Ashwin Kamath

Are the Newer Antidiabetic Agents Worth the Cost

Type 2 Diabetes Mellitus (T2DM) is a multisystem metabolic disease that requires lifelong medical management. While the burden of T2DM to society can be measured in dollars and rupees, the cost of T2DM to the patient may be immeasurable, reflecting the daily challenges of this chronic disease and uncertain quality of life. Citizens of the 21st century are experiencing a pandemic of T2DM which has motivated development of an armamentarium of new antidiabetic drugs. The new antidiabetic medicines, classified by mechanism of action, include: (i) the glucagon like polypeptide (GLP-1) analogues exenatide and liraglutide; (ii) the renal sodium glucose transport-2 (SGLT-2) inhibitors canagliflozin and dafagliflozin; (iii) the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin; (iv) the amylin analogue pramlinitide; and (v) the insulin analogues: aspart, lispro, and glargine. The older, conventional antidiabetic medicines such as glibenclamide, glimepiride, metformin, pioglitazone, and the insulin preparations are, largely, much less expensive and therefore more affordable to the diabetic patient than the newer drugs. Furthermore, it is known that patient compliance with antidiabetic treatments, almost exclusively, depends on the direct cost to the patient [1]. This problem of compliance is magnified by the fact that antidiabetic treatments are lifelong and, hence, present the diabetic patient with substantial financial, behavioral and emotional challenges which must be overcome. Another challenge is that patients may not have health insurance, but even if they do, health insurance policies often do not cover drugs for outpatient use. n nZhang et al., analysed the benefits and harms of antihyperglycaemic treatment regimens considering clinical effectiveness, quality of life, and cost. They found that older agents like sulfonylureas were associated with greater benefit in terms of both life-years, quality adjusted life years, and less expensive compared with newer glucose lowering agents like, sitagliptin and exenatide. Monthly medication cost (USD) of metformin 81.75, sulfonylurea 54.85, whereas newer medications like GLP-1 agonist 325.97, DPP-4 inhibitor 232.84 [2]. n nLimited knowledge of the longterm safety of the newer antidiabetic agents is another important issue. For example, it has been reported that, a 51-year-old woman with longstanding T2DM developed liraglutide induced acute pancreatitis. Her symptoms resolved after withdrawal of this GLP-1 analogue [3]. GLP-1 agonists are contraindicated in patients with histories of pancreatitis, glomerular filtration rate < 30 mL/min, or gastroparesis. Another report demonstrates a significant risk of subclinical pancreatic inflammation, pancreatic cancer, and neuroendocrine tumours in users of exenatide [4]. The DPP-4 inhibitors are commonly associated with nasopharyngitis, headache, and respiratory infections, but pancreatitis, pancreatic cancer, elevation of hepatic enzyme activity; skin reactions and severe joint pain are also reported in users of DPP-4 inhibitors [5]. The SGLT-2 inhibitors are known to cause urinary and genital tract infections, dehydration, and hyperkalaemia. As per a recent report of a 60-year-old man with T2DM treated with glimepiride, metformin, insulin, and canagliflozin developed hypercalcaemia due to intestinal and urinary calcium absorption possibly due to inhibition of SGLT by the canagliflozin [6]. These are but a few examples of why more research is needed to support the safe use of these novel antidiabetic agents. Apart from the financial challenges faced by diabetic patients there is substantial uncertainty about the safety of the newer antidiabetic drugs—newer is not necessarily better.

