared to the control group (17.5% vs. 6.0%, p = 0.021). The frequency of its corresponding genotype CYP2C9*1/*2 was higher in cases compared to the control group (10% vs. 6% with p = 0.036); the same was true for genotype CYP2C9*2/*2 (7% vs. 3.5% with p = 0.028). Logistic regression analysis evidenced potential association of CYP2C9*2 allele and its genotypes with SIH. When adjusted for confounding factors such as age, weight, sex, mean daily dose of sulphonylurea, and triglyceride level, the association between the CYP2C9*2 allele and hypoglycaemia remained consistent. Confounding factors played no role in SIH (insignificant p-value) because both groups (cases and controls) were closely matched in term of age, weight, sex, mean daily dose of sulphonylurea, and triglyceride levels. Our study suggests that genetic information about a patient's CYP2C9 gene/enzyme can potentially assist physicians in prescribing the most suitable and safest drug, based on their genetic make-up.

382-P: Is Sulphonylurea-Induced Hypoglycaemia Hyped among Clinicians?

Aim: To assess the risk of hypoglycaemia (TBR) in persons with diabetes who are on SUs with fairly controlled diabetes (HbA1c between 7 to 8%) . Background: Sulphonylurea (SU) is conventionally used as a powerful glucose lowering agent and is known to increase the risk of hypoglycaemia. This paper is an attempt to study the effect of SUs on persons with diabetes by introducing continous glucose monitoring (CGM/AGP) which can help clinicians optimise diabetes treatment along with nutrition which can reduce the risk of hypoglycaemia. Methodology: A retrospective analysis was done at our diabetes care centre. A total of 300 persons with type 2 diabetes on AGP and on SU therapy were studied. Only those persons with HbA1c between 7 to 8%, indicating fairly controlled diabetes were included. Results: It was observed that no hypoglycaemia was present in 74% of the persons under study as per AGP data. Only 26% had hypoglycaemia grade 1 with less than 5% TBR; 2% had hypoglycaemia in TBR more than 5%, out of which only one person reported symptoms of severe hypoglycaemia. One of the AGP data of person with diabetes is attached in the image. Conclusion: Judicious use of sulphonylureas does not increase risk of hypoglycaemia (Time Below Range) in type 2 diabetics as traditionally believed. Disclosure T.C.Vyas: None. B.D.Saboo: None. K.Chennamsetti: None. J.Kesavadev: None. B.Saboo: None. D.Hasnani: None. V.Chavda: None. D.Panchal: None.

α2-Adrenoceptor Regulation of Blood Glucose Homeostasis

The α(2A)-adrenoceptor has been identified as an important regulator of blood glucose homeostasis. α(2A)-Adrenoceptors on pancreatic β-cells inhibit insulin secretion, and α(2A)-adrenoceptors on sympathetic nerves and on adrenomedullary chromaffin cells limit sympathoadrenal output. Recently, human α(2A)-adrenoceptor gene polymorphisms that influence α(2A)-adrenoceptor expression and function have been described. Increased α(2A)-adrenoceptor expression has been associated with impaired glucose-stimulated insulin secretion, elevated fasting blood glucose levels and an increased risk of type 2 diabetes. Accordingly, administration of α(2)-adrenoceptor agonists generally increases blood glucose levels, in spite of the ensuing sympatholysis that would be expected to lower blood glucose as a result of diminished α(1)- and β-adrenoceptor activation. α(2)-Adrenoceptor antagonists increase insulin secretion and reduce blood glucose levels by inhibiting tonically active α(2A)-adrenoceptors on pancreatic β-cells, but may also enhance sympathoadrenal output. In addition, α(2)-adrenoceptor antagonists potentiate the insulinotropic effect of sulphonylurea drugs, pointing to a potentially serious adverse drug interaction when the two classes of drugs are combined. The α(2)-adrenoceptor antagonist atipamezole is widely used in veterinary medicine, and sulphonylureas are prescribed for the treatment of type 2 diabetes in cats and dogs. Even if no dedicated α(2)-adrenoceptor antagonists are in clinical use in humans, some antipsychotic and antidepressant drugs are relatively potent α(2)-adrenoceptor antagonists. In the treatment of type 2 diabetes, α(2)-adrenoceptor agonists could possibly protect against sulphonylurea-induced hypoglycaemia, and α(2)-adrenoceptor antagonist drugs could improve insulin secretion. The potential usefulness of such drugs may vary between individuals, depending on α(2A)-adrenoceptor genetics, sympathetic tone and concomitant pathological conditions, such as cardiovascular disease and obesity.

