Current Drug Safety - Volume 16, Issue 1, 2021

Background: Diabetic peripheral neuropathy (DPN) is traditionally divided into large and small fibre neuropathy (SFN). Damage to the large fibres can be detected using nerve conduction studies (NCS) and often results in a significant reduction in sensitivity and loss of protective sensation, while damage to the small fibres is hard to reliably detect and can be either asymptomatic, associated with insensitivity to noxious stimuli, or often manifests itself as intractable neuropathic pain. Objective: To describe the recent advances in both detection, grading, and treatment of DPN as well as the accompanying neuropathic pain. Methods: A review of relevant, peer-reviewed, English literature from MEDLINE, EMBASE and Cochrane Library between January 1st 1967 and January 1st 2020 was used. Results: We identified more than three hundred studies on methods for detecting and grading DPN, and more than eighty randomised-controlled trials for treating painful diabetic neuropathy. Conclusion: NCS remains the method of choice for detecting LFN in people with diabetes, while a gold standard for the detection of SFN is yet to be internationally accepted. In the recent years, several methods with huge potential for detecting and grading this condition have become available including skin biopsies and corneal confocal microscopy, which in the future could represent reliable endpoints for clinical studies. While several newer methods for detecting SFN have been developed, no new drugs have been accepted for treating neuropathic pain in people with diabetes. Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors and anticonvulsants remain first line treatment, while newer agents targeting the proposed pathophysiology of DPN are being developed.

Proliferative diabetic retinopathy and diabetic macular edema can be a potentially sightthreatening disease if not treated correctly. It is directly correlated to the duration of diabetes and how well managed the patients' diabetes is. In the last 15 years, the treatment of diabetic eye disease has taken a quantum leap in methodology due to the group of biological agents named antivascular endothelial growth factor (anti-VEGF). The introduction of the first biological agent has revolutionized the treatment, not only in diabetic eye disease but also across most inflammatory eye diseases, causing leakage of fluid from the blood vessels i.e., in age-related macular degeneration. The availability of these biological agents, despite their considerable costs, have significantly improved the outcomes measured in visual acuity compared to more traditional treatments of diabetic retinopathy in the form of sole laser treatment and glycemic control. The agents demonstrate a favorable safety profile, but if the rarest and most severe side effects occur, there is a potential total loss of vision. This review aims to make an overview of the current pharmaceutical therapeutic options in the treatment of diabetic macular edema. This includes laser therapy, intravitreal steroids, and a primary focus on intravitreal antivascular endothelial growth factors.

Background: Despite substantial improvements over the years, diabetes mellitus is still associated with cardiovascular disease, heart failure, and excess mortality. Objective: The objective of this article is to examine existing data on the reduction of cardiovascular morbidity and mortality in diabetes. Control of glycemia, lipid levels, and blood pressure are described in brief. The main scope of this article is, however, to review the glucose-independent cardiovascular effect of antidiabetic pharmacological agents (mainly other than insulin). Methods: The article is a narrative review based on recently published reviews and meta-analyses complemented with data from individual trials, when relevant. Results and Discussion: Older data suggest a cardioprotective role of metformin (an inexpensive and safe drug); a role to date not convincingly challenged. The cardiovascular effects of thiazolidinediones, sulphonylurea, and glinides are debatable. Recent large-scale cardiovascular outcome trials suggest a neutral profile of dipeptidyl peptidase 4 inhibitors, yet provide compelling evidence of cardioprotective effects of glucagon-like 1 receptor antagonists and sodium-glucose transporter 2 inhibitors. Conclusion: Metformin may have a role in primary and secondary prevention of cardiovascular disease; glucagon-like 1 receptor antagonists and sodium-glucose co-transporter 2 inhibitors play a role in secondary prevention of atherosclerotic cardiovascular disease. Sodium-glucose transporter 2 inhibitors have a role to play in both primary and secondary prevention of heart failure; yet, they carry a small risk of the potentially dangerous adverse effect, euglycemic diabetic ketoacidosis.

