Virendra Rambiritch

Dose-response relationships of sulfonylureas: will doubling the dose double the response?

type 2 diabetes mellitus is currently a global health problem. Although the armamentarium of oral hypoglycemic agents is continuously expanding, sulfonylureas (SUs) are still extensively used for the management of type 2 diabetes mellitus. However, despite decades of use, there is controversy as to the dosing of SUs. Despite many dose-response relationship studies indicating that SUs should be prescribed at lower doses, their dose recommendations remain unchanged. Moreover, studies have demonstrated that high doses of SUs may result in a deterioration of glycemic control and increased frequency of protracted hypoglycemic episodes. In view of the controversial dose-response relationship of SUs, it is suggested that the dose of SUs be titrated against glycemic parameters of blood glucose and glycated hemoglobin.

An identification of the risk factors implicated in diabetic ketoacidosis (DKA) in type 1 and type 2 diabetes mellitus

Abstract Background Despite improvements in therapy and disease monitoring, diabetic ketoacidosis (DKA) remains a potentially fatal consequence of diabetes. This retrospective study was undertaken to establish and identify those risk factors that are responsible for the onset of DKA. Methods The medical records of 77 patients from Addington Hospital, who satisfied the criteria for inclusion in the study of DKA, were reviewed (60 type 1 diabetes mellitus (DM) patients and 17 type 2 DM patients). Results More juveniles were admitted for multiple DKA episodes (65%) than non-juveniles (35%). DKA was present in 23% of newly diagnosed type 1 DM patients on first presentation. Infection was present in 40% of type 1 DM patients with single DKA episodes, and in 45% of type 1 DM patients with multiple DKA episodes. A total of 23.2% of all admissions for single DKA involved non-compliance with medication usage and was implicated in 32% of multiple DKA episodes. Family and/or school problems presented in 7% of single DKA episodes and in 4% in multiple DKA episodes. In the present study, the overall mortality rate was 2.5% (n=2). Conclusions This study showed that the most important risk factors implicated in DKA are infection, non-compliance and newly diagnosed diabetes, followed by family and/or school problems, low socio-economic status and omission of insulin.

Optimal utilisation of sulphonylureas in resource- constrained settings

Summary Abstract Sulphonylureas (SUs) are oral anti-diabetic drugs (OADs) that were introduced more than 60 years ago. Clinicians are familiar with their use and they remain extensively used. However, the SU class is associated with adverse effects of weight gain and hypoglycaemia. In addition, their effects on cardiovascular events remain contentious. Newer classes of anti-diabetic agents have been developed and these agents are weight neutral (di-peptidyl peptidase IV inhibitors), while others reduce weight (glucagon-like peptide analogues and sodium glucose co-transporter inhibitors). Furthermore, the newer agents are less likely to cause hypoglycaemia and have a potentially better cardiovascular safety profile. However, the newer agents are more costly than SUs and their long-term safety is unknown. It is therefore likely that SUs will continue to be used, and more so in resource-limited settings. One may mitigate the adverse effects of weight gain and hypoglycaemia associated with the SU class by using members within this class that are less probable to cause these adverse effects. Furthermore, the specific SU must be used at the lowest effective therapeutic dose. In patients at high risk of SU-induced hypoglycaemic episodes (frail, clinically significant renal impairment), or patients in whom hypoglycaemic episodes may have devastating effects (bus drivers), newer anti-diabetic agents may be a justifiable alternative option.

glibenclamide in patients with poorly controlled type 2 diabetes: a 12-week, prospective, single-center, open-label, dose-escalation study