Severe hyperkalaemia resulting from octreotide use in a haemodialysis patient

A 48-year-old man, with end-stage renal disease (ESRD) on haemodialysis, presented to the emergency department with sulphonylurea-induced hypoglycaemia. His hypoglycaemia was persistent despite glucose infusion, so he was treated with octreotide. Octreotide administration reversed the hypoglycaemia but also resulted in severe hyperkalaemia. The patient was urgently dialysed, the octreotide was discontinued and his potassium normalized. We believe that the hyperkalaemia was caused by octreotide-induced insulin suppression and resultant impaired cellular potassium uptake. Although octreotide may be an effective therapy in refractory sulphonylurea-induced hypoglycaemia, it should be used with caution in patients on dialysis.

Are hypoglycaemia and other adverse effects similar among sulphonylureas?

This review provides an updated overview of the adverse effects of sulphonylureas and identifies factors associated with variation in adverse effect rates among sulphonylureas published by different studies. A search of Medline, Embase, Current Contents and Cochrane Library was conducted to identify all papers related to sulphonylureas and adverse effects published from 1950-2001. The reference lists of all relevant papers were also searched for additional articles. The frequency of sulphonylurea-induced hypoglycaemia varied from 1.8-59%. Severe hypoglycaemia due to sulphonylurea use has been reported from 1.9-3.5%. Variation in hypoglycaemia rates may be due to differences in definitions, methods to detect and to collect information, patient characteristics, patient knowledge of the condition, threshold for symptoms, and activity level during hypoglycaemia. Other adverse effects associated with sulphonylurea use include bodyweight gain, gastrointestinal distress, disulphiram-like syndrome, dermatological reactions, haematological changes, ocular problems, and the syndrome of inappropriate secretion of antidiuretic hormone. Bodyweight gain has been reported to vary from 1.7-4.8 kg, according to the United Kingdom Prospective Diabetes Study (UKPDS-33). Controversy exists regarding cardiovascular adverse effects, but the consensus is to exercise caution in the use of these drugs as first-line therapy for patients with diabetes mellitus and coronary artery disease. The benefits of sulphonylurea treatment should be weighed against the risks associated with them. More work in this area is needed to homogenise the definition of hypoglycaemia, to get consensus on the methods for detection and data collection, as well as to further patient and physician education.

Metformin-associated lactic acidosis: a rare or very rare clinical entity?

Lactic acidosis is a well recognized complication of biguanide therapy which is potentially serious. Although the prevalence of metformin-associated lactic acidosis (MALA) is much lower than that associated with phenformin, it is still being reported sporadically which raises concerns for the practising clinicians. We review the currently available world-wide data of the prevalence of MALA, the risk factors for its development and the current practical guidelines on the use of metformin to minimize the risk of this potential hazard. An extensive literature search was conducted from both Medline and Ovid (1965-98) using the following keywords: 'Type 2 diabetes mellitus', 'oral hypoglycaemic drugs', 'biguanides', 'metformin-associated lactic acidosis' and 'renal impairment'. MALA was found to be a very rare clinical entity, being 20 times less common than phenformin-associated lactic acidosis. Amongst all the risk factors, renal impairment appears to be the major precipitating factor for the development of MALA in metformin-treated patients. We also found cases of MALA where no precipitating factors were identified and the underlying mechanism in these cases remains unclear. Practical recommendations of metformin use to minimize the risk of MALA have been listed based on previous reports. The low prevalence of MALA is comparable to the prevalence of sulphonylurea-induced hypoglycaemia. Metformin has many beneficial metabolic effects in the management of Type 2 diabetes mellitus. Provided that the recommended guidelines for metformin use are strictly adhered to, its widespread use would be safe and the incidence of MALA will be further reduced.

