Hypoglycaemia in Clinical Diabetes

FREQUENCY OF HYPOGLYCAEMIA IN TYPE 2 DIABETES 247trials may not be representative of the patient characteristics observed and the therapeuticinterventions employed within an unselected diabetic out-patient population and this maylimit the extent to which such data can be extrapolated. Table 11.2b summarises availableepidemiological data on hypoglycaemia in type 2 diabetes.Hypoglycaemia and Oral Antidiabetic AgentsHypoglycaemia caused by oral antidiabetic agents is primarily associated with the insulinsecretagogues. It is seldom a side-effect of treatment with thiazolidinediones or alphaglucosidaseinhibitors, and has been reported only infrequently in association with metformin,usually when food intake is restricted (UK Prospective Diabetes Study (UKPDS) Group1998a, United Kingdom Prospective Diabetes Study Group 1998c). The frequency of hypoglycaemiasecondary to sulphonylurea therapy is considerably lower than that attributedto insulin (UK Prospective Diabetes Study (UKPDS) Group 1998b; Miller et al., 2001;Leese et al., 2003) but is probably underestimated (Hartling et al., 1987). In a retrospectivesix-month study in England of 219 people with type 2 diabetes treated with sulphonylureasand metformin, 20% of those taking sulphonylureas (either alone or in combination withmetformin) had experienced hypoglycaemic symptoms (Jennings et al., 1989). Sulphonylureascan also cause severe hypoglycaemia. Over a seven-year period, the Swedish AdverseDrug Reactions Advisory Committee reported 19 cases of glipizide-associated severe hypoglycaemiapresenting with reduced consciousness, with two deaths (Asplund et al., 1991).Incidences of severe hypoglycaemia of 0.224 episodes per 100 person-years with longactingsulphonylureas versus 0.075 episodes per 100 patient-years were reported among 28patients (median age 73 years) who were admitted to hospital with severe hypoglycaemia inSwitzerland (Stahl and Berger, 1999). The frequency of severe hypoglycaemia may be underestimatedin this study as patients receiving treatment in the community were excluded. Arecent study, A Diabetes Outcome Progression Trial (ADOPT), in which newly diagnosedpatients with type 2 diabetes were randomised to treatment with rosiglitazone, metformin andglibenclamide for a median of four years, prospectively recorded the hypoglycaemic eventsassociated with each treatment (Kahn et al., 2006). One (0.1%) serious and 142 (9.8%) totalevents were recorded for rosiglitazone, one (0.1%) serious and 168 (11.6%) total events formetformin and eight (0.6%) serious and 557 (38.7%) total events for glibenclamide.The frequency of hypoglycaemia relates to the individual pharmacokinetic propertiesof each sulphonylurea (Table 11.3), with the long-acting agents such as chlorpropamide,glibenclamide and long-acting glipizide being associated with the greatest risk (Stahl andBerger, 1999; Del Prato et al., 2002; Rendell 2004). Glibenclamide is associated with agreater risk of severe hypoglycaemia than gliclazide (Tessier et al., 1994) because activemetabolites prolong its hypoglycaemic effects for 24 hours (Jonsson et al., 2001; Rendell2004). Glibenclamide also attentuates the glucagon response to hypoglycaemia in nondiabeticvolunteers (ter Braak et al., 2002) and in people with type 2 diabetes (Landstedt-Hallin et al., 1999; Banarer et al., 2002). Several drugs may potentiate the hypoglycaemiceffects of sulphonylureas (Table 11.4). Risk factors for severe hypoglycaemia associated withsulphonylurea therapy include age, a past history of cardiovascular disease or stroke, renalfailure, reduced food intake, alcohol ingestion and interactions with other drugs (Hartlinget al., 1987; Seltzer et al., 1989; Asplund et al., 1991; Campbell et al., 1994; Shorr et al.,1997; Ben-Ami et al., 1999; Burge et al., 1999; Harrigan, et al., 2001).