Introduction: People with diabetes could have an increased risk of falls as they show more complications, morbidity and use of medication compared to the general population. This study aimed to estimate the risk of falls and to identify risk factors associated with falls in people with diabetes. The second aim was to estimate fall-related injuries, such as lesions and fractures, including their anatomic localization in people with diabetes compared with the general population. Methods: From the Danish National Patient Register, we identified people with Type 1 Diabetes (T1D) (n=12,975) Type 2 Diabetes (T2D) (n=407,009). The cohort was divided into two groups, with respective control groups matched on age and sex (1:1). All episodes of people hospitalized with a first fall from 1996 to 2017 were analyzed using a Cox proportional-hazards model. Risk factors such as age, sex, diabetic complications, a history of alcohol abuse and the use of medication were included in an adjusted analysis. The incidence rate, incidence rate difference and incidence rate ratio (IRR) of falls and the anatomic localization of fall-related injuries as lesions and fractures were identified. Results and Discussion: The cumulative incidence, of falls requiring hospital treatment, was 13.3% in T1D, 11.9% in T2D. In the adjusted analysis, T1D and T2D were associated with a higher risk of falls [T1D, Hazard Ratio (HR): 1.33 (95% CI: 1.25 - 1.43), T2D, HR: 1.19 (95% CI:1.16 - 1.22), respectively]. Women [group 1, HR 1.21 (CI:95%:1.13 - 1.29), group 2, HR 1.61 (CI:95%:1.58-1.64)], aged >65 years [groups 1, HR 1.52 (CI:95%:1.39 - 1.61), group 2, HR 1.32 (CI:95%:1.58-1.64)], use of selective serotonin receptor inhibitors (SSRI) [group 1, HR 1.35 (CI:95%:1.1.30 - 1.40), group 2, HR 1.32 (CI:95%:1.27-1.38)], opioids [group 1, HR 1.15 (CI:95%:1.12 - 1.19), group 2, HR 1.09 (CI:95%:1.05-1.12)] and a history of alcohol abuse [group 1, HR 1.77 (CI:95%:1.17 - 2.15), group 2, HR 1.88 (CI:95%:1.65-2.15)] were significantly associated with an increased risk of falls in both groups. The IRR of fall-related injuries as hip, radius, humerus and skull/facial fractures were higher in people with T2D than controls [IRR 1.02 (CI:95%:1.01-1.04), IRR 1.39 (CI:95%: 1.18-1.61), IRR 1.24 (CI:95%: 1.12-1.37) and IRR 1.15 (CI:95%:1.07-1.24)]. People with T1D had a higher IRR of hip fractures than controls [IRR: 1.11 (CI:95%:1.02 – 1.23)]. Conclusion: People with diabetes have an increased risk of first fall and a higher incidence of fall- related injuries, including fractures. Advanced aging and sex are non-modifiable risk factors, whereas diabetes, the use of SSRIs and opioids and alcohol abuse could be potentially modifiable risk factors for falls. Gaining information on risk factors for falls could guide the management of diabetes treatment, i.e., choice of drugs, which enables us to improve treatment, particularly in people with a high risk of falls and fractures associated with high mortality.

Background: Treatment with sodium-glucose co-transporter-2-inhibitors (SGLT2-Is), such as canagliflozin, has been associated with an increased risk of lower limb amputations (LLAs) in type 2 diabetes mellitus (T2DM). However, conflicting results have been reported for different SGLT2-Is and the underlying mechanism is unclear. Objective: To investigate the risk of LLA and diabetic foot ulcer with SGLT2-I use compared to other anti-diabetic drugs and to explore hypovolemia as a potential underlying mechanism. Methods: A cohort study was conducted using data from the Clinical Practice Research Datalink GOLD (2013-2019). The study population (N=51,847) consisted of T2DM patients over 18 years of age with at least one prescription of a non-insulin anti-diabetic drug. Concomitant diuretic use and the presence of signs of hypovolemia were determined to assess the potential underlying mechanism. Cox proportional hazard models were used to estimate the hazard ratio (HR) for LLA in current SGLT2-I use versus current sulphonylurea (SU) use. Analyses were adjusted for lifestyle variables, comorbidities, and concomitant drug use. Results: Current SGLT2-I use was not associated with an increased risk of LLA compared to current SU use (fully adjusted HR 0.70; 95% confidence interval 0.38-1.29). Concomitant use of diuretics and the presence of signs of hypovolemia were not associated with an increased risk of LLA. Conclusion: Use of SGLT2-Is, with or without signs of hypovolemia, was not associated with an increased risk of LLA or DFU versus current SU use. Future studies powered to detect potential differences between individual SGLT2-Is are required to rule out a canagliflozin-specific effect.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been associated with increased risk of diabetic ketoacidosis (DKA) in both people with type 1 and type 2 diabetes mellitus. Few studies using data from high-quality registries exist that attempt to determine the real- world impact of the increasing use of this drug. Objective: The aim of this study was to investigate the incidence and risk of DKA in connection with SGLT2i treatment in Denmark between 2013-2017. Methods: A nationwide retrospective cohort of people with type 2 diabetes mellitus using SGLT2i or glucagon-like peptide-1 receptor agonists (GLP1-RA) was established and analysed using both Cox-proportional hazard regression and Kaplan-Meier survival analysis. Results: The 37,058 individuals included in the cohort, were made up of SGLT2i (10,923), GLP1- RA (18,849), SGLT2i+insulin (2,069), and GLP1-RA+insulin (10,178) users. The incidence rate (IR) of DKA was 0.84 (95% CI 0.49-1.44) and 0.53 (95% CI 0.36-0.77) for the SGLT2i and GLP1-RA groups, respectively. There was no statistically significant increase in the risk for DKA with SGLT2i use (HR 1.02, 95% CI, 0.44-2.36). However, for the SGLT2i+insulin and GLP1- RA+insulin groups, IRs were 3.47 (95% CI 1.92-6.27) and 0.97 (95% CI 0.68-1.37) respectively, and the risk was statistically significantly higher (HR 5.42, 95% CI 2.16-13.56). Conclusion: We observed no significant increase in the risk of DKA for SGLT2i users compared to GLP1-RA. However, a significantly higher IR of DKA was observed with concomitant insulin use, and the risk of DKA was considerably higher for the SGLT2 group using insulin.

