Consequences of inadequate use of glucose lowering drugs and associated risk factors

Abstract: Diabetes Mellitus is characterized by chronically elevated blood glucose levels, hyperglycaemia. Consistent adherence to appropriate glucose-lowering drug therapy is fundamental to prevent disease progression, diabetes-related complications and premature death. If patients do not dispense, do not take their medication, or if the drugs are not prescribed according to evidence-based medicine, the consequences may be serious. The purpose of this thesis was to study acute consequences of inadequate use of glucose-lowering drugs, and its associated risk factors. In Study I the impact of symptomatic hypoglycaemia on medication adherence, patient satisfaction with treatment, and glycaemic control was studied in patients with type 2 diabetes treated with metformin and SU. The main finding was that adherence was negatively associated with the severity of the experienced hypoglycaemic symptoms. Despite poorer adherence to glucose-lowering drugs, the group with more severe hypoglycaemia showed better glycaemic control compared to the group with milder symptoms. The results suggest that glycaemic control is achieved at the expense of symptoms of hypoglycaemia in patients treated with metformin and SU. Dissatisfaction with medicine and barriers to medication adherence were more likely among patients with more severe hypoglycaemia. The study shows that only 40 % of the patients treated with metformin and SU in a primary care setting achieved the HbA1c target. Hypoglycaemia seems to refrain both patients and physicians from adherence to the best possible use of glucose lowering drugs. In Study II, potential risk factors associated with fatal hyperglycaemia were studied in deceased individuals with dispensed glucose-lowering drugs from pharmacies and their matched living controls. A significantly larger proportion of those who died due to hyperglycaemia lived in single households, had a history of psychiatric illness, was treated with insulin and had known alcohol abuse as compared to controls. Highly elevated glucose levels (HbA1c ≥75 mmol / mol) at the last health care visit were significantly associated with an increased risk of fatal hyperglycaemia. A larger proportion of the deceased had unsatisfactory refill adherence of glucose-lowering drugs. In addition, we found that 48 (15%) of the deceased individuals were undiagnosed. In Study III, reference concentrations for fatal metformin intoxications and associated risk factors were studied in a nationwide group of deceased, with detected metformin in the blood. The extensive information from forensic autopsy results and police reports was supplemented with detailed information on medical history, dispensed drugs and diabetes-related variables from several linked national registries. The verified reference concentrations for metformin may be particularly useful in cases where complementary information is missing. Metformin intoxication was intentional only in eight cases (23%), suggesting that high drug concentrations in the post-mortem context may not always be due to an acute high intake of the drug. The study shows that the most common risk factor in metformin intoxications was contraindications to the use of metformin, including; alcohol abuse and renal dysfunction. In this study, less than half of the study population achieved the recommended HbA1c target, based on the treatment goals listed in the national guidelines. Conclusions: The results confirm that high blood glucose levels need clinical attention, as an indication of inadequate use of glucose lowering drugs, which may lead to serious consequences. Further, unsatisfied refill adherence of GLD is associated with fatal hyperglycaemia in individuals with diabetes. Increased understanding of patient-reported outcome measures could improve the care of individuals with diabetes mellitus. The results also indicate that socio-economic and psychosocial factors, e.g. single households and / or alcohol abuse, should be noted as they may be important risk factors that seemingly are equally important as traditional risk factors. The included studies collectively indicate that both patient behaviour and the physician’s clinical inertia represent crucial barriers to appropriate use of glucose lowering drugs. Finally, by linking forensic toxicology data with national registries, we have revealed results of importance to improve adequate use of glucose lowering drugs and which may contribute to prevent patients from severe consequences due to inadequate use of glucose lowering drugs. This thesis demonstrates a public health-oriented application of medico-legal autopsies results, beyond their immediate and isolated use in forensic medicine.