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Analysis of Burden and Outcomes of Oral Hypoglycaemic Agent Induced Adverse Drug Effects at a Tertiary Care Centre
Correspondence Address :
Dr. Alhad Ajay Mulkalwar,
Intern, Department of Medicine, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, Maharashtra, India.
E-mail: alhad.mulkalwar@gmail.com
Introduction: Recent studies, both globally as well as in India, have depicted an alarming rise in the prevalence of Diabetes Mellitus (DM). Oral Hypoglycaemic Agents (OHAs) are the most common drugs used in the treatment of type 2 diabetes mellitus. There are numerous established Adverse Drug Reactions (ADR) associated with their use, such as, hypoglycaemia, weight gain, gastrointestinal disturbance, lactic acidosis and fluid retention.
Aim: To assess the incidence of ADRs, clinical profile, severity and causality among the admitted patients, taking OHAs, in a tertiary care hospital.
Materials and Methods: This was a hospital-based, prospective, observational, non interventional cohort study undertaken at the General Medicine Wards of a public teaching hospital, Seth GSMC and KEMH, Mumbai, Maharashtra, India. The present study was conducted in the Department of Medicine from June 2017 to December 2018. The patient’s data was recorded using a structured ADR reporting form. The baseline parameters, medical history and underlying diseases, clinical data, characteristics of ADRs and details of medication responsible for ADRs as well as medication for treatment of ADRs were recorded. The data was analysed using descriptive statistics with the Statistical Packages for the Social Sciences (SPSS) version 26.0 software.
Results: Out of 164 patients admitted due to ADRs, within the study period, 48 (29.3%) patients had developed ADRs due to OHAs (sulfonylureas). The severity of ADRs of five patients fell under the moderate category (three males in the age group of 61-80 years and two females in the age group of 21-40 years), all of whom successfully recovered. The remaining 43 (89.6%) were associated with severe ADRs. Four patients had succumbed to the ADR while one reported further sequelae, and the rest of the patients recovered (one was still recovering at the time of data analysis).
Conclusion: Sulfonylurea-induced hypoglycaemia is the most common ADR seen in patients on treatment of type 2 diabetes mellitus. Presence of systemic co-morbidities and polypharmacy are significant risk factors associated with OHA-induced ADRs.
Adverse drug reactions, Polypharmacy, Sulfonylurea drugs
The World Health Organisation (WHO) defined an Adverse Drug Reaction (ADR) as “a noxious, unintended, and undesirable effect that occurs as a result of dose normally used in man for diagnosis, prophylaxis, and treatment of disease or modification of physiological function. Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility (1). ADRs are a major public health problem. They are considered a leading cause of morbidity and mortality (2). Estimated 2.9-5% hospital admissions are due to ADRs and approximately 35% of hospitalised patients experience an ADR during their hospital stay (3). Adverse drug events can range from mild to life threatening reactions resulting in inconvenience or serious morbidity and mortality besides being a financial burden on the society (4).
Diabetes Mellitus (DM) is a chronic metabolic disorder characterised by hypoglycaemia and associated with a high risk of numerous complications (5). The prevalence of type 2 DM is rising throughout the world, in developed as well as developing countries (6),(7). At present, a total of 415 million people are affected by diabetes globally and this number is set to rise beyond 642 million by 2040 (8). In India, over 65.1 million individuals have been diagnosed with the disease and the estimates suggest that roughly 89 million patients may develop by 2030 (9),(10). Patients with type 2 DM require pharmacotherapy throughout life; they also need to have a proper and regular diet along with physical activity so as to maintain the blood sugar levels within normal levels (11). Diabetes mellitus is affecting India badly leading to increased morbidity with increasing treatment cost. The current pharmacotherapy of diabetes mellitus includes treatment with drugs such as insulin and oral hypoglycaemic agents. With increase in the number of medication, the chances of ADRs also increase, contributing to morbidity and loss of productivity (12).
Oral Hypoglycaemic Agents (OHAs) are the most common drugs used in type 2 DM. There are numerous established ADRs associated with their use such as hypoglycaemia, weight gain, gastrointestinal disturbance, lactic acidosis and fluid retention (13). Adequate counselling about ADRs and early reporting of the same to physician is essential to avoid such predictable ADRs (12). Pharmacovigilance of anti-diabetic drugs can play an important role in identifying ADRs and providing valuable feedback to physicians. However, the Pharmacovigilance Programme of India is still in its budding stage (14).
The present study aimed to assess the incidence of ADRs among the admitted patients in a tertiary care hospital taking OHAs. It also assessed the clinical profile of patients with OHA associated ADRs, along with the severity, causality and preventability of these ADRs.
This was a hospital-based, prospective, observational, non interventional cohort study undertaken at Seth GSMC and KEMH, Mumbai, Maharashtra, India. It was conducted in the General Medicine Wards. The study spanned in the Department of Medicine from June 2017 till December 2018, the study was initiated after obtaining approval from the Departmental Review Board and the Institutional Ethics Committee (IEC/167/2017).
Inclusion criteria: All consenting patients, of age >21 years, either admitted in the Medical Wards of the hospital for ADR following use of OHAs or those who developed OHA-induced ADRs while admitted in the medical wards were included in the study.
Exclusion criteria: Patients on insulin therapy, those with intentional or accidental poisoning, drug abuse (except alcohol) and non compliance to the prescribed medications were excluded from the study.