Background: Self-treatment with antibiotics involves obtaining medicines without a prescription, sharing medicines with members of one’s social circle, or using leftover medicines stored at home. Objective: Assess the prevalence, knowledge level, reasons for practicing self-treatment of antibiotic among undergraduate university students. Methods: The study was conducted cross-sectional on a sample of 201 students. A pre-validated questionnaire called “self-treatment with antibiotics”, containing 27 close-ended questions, was administered to each subject. Data were analyzed using SPSS version 16 and the results were expressed as counts and percentages. Results and Discussion: Knowledge about self-treatment with antibiotics was good in general, and health-related students had a better level of knowledge about self-treatment with antibiotics than non-health-related students. The majority of the participants had not used self-treatment with antibiotics. Gender, age, and the last time antibiotic taken affected self-treatment with antibiotics. The most common indication for self-treatment with antibiotics was flu, cold, and tonsillitis. The most common reason for practicing self-treatment with antibiotics was being considered as a convenient and rapid solution. Internet was the main source for university students regarding knowledge about antibiotic use and resistance. Conclusion: Self-treatment with antibiotics is affected by several social and demographic variables, and the role of media, public policies, university curricula as well as physicians and pharmacists should be enforced and activated to eliminate inappropriate uses of antibiotics and to correct misconceptions that encourage self-treatment with antibiotics.

Background: Around 2-3% of hospitalizations have been reported due to dermatological adverse drug reactions. Recent studies suggest that climatic variations affect the skin barrier function and extreme conditions aggravate skin disorders. Objective: The present study was designed to compare the impact of climatic variations on drug-induced skin reactions in the Northern and Eastern regions of India. Methods: We performed a one-year retrospective study to evaluate the impact of climatic variations (temperature and humidity) on drug-induced skin reactions in the Eastern (Kalyani, West Bengal) and Northern (Karnal, Haryana) regions. Drug-induced skin reactions were reported month-- wise in both the Eastern and Northern regions. Temperature and humidity levels were also noted month-wise in both regions. The direct correlation between climatic variations and the number of drug reactions were assessed using Pearson#136;s correlation and quadratic regression analysis. Results and Discussion: Overall, 99 and 81 dermatological adverse drug reactions were reported in tertiary care hospitals in the Northern and Eastern regions, respectively. During the summer season, the humidity level was found to be low in the Northern region as compared to the Eastern region. During this period, drug-induced skin reactions were reported significantly (p<0.05) more in the Northern region as compared to the Eastern region. Furthermore, quadratic regression analysis revealed that climatic variations contributed to drug reaction variability in the Northern region (68.5%) and Eastern region (23.5%). Conclusion: Therefore, the difference in the prevalence of drug-induced skin reactions may be related to the different climatic conditions among these two regions. Further studies in controlled climatic conditions should be performed for definitive correlations and to look into possible solutions.