Background The purpose of this study was to investigate the effect of glibenclamide dose escalation on blood glucose and insulin in patients with poorly controlled type 2 diabetes. Methods Twenty-two subjects with type 2 diabetes were administered increasing doses (0, 2.5, 5, 10, and 20 mg/day) of glibenclamide at 2-week intervals. Glibenclamide, glucose, and insulin determinations were performed. Results The decrease in mean blood glucose from zero dose was 20%, 22%, 26%, and 28% for doses of 2.5, 5, 10, and 20 mg/day, respectively, which was significant from zero dose to 2.5 mg/day (P≤0.001). There were no significant decreases in glucose concentration beyond 2.5 mg/day. The percentage increase in mean insulin from zero dose was 51%, 58%, 44%, and 33% for 2.5, 5, 10, and 20 mg/day respectively. Mean blood insulin increased significantly from zero dose to 2.5 mg/day (P≤0.001). There were no significant increases in mean insulin concentration beyond 2.5 mg/day. Conclusion The results of this study suggest that increasing doses of glibenclamide do not produce a proportional increase in insulin secretion or a proportional decrease in blood glucose concentration.

Population pharmacokinetic modeling of glibenclamide in poorly controlled South African type 2 diabetic subjects

Aim The aim of this study was to describe the pharmacokinetics (PK) of glibenclamide in poorly controlled South African type 2 diabetic subjects using noncompartmental and model-based methods. Methods A total of 24 subjects with type 2 diabetes were administered increasing doses (0 mg/d, 2.5 mg/d, 5 mg/d, 10 mg/d, and 20 mg/d) of glibenclamide daily at 2-week intervals. Plasma glibenclamide, glucose, and insulin determinations were performed. Blood sampling times were 0 minute, 30 minutes, 60 minutes, 90 minutes, and 120 minutes (post breakfast sampling) and 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, and 420 minutes (post lunch sampling) on days 14, 28, 42, 56, and 70 for doses of 0 mg, 2.5 mg, 5.0 mg, 10 mg, and 20 mg, respectively. Blood sampling was performed after the steady state was reached. A total of 24 individuals in the data set contributed to a total of 841 observation records. The PK was analyzed using noncompartmental analysis methods, which were implemented in WinNonLin®, and population PK analysis using NONMEM®. Glibenclamide concentration data were log transformed prior to fitting. Results A two-compartmental disposition model was selected after evaluating one-, two-, and three-compartmental models to describe the time course of glibenclamide plasma concentration data. The one-compartment model adequately described the data; however, the two-compartment model provided a better fit. The three-compartment model failed to achieve successful convergence. A more complex model, to account for enterohepatic recirculation that was observed in the data, was unsuccessful. Conclusion In South African diabetic subjects, glibenclamide demonstrates linear PK and was best described by a two-compartmental model. Except for the absorption rate constant, the other PK parameters reported in this study are comparable to those reported in the scientific literature. The study is limited by the small study sample size and inclusion of poorly controlled type 2 diabetic subjects.

Role Of Gastroscopy In Gastro-Oesophageal Reflux Disease (GORD)