Study Procedure
The patient’s data was recorded using a structured ADR reporting form. The baseline parameters were assessed to obtain relevant data on demographics, clinical condition, co-morbidities, relevant laboratory data and medications used. The medical history and underlying diseases, clinical data, characteristics of ADRs and details of medication responsible for ADRs (suspected drug, dosage, route of administration, indication, date of beginning and stopping therapy, concomitant drugs) as well as medication for treatment of ADRs were obtained from the clinical notes, medication charts, clinical examination, interviews with patient or his/her relatives or caregivers or ward staff, the treatment sheets, drug administration charts, dispensing records and pill/injection count validation. All patients were followed-up till discharge from the hospital or till death. The ADRs were recorded in detail in a descriptive format. The onset, duration and progress as well as the systems affected, the drugs and the class of drugs causing the ADRs, the severity as well as the seriousness of the reactions and the treatment given for the same were recorded. Data pertaining to the adverse event was collected- the likely causative drug/class of drug, causality (WHO-UMC scale) (15), severity (Hartwig and Siegel scale) (16), avoidability (Halla’s criteria) (17) and outcome.
Statistical Analysis
The data was analysed using descriptive statistics with the Statistical Packages for the Social Sciences (SPSS) version 26.0 software.
Out of the 164 patients admitted due to ADRs within the study period, 48 (29.3%) developed ADRs due to OHAs (26 males and 22 females). All the patients were on OHAs of the class sulfonylurea-glimepiride (n=38), glibenclamide (n=7), and glicazide (n=3).The age and gender distribution of the subjects is given in (Table/Fig 1).
The mean duration of stay was 3.9±2.034 days. Most of the patients (n=43) had co-morbidities. the recovered patients had a mean hospital stay of 2.2 days (extended hospital stay after diagnosis of the ADR). The causality of all subjects (n=48) was found to be probable (WHO-UMC scale). Almost 90% of the patients (n=43) suffered from severe ADRs; 87.5% of the patients (n=42) showed complete recovery as depicted in (Table/Fig 2). The severity of ADRs of five patients fell under the moderate category (three males in the age group of 61-80 years and two females in the age group of 21-40 years), all of whom successfully recovered. The remaining 43 (89.6%) were associated with severe ADRs.
All the subjects who succumbed to the OHA-induced adverse were elderly (age >60 years) males with significant co-morbidities. All oral hypoglycaemic related ADRs in the study were metabolic in nature, manifesting as hypoglycaemia. Of these, 11 patients had missed meals while some had insufficient blood sugar monitoring at the community level. Co-morbidities were seen in 90% of the patients (n=43). Polypharmacy was another frequent risk factor in the study population, seen in 54% of the patients (n=26). Four cases of OHA- induced hypoglycaemia were fatal. As per the Halla criteria, maximum patients (n=43) had developed ADRs which were ‘possibly avoidable’. The patient details are presented as a supplement table.
Sulfonylureas are the most commonly prescribed class of drugs to treat Type 2 Diabetes Mellitus and hypoglycaemia remains its most common ADR (18). In accordance with the same, all OHA related ADRs in the present study were found to be due to sulfonylureas, and all of them were metabolic in nature, manifesting as hypoglycaemia. Hypoglycaemia is most likely to occur after a missed meal, (18) which was also reported in 11 of the study patients. In this study, out of 48 ADRs assessed, 45 (93.75%) could have been avoided by more than usual effort by the physician or patient. Studies have reported that only few patients started on OHAs are informed about the adverse effects by their physicians in pre-medication stage and this factor has a significant association with incidence of adverse effects (19). Physicians should inform patients about the possible ADRs, which might help them cope with unpleasant adverse effects and also enhance adherence to the pharmacotherapy (20). It is a well-established fact that as the number of medications increase, the chances of developing ADRs also increase (21). Polypharmacy (higher drug count) and higher co-morbidity scores have been consistently reported as risk factors for ADRs, especially amongst geriatric patients (22). The present study was no different; with two of the major risk factors in the patients being presence of significant co-morbidities (N=43) and polypharmacy (N=26), both of which were also present in the four elderly males who succumbed to the ADR. It should be noted that in the present study, for those with OHA induced hypoglycaemia, diabetes was not considered a risk factor, since, it was the reason for treatment.
Limitation(s)
The study evaluated the patients admitted to the internal medicine wards only. The study did not calculate the costs based on duration of hospitalisation alone. The patients were brought to the hospital after a prolonged period of uncorrected hypoglycaemia and had sustained hypoglycaemic brain damage. The assessment of whether an ADR has increased the length of stay or caused death, and in particular whether it is due to the underlying disease or due to an ADR, can be extremely difficult.
Patients being treated with sulfonylurea drugs are susceptible to hypoglycaemia, especially after missed meals. Presence of systemic co-morbidities and polypharmacy are significant risk factors associated with the same. Polypharmacy is a risk factor that is liable to increase since life expectancy is increasing, and co-morbidities are likely to increase with age. Thus, with the increasing prevalence of polypharmacy, one should be more watchful for ADR and review all ongoing prescriptions for unnecessary medications, especially in geriatric patients.
DOI: 10.7860/JCDR/2022/55130.16401
Date of Submission: Jan 21, 2022
Date of Peer Review: Feb 25, 2022
Date of Acceptance: Apr 12, 2022
Date of Publishing: May 01, 2022
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA
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