Evaluation of Potential Drug-Drug Interactions with Medications Prescribed to Geriatric Patients in a Tertiary Care Hospital

Background and Objectives The drugs most commonly implicated in major potential interactions are those used in the day-to-day clinical management of elderly patients with chronic diseases. This study is planned to evaluate the profile of drug-drug interactions in the medications prescribed to elderly population and also to identify the possible predictors for potential drug-drug interactions in the elderly. Methods This cross-sectional study included patients aged above 60 years with a minimum of two drugs in the prescriptions. Data were collected from medical prescriptions and patients medical records. The data collected included demographic characteristics such as age, gender, height, weight, educational status, socioeconomic status, medical history, and medications prescribed. The prescriptions were analyzed for the potential drug interactions using Lexi-Interact™ Online, an online software to check drug-drug interactions. Results A total of 209 patients were included in the study, among them 104 (49.8%) were males and 105 (50.2%) were females. The mean number of medications received was 6.53u2009±u20092.15 per prescription. Around 138 (66%) patients received more than six medications. The mean number of potential drug interactions seen in the prescription of these patients was 3.17u2009±u20092.78. Around 18.2% patients had more than five drug interactions. Major drug interactions were observed in 21.42% of cases. Around 3.02% of drug interactions belonged to risk category X, i.e., to be avoided. Logistic regression analysis showed that age above 70 years was associated with the presence of drug interactions. Increased number of medication was independently associated with the occurrence of drug interactions. The presence of drug interactions was not associated with increased number of comorbidities. Conclusion A significant number of potential drug-drug interactions were seen in the prescriptions of elderly patients. Increasing age and polypharmacy were identified as the predictors of potential drug interactions.

Health Literacy Status and Understanding of the Prescription Instructions in Diabetic Patients

This study aimed to assess the health literacy (HL) of patients having diabetes mellitus, their understanding of prescription instructions (PI), and the correlation between HL and understanding of PI. A cross-sectional survey was conducted in 263 adult diabetic patients who were assessed for their understanding of route of intake of the prescribed medication(s), frequency of intake, number of medication(s) to be consumed each time, indication for the medication(s), and the relation of drug intake with food. The HL of the patients was assessed by using Rapid Estimate of Adult Literacy in Medicine, a screening test comprising of 66 health-related words. The number of correctly pronounced words was used to assign a grade-equivalent reading level. There was a significant difference in the understanding of PI in patients with low and high HL levels. A significant difference was observed between the mean total score for interpreting PI in patients with 7 or fewer years of education compared with the other groups with a higher educational status (P < 0.001). To conclude, diabetic patients with low HL level will have difficulty in understanding PI. Hence, an alternative comprehensive strategy needs to be adopted in clinical practice in these patients to provide them the instructions to take medications properly.

Melatonin for Atypical Antipsychotic-Induced Metabolic Adverse Effects: A Meta-Analysis of Randomized Controlled Trials

The objective of our study was to determine the effect of melatonin administration on atypical antipsychotic-induced metabolic adverse effects in patients with psychiatric disorders. A systematic search was performed in PUBMED, Cochrane Library, Scopus, Web of Science, and EBSCOhost electronic databases. Randomized controlled trials studying the effect of melatonin on antipsychotic-induced metabolic adverse effects were identified and subjected to meta-analysis. Four studies were included in the meta-analysis, including 57 patients on melatonin and 61 patients on placebo. Melatonin produced a significant decrease in the diastolic blood pressure compared with placebo (mean difference = −4.44 [95% CI, −7.00 to −1.88]; p = 0.0007; I2 = 13%), but not the systolic blood pressure (mean difference = −4.23 [95% CI, −8.11 to −0.36]; p = 0.03; I2 = 0%). Although a decrease in the body mass index was seen in the melatonin group, the difference was not significant in the random-effects analysis model. To conclude, in patients on atypical antipsychotics, melatonin at a dose of up to 5u2009mg/day for a treatment duration of up to 12 weeks attenuated the rise in diastolic blood pressure compared with placebo but had no significant effects on other metabolic parameters.