Introduction: Chronic spontaneous urticaria (CSU) is characterized by recurrent hives without a known trigger. While certain drugs are associated with urticaria exacerbations, the overall drug allergy incidence in CSU is unknown. We hypothesized that the incidence of drug allergy in CSU would be greater than the general population and that there would be distinguishing clinical features of drug-allergic CSU patients. Methods: 362 adult CSU patients seen over a 10-year period at a University Allergy/Asthma clinic were identified. Patients reported no drug allergies or any drug allergy. Multiple drug allergies were defined as allergies to ≥ 2 chemically unrelated drugs. Using Chi-square or Wilcoxon analysis, we compared demographic features of CSU with and without drug allergy and with multiple vs. single drug allergy. Results and Discussion: Overall, 202 CSU patients (56%) reported drug allergy. Drug allergic CSU patients were older, with a greater proportion of whites and higher BMI vs. CSU without drug allergy (p=0.002, p=0.047, p=0.004, respectively). Penicillin was the most common drug allergy, with urticaria the most frequently reported reaction. Female sex, white race, older age at the visit, and co-existing asthma were more common in multiple drug allergy (n=115) vs. single drug allergy (p=0.002, p=0.02, p=0.03, p=0.0002, respectively). Conclusion: In CSU, the prevalence of self-reported drug allergies was higher than the general population. Drug allergy is associated with older age, white race and higher BMI, while multiple drug allergy was also associated with asthma. These CSU sub-populations should be studied to avoid the potential for morbidity associated with less efficacious and more costly drugs.

Background: Autoimmune polyglandular syndrometype-2 (APS-2) is an uncommon endocrine disorder of Addison’s disease with an autoimmune thyroid disorder and/or type 1 diabetes mellitus. The diagnosis is more challenging when a patient presents with nonspecific neuropsychiatric features with hypothyroidism in the setting of unrecognized Addison’s disease. Case Report: We report a case of subclinical autoimmune hypothyroidism presented with nonspecific neuropsychiatric symptoms precipitated by stress. Despite levothyroxine treatment, her symptoms deteriorated and she was admitted with persistent vomiting and hypovolemic shock. Clinical features and laboratory parameters were suggestive of underlying adrenocortical insufficiency. Preexisting autoimmune hypothyroidism combined with Addison's disease confirmed the diagnosis of unrecognized APS-2. She remarkably improved and her thyroid function tests also normalized with the treatment of corticosteroids only. Review of the Literature: We identified only five published case reports of our title by searching the database. Neufeld and Betterle have reported their data of APS-2 and concluded that a full- blown clinical picture of two or more components of the syndrome is like the tip of the iceberg. Conclusion: The patients of one major component of APS-2 should be screened for other components of the disease to pick up latent cases. Addison’s disease should be ruled out in patients of hypothyroidism who are intolerant to levothyroxine.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint and systemic involvement. Tofacitinib is a JAK- inhibitor that is an effective agent in the treatment of active RA. Varicella zoster virus(VZV) reactivation is among the most important adverse effects of tofacitinib. Ramsay-Hunt syndrome(RHS) is a rare clinical condition that develops as a result of VZV reactivation and progresses with hearing loss, dizziness, and facial nerve paralysis. Objective: To present a case of Ramsay-Hunt syndrome due to varicella zoster reactivation in a RA patient using tofacitinib. Case Report: A 63-year-old female RA patient under tofacitinib treatment was admitted to the rheumatology outpatient clinic due to widespread skin rashes on her face and ear, and hearing loss. On inspection widespread erythematous, vesicular rashes on the left side of the face, lips, around the eye and in the ear, and mild facial paralysis on the left side were detected. On laboratory investigations, acute phase reactants were increased. Serological study for specific antibodies against varicella zoster virus showed higher titers. Dermatology and ear nose throat specialist consultations were performed, and varicella zoster lesions on the left inner ear, face, and mild facial paresis were considered. According to clinical and laboratory findings, the patient was diagnosed with RHS triggered by tofacitinib. Tofacitinib and methotrexate were discontinued, and intravenous acyclovir was started. On the control examination, the patient's skin lesions and facial nerve paralysis regressed. Conclusion: Herein, we reported the fırst case of tofacitinib-induced RHS in a patient with RA. This may be another side effect of biologic treatment. New studies are needed on this subject.

Methotrexate is an anti-metabolite, anti-cancer drug frequently used in the treatment of extensive chronic plaque psoriasis. Psoriatic plaque erosion is a rare toxic side effect of single-dose methotrexate and is described as a sign of impending pancytopenia. Here, we report a case of a 48- year-old male presented with multiple oral and genital erosions, accompanied by fissuring over palm and soles for 5 days. His laboratory tests revealed severe pancytopenia and nephropathy. He had a history of chronic plaque psoriasis for which he took a single dose of 15 mg methotrexate. During the hospital stay, the patient needed folate antagonist, granulocyte colony-stimulating factor (G-CSF), intravenous fluids, blood transfusions, and platelet transfusions. He recovered within 12 days of admission.