Sulphonylurea‐induced hypoglycaemia in elderly people with diabetes

Practical Diabetes InternationalVolume 11, Issue 3 p. 102-103 Review ArticleFree Access Sulphonylurea-induced hypoglycaemia in elderly people with diabetes IW Campbell FRCP(Ed), Corresponding Author IW Campbell FRCP(Ed) Consultant Physician n/a@dne.dne Victoria Hospital, KirkcaldyCorrespondence to: Dr IW Campbell, Diabetic Department, Victoria Hospital, Kirkcaldy, Fife KY2 5AHSearch for more papers by this authorJ Chalmers MRCP(UK), J Chalmers MRCP(UK) Research Fellow Victoria Hospital, KirkcaldySearch for more papers by this authorOM Herlihy MB BCh(IRL), OM Herlihy MB BCh(IRL) Medical Registrar Victoria Hospital, KirkcaldySearch for more papers by this author IW Campbell FRCP(Ed), Corresponding Author IW Campbell FRCP(Ed) Consultant Physician n/a@dne.dne Victoria Hospital, KirkcaldyCorrespondence to: Dr IW Campbell, Diabetic Department, Victoria Hospital, Kirkcaldy, Fife KY2 5AHSearch for more papers by this authorJ Chalmers MRCP(UK), J Chalmers MRCP(UK) Research Fellow Victoria Hospital, KirkcaldySearch for more papers by this authorOM Herlihy MB BCh(IRL), OM Herlihy MB BCh(IRL) Medical Registrar Victoria Hospital, KirkcaldySearch for more papers by this author First published: 01 May 1994 https://doi.org/10.1002/j.1528-252X.1994.tb00019.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Berger W. Incidence of severe side-effects during therapy with sulphonylureas and biguanides. Horm Metab Res 1985; 15(Suppl): 111– 5 2Campbell IW. Metformin and the sulphonylureas: the comparative risk. Horm Metab Res 1985; 15(Suppl): 105– 11 3Gerich JE. Oral hypoglycemic agents. N Engl J Med 1989; 34: 1231– 15 4Jennings AM, Wilson RM, Ward JD. Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Diabetes Care 1989: 12: 203– 8 5Ferner RE. Oral hypoglycemic agents. Med Clin North Am 1988; 72: 1323– 55 6Campbell IW. Hypoglycaemia and Type 2 diabetes: sulphonylureas. In: BM Frier, BM Fisher (eds). Hypoglycaemia and Diabetes. London: Edward Arnold. 1993. 387– 92 7Seltzer HS. Severe drug-induced hypoglycemia: a review. Comprehensive Therapy 1979; 5: 21– 9 8Palatrick W, Meaterall RC, Tenebein M. Clinical spectrum of sulfonylurea-overdose and experience with diazoxide therapy. Arch Intern Med 1991; 151: 1859– 62 9Marri G, Cozzolino G, Palumbo R. Glucagon in sulphonylurea hypoglycaemia. Lancet 1968: 1: 303– 4 10Asplund K, Wiholm B-E, Lithner F. Glibenclamide-associated hypoglycaemia: a report on 57 cases. Diabetologia 1983; 24: 412– 7 11Asplund K, Wiholm B-E, Lundman B. Severe hypoglycaemia during treatment with glipizide. Diabet Med 1991: 8: 726– 31 Citing Literature Volume11, Issue3May/June 1994Pages 102-103 ReferencesRelatedInformation

Octreotide: A New Treatment for Severe Sulphonylurea-Induced Hypoglycaemia

Octreotide: A New Treatment for Severe Sulphonylurea-Induced Hypoglycaemia

Pharmacokinetic Optimisation of Oral Hypoglycaemic Therapy

Two main classes of oral hypoglycaemic drugs, the sulphonylureas and the biguanides, are currently used in the therapy of type II, non-insulin-dependent diabetes mellitus (NIDDM). The basic pharmacokinetic properties of these agents are discussed with a view to efficient and safe treatment. Both first- and second-generation sulphonylureas are rapidly absorbed from the gastrointestinal tract. In the plasma compartment, these drugs are strongly bound to serum proteins. All sulphonylureas are metabolised in the liver, and the metabolites and the parent drugs are eliminated mainly in the urine, but also (second-generation derivatives) in the faces. Rapid- and short-acting sulphonylureas may improve early insulin release and promote better postprandial glucose control. Long-acting derivatives may ensure better control of overnight glycaemia. The elderly are at risk of developing severe sulphonylurea-induced hypoglycaemia, and in this population the agent chosen should have a short or intermediate duration of action and no active metabolites. Caution is needed when prescribing any sulphonylurea in patients receiving drugs known to affect sulphonylurea action, and in those with impaired liver and/or kidney function. The bioavailability of the biguanides ranges from 40 to 60%. Binding to plasma proteins is absent or very low. Metformin and buformin are not metabolised and are excreted in the urine; phenformin undergoes hepatic hydroxylation and is excreted in both urine and faeces. Metformin is the only agent of this class currently recommended for clinical use. The main indications of metformin treatment are NIDDM associated with obesity and/or hyperlipidaemia, and in combination with sulphonylurea both as primary treatment and when secondary failure occurs with sulphonylurea alone. Lactic acidosis may develop in patients receiving therapy with biguanides, especially in the presence of a preexisting contraindication to their use.

Sulphonylurea-induced hypoglycaemia

Sulphonylurea-induced hypoglycaemia