Over-the-counter medications containing diphenhydramine and doxylamine used by older adults to improve sleep, a Letter

We read with immense interest the article by Abraham et al. [1] regarding use of over-the-counter (OTC) medications containing diphenhydramine/doxylamine (DIPH/ DOX) by older adults to improve sleep. A number of studies have focussed on the prescription of drugs considered inappropriate in the elderly population as per the Beers criteria [2]. However, consideration of the issue of self-medication involving OTC medications containing potentially inappropriate medications is equally important, especially for chronic conditions where patients may not be inclined to visit their physicians frequently due to socioeconomic reasons and, thereby, take the aid of the easily available OTC medications. While the study by Abraham et al. is important in this regard, we would like to highlight a few issues with regard to the study methodology and results. First, the data was collected through a mail survey. The authors have rightly mentioned the possible study limitations due to recall bias or inaccuracy of responses. In addition, it is also possible that some participants after having gone through the survey items sought the answers and then responded accordingly. For example, for the question on active ingredients, the participants might have looked at their medications before responding. This is also important considering that most of the participants were well educated. Although the educational status of the study participants is mentioned as a limitation with regard to the generalizability of study results, we think that the lack of awareness regarding the safety risks of the OTC medications containing DIPH/DOX in this population conveys the magnitude of the problem to be expected in populations with lower overall education levels. Abraham et al. [3] have used the education status as a proxy to measure health literacy. However, good education status does not always mean better health literacy. This is supported by findings of the current study as well. Hence, it would have been ideal if an appropriate instrument was used to measure health literacy rather than rely on educational status. Secondly, the finding that participants using DIPH/DOX products were less aware of any safety risks in taking the OTC sleep medications needs further elaboration. It is not clear what type of safety risks were mentioned by the participants in the two groups and how these were judged by the authors. As mentioned earlier, the issue of actively seeking answers before responding might have confounded the results. Thirdly, the interpretations with regard to gender and age groups are not reliable since the sample size was small, and no statistical methods were used to compare the data. Lastly, the listed OTC medications containing DIPH/ DOX also contain antipyretics and analgesics. In case of combination medications, it is possible that the primary aim of taking the medication was to relieve pain rather than aid sleep. Also, if the medications containing analgesics were indeed taken as sleeping aids, this is a cause for serious concern. In addition, while the study focussed on DIPH/DOX, the participants in the non-DIPH/DOC containing OTC medications may have been on other first generation antihistaminics which are also to be avoided as per Beers criteria [2]. It is unclear whether the authors have taken this into account. Notwithstanding the above limitations, the study findings do emphasize the need for further research in this area, & Ashwin Kamath ashwin.kamath@manipal.edu

Effect of Alternate Nostril Breathing Exercise on Experimentally Induced Anxiety in Healthy Volunteers Using the Simulated Public Speaking Model: A Randomized Controlled Pilot Study

A randomized controlled pilot study was carried out to determine the effect of a 15-minute practice of ANB exercise on experimentally induced anxiety using the simulated public speaking model in yoga-naïve healthy young adults. Thirty consenting medical students were equally divided into test and control groups. The test group performed alternate nostril breathing exercise for 15 minutes, while the control group sat in a quiet room before participating in the simulated public speaking test (SPST). Visual Analog Mood Scale and Self-Statements during Public Speaking scale were used to measure the mood state at different phases of the SPST. The psychometric scores of both groups were comparable at baseline. Repeated-measures ANOVA showed a significant effect of phase (p < 0.05), but group and gender did not have statistically significant influence on the mean anxiety scores. However, the test group showed a trend towards lower mean scores for the anxiety factor when compared with the control group. Considering the limitations of this pilot study and the trend seen towards lower anxiety in the test group, alternate nostril breathing may have potential anxiolytic effect in acute stressful situations. A study with larger sample size is therefore warranted. This trial is registered with CTRI/2014/03/004460.