Abstract Background This two-year study is a retrospective analysis of records of patients diagnosed with gastro-oesophageal reflux disease (GORD) at a private medical aid society for the period January 2002 to December 2003. In this study of GORD and its complications, the use of gastroscopy as a staging criteria and the cost of treatment were evaluated. Patients with alarming symptoms (chronic gastrointestinal bleeding, progressive unintentional weight loss, progressive difficulty in swallowing, persistent vomiting, iron deficiency anaemia, epigastric mass or suspicious barium meal), those with complications of GORD (erosive oesophagitis, ulcerative oesophagitis, oesophageal strictures, Barretts oesophagus and oesophageal adenocarcinoma), and patients in whom symptoms have not resolved need to have a gastroscopy performed. If left untreated, some of these symptoms could lead to more severe and serious complications. Accurate recognition of these symptoms will help to identify, evaluate and treat patients timeously. The use of the gastroscopy allows for the detection of complications of GORD, which helps to identify patients with complications timeously and avoids, delays or stops the progression of the complications of GORD. However, the unnecessary use of gastroscopy in patients without complications results in unnecessary costs. Patients without alarming symptoms or complications should be treated empirically with proton pump inhibitors (PPIs) to resolve the symptoms of GORD. Methods One thousand seven hundred and fifty-three patients with GORD were identified from computer records at a private medical aid society for the period January 2002 to December 2003. These patient records were retrospectively analysed using the computer database. All newly diagnosed GORD patients (n = 586) who were on drug therapy were included in the study. These patients were divided into two subsets: those without gastroscopy (n = 211) and those with gastroscopy (n = 375). The latter group was further identified as those that had undergone one (n = 232) or more than one gastroscopy (n = 143). Patients were further subdivided into those with and without complications. The choice of the study population was not based on the complication or the severity of the symptoms, but on whether or not the attending doctor chose to have a gastroscopy done. Results The number of complications detected in patients with more than one gastroscopy was the highest (34%; n = 48) in comparison to patients with one gastroscopy (21%; n = 49) or without gastroscopy (7%; n = 15) (p < 0.001). The odds or chances of having complications were significantly greater in patients with one gastroscopy compared to those without gastroscopy (OR 3.5; 95% CI: 1.8–6.9). Having an additional gastroscopy increased the odds of complications significantly compared to patients with just one gastroscopy (OR 1.9; 95% CI: 1.1–3.1). Barretts oesophagus occurred in 1.9% (n = 4) of patients without gastroscopy and in 15.7% (n = 59) of patients with gastroscopy (p < 0.001). Discussion Patients without gastroscopy presented with the lowest number of complications. The performance of gastroscopy in patients with alarming symptoms or complications may have resulted in more complications being detected. In subjects without gastroscopy, the prevalence of Barretts oesophagus was low. The proportion of subjects with complications is strongly associated with the number of gastroscopies they had undergone. Multiple gastroscopies increased the likelihood of detecting complications. Thus, a gastroscopy should only be performed if the symptoms of GORD do not resolve or if the patient has alarming symptoms or complications after empirical therapy. Conclusion The performance of gastroscopy in patients who had not undergone a gastroscopy before may have resulted in more complications being detected. Having more than one gastroscopy significantly increased the odds of detecting complications compared to patients with who had only undergone one gastroscopy. Patients without alarming symptoms should be treated empirically for one to two months, and a gastroscopy should only be performed if the symptoms do not resolve or if the patients experience complications or alarming symptoms.1 This study was confined to a single medical aid society. For comparison, other medical aids should be included.

Non-referral of potential organ donors in South Africa: insights, challenges and ethical dilemmas

Traditionally, minimal potential organ donor referrals emanate from general medicine departments. We use a clinical vignette to draw attention to challenges related to referral of potential organ donors from general internal medicine departments. In addition, we provide potential solutions to overcome challenges and reflect on the ethical issues of non-referral of potential organ donors. It is hoped that this paper will increase the awareness of organ donation in the medical fraternity in Africa and thus mitigate critical shortages of organs for transplantation.

Glibenclamide population pharmacokinetic/pharmacodynamic modeling in South African type 2 diabetic subjects

Aim To determine the effective dose of glibenclamide by quantifying the dose–response relationship in South African type 2 diabetic patients. Patients and methods A total of 24 type 2 diabetic patients participated in a glibenclamide dose-escalation study during which glibenclamide, glucose, and insulin concentrations were quantified, while the dose of glibenclamide was progressively increased. All except four subjects contributed data on all dose-escalation steps; however, data from all 24 patients were included in the model-based analysis. Pharmacokinetic/pharmacodynamic (PKPD) relationships were modeled using the software Nonmem®. Six models were utilized to explore the effect of alternative glibenclamide dose and plasma concentration inputs on various metrics of glucose response. Results Six models adequately described the experimental data. The effective dose for a glucose-lowering effect suggested by PKPD modeling is less than 5 mg/day. Doses beyond 5 mg/day do not meaningfully add to glibenclamide effects on blood-glucose response. Conclusion The effective dose of glibenclamide, suggested by PKPD modeling, is less than 5 mg/day. Higher doses of glibenclamide, eg, 15 mg/day as originally recommended by the manufacturer, do not produce further decrease in the blood glucose level but may predispose the patients to adverse effects.