The Current Status of New Antidiabetic Drugs

Dear Editor, Type 2 diabetes mellitus (T2DM) is a world-wide public health problem [1]. As such, the Food and Drug Administration (FDA), pharmaceutical companies and medical researchers/practitioners should be discussing the costs vs. the benefits for economically-disadvantaged populations that are disproportionately affected by T2DM and, therefore, suffering the most [2]. The current debate about new antidiabetic drugs is focused mainly on pharmacological efficacy and does not take into account the multimodal mechanisms and treatments for this complex disease [3]. Whether the statistically-significant positive results demonstrated for these drugs translate into real benefits for patients in real-life clinical settings has yet to be established. The multimodal principle of treatment, although welltaught in most medical schools, is often ignored in real-life, particularly when expensive drugs are readily available. For example, treatment of T2DM should start with the least costly, yet effective, nonpharmacological interventions, such as diet/exercise/lifestyle changes, thereafter progressing to first-line gluconeogenesis suppressors, such as metformin and later sulfonylureas. Only after such interventions have failed should the newer, very expensive GLP-1 agonists and SGLT2 inhibitors be introduced [3, 4]. Research should be carefully designed to determine whether the newer drugs benefit patients after diet/ lifestyle changes and standard treatments have failed. Such studies of multimodal treatment for T2DM should include not one, but several, intensities of diet/lifestyle modifications even before standard drug treatments are employed. Likewise, several intensities of standard drug treatments should be used in the presence and in the absence of different intensities of diet/exercise/ lifestyle modifications. The newer antidiabetics should be similarly added to the experimental regimens. Early introduction of SGLT2 inhibitors without trying the safer treatment options first may result in unnecessary harm [5], as well as increased cost to patients for whom diet/lifestyle and standard drugs may work in the correct combinations. Indeed, this approach is in accordance with the principles of personalized medicine, one of the most promising goals of 21 century medical practice. In the recent past, a rapid rise in the prevalence of metabolic syndrome has been observed globally, especially in developing countries like India. This increased prevalence of metabolic syndrome is thought to be an important predisposing factor for the current epidemic of T2DM [6, 7]. Complex environment-gene interactions give rise to most, if not all, human diseases, and metabolic syndrome is no exception. For example, two single-nucleotide polymorphisms (SNPs) of apolipoprotein C3 (APOC3), T > C 455 and C > T 482, alone or in combination with the fatty acid binding protein-2 (FABP2), Ala54Thr SNP, appear to be associated with a high risk for developing metabolic syndrome [8]. Even in populations such as those in India with low-fat diets, individuals with these genetic risk factors do not usually escape metabolic syndrome. This knowledge Ltter to he eitor

Prescribing generic drugs using a generic name: Are we teaching it right?

The Indian Medical Council (Professional conduct, Etiquette and Ethics) Regulations, 2002, state that Every physician should, as far as possible, prescribe drugs with generic names and he/she shall ensure that there is a rational prescription and use of drugs.. Undergraduate medical students are introduced to drug nomenclature early on during their pharmacology course. They are told that generic name or, more appropriately, non-proprietary name (usually international non-proprietary name INN), is to be used while writing prescriptions.

Willingness to participate in a clinical trial and understanding of informed consent information among medical students.

Studies have shown that the decision to participate or not participate in a clinical trial does not necessarily imply that the volunteers have completely understood the clinical trial process. A study carried out among medical and non-medical student volunteers revealed that even though the former group had a better recollection of the key facts, their understanding was still below expectation. In our study, medical students were invited to voluntarily take part in a hypothetical exercise in which they were presented with an informed consent form to indicate their willingness to participate in an anti-malarial drug trial. They were encouraged to clarify their doubts and asked to answer a questionnaire to determine their willingness/unwillingness. They were asked to state their reasons and recall key information given in the informed consent form. Responses were submitted by 155 students and 51% of the respondents consented to participate in the trial. As many as 13.5% did not know the name of the drug under study, 14.8% could not recall the main adverse effects to be expected, and 12.3% did not know that they could opt out of the study, this being significantly more in those who had consented to participate (p0.0. As is evident from our study, even presenting a detailed consent form containing an explanation might leave a considerably large number of potential volunteers with an incomplete understanding of the study. Therefore, it is necessary to make an active effort to ensure that the counselling of the volunteers is based on their ability to comprehend the information provided.