Raktim Kumar Ghosh

SGLT2 Inhibitors: A New Emerging Therapeutic Class in the Treatment of Type 2 Diabetes Mellitus

The incidence of type 2 diabetes mellitus is increasing worldwide. The existing therapeutic classes of antidiabetic drugs are not adequately effective in maintaining long‐term glycemic control in most patients, even when used in combination. One emerging novel therapeutic class of antidiabetic drugs is sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 accounts for 90% of the glucose reabsorption in the kidney. The SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels in an insulin‐independent manner. Dapagliflozin, the most prominent molecule in this class, is currently in a phase III clinical trial. Other members of this class (eg, sergliflozin, remogliflozin) are also in different phases of clinical trials. This class of novel agents can effectively control blood sugar level without producing weight gain or hypoglycemia. Results of ongoing phase III clinical trials are crucial to determine whether the risk‐benefit ratio will allow approval of this new class of drugs for the management of type 2 diabetes mellitus.

Recent advances in antiretroviral drugs

Importance of the field: Acquired immunodeficiency syndrome (AIDS) is one of the leading causes of death worldwide. Although the combination therapies of highly active antiretroviral therapy (HAART) have significantly contributed to virological suppression, improved immune function and quality of life, issues such as tolerability, drug–drug interactions and cross-resistance amongst members of a particular drug class still pose a significant barrier to long-term successful treatment. There is a constant need for newer anti HIV drugs with increased potency and improved pharmacokinetic properties either in the existing classes or drugs from new classes that target several new steps in HIV replication cycle. Areas covered in this review: The authors have discussed newer antiretroviral drugs belonging to second-generation nucleoside analog reverse transcriptase inhibitors (amdoxovir, elvucitabine, apricitabine, racivir), non-nucleoside analog reverse transcriptase inhibitors (etravirine, rilpivirine), protease inhibitors (darunavir, tipranavir) as well as emerging new classes, i.e., fusion inhibitors (enfuvirtide, sifuvirtide), CCR5 inhibitors (maraviroc, vicriviroc, PRO 140, PRO 542), CD4-receptor inhibitors (ibalizumab), integrase inhibitors (raltegravir, elvitegravir, GSK-1349572), maturation inhibitors (bevirimat), cobicistat (pharmacoenhancer), lens epithelium-derived growth factor inhibitors and capsid assembly inhibitors. What the reader will gain: The reader will gain an understanding of the mechanism of action, mechanism of resistance, stages of development and important clinical trials related to the newer antiretroviral drugs and future potential of these drugs. Take home message: The initial clinical trial data of these newer drugs are very encouraging for the long-term successful control of HIV in both treatment-naïve and treatment-experienced patients.

Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: A comprehensive review of clinical and preclinical studies

Diabetes is a leading cause of morbidity and mortality worldwide. Management of diabetes is changing at a rapid pace. Three new classes of antidiabetic drugs including GLP-1 (Glucagon-like peptide 1), DPP-IV (Dipeptidyl peptidase IV) and SGLT2 (Sodium glucose cotransporter 2) inhibitors have been approved in the last few years. Treating diabetes with the antidiabetic drug does not always reduce the cardiovascular complications of diabetes. On the contrary, there was a huge controversy regarding the effect of rosiglitazone on cardiovascular risk reduction a few years ago. Since then, submission of postmarketing cardiovascular outcome study data has been mandated by US FDA and other drug regulatory agencies for newer antidiabetic medications. This is to avoid further premature claims regarding cardiovascular harm or safety of the newer classes. We already have some cardiovascular safety data available on DPP-IV and GLP-1 groups of medications. Dapagliflozin, canagliflozin, and empagliflozin are currently approved SGLT2 inhibitors. We do not have sufficient cardiovascular outcome data available for this novel class. However, this group of drugs, which act by increasing renal glucose excretion, have also shown some non-glycemic benefits including weight reduction, blood pressure control, diuretic action, renal protection, decrease in arterial stiffness and uric acid reduction. Empagliflozin, a new member of SGLT2 class, showed significant cardiovascular morbidity and mortality benefit in recently published EMPA-REG OUTCOME trial. The authors summarize all the published clinical and preclinical cardiovascular outcome data of SGLT2 inhibitors, including recently completed and ongoing major clinical trials in this comprehensive review.

Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data

The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulations tests affected, available clinical and preclinical data, and the need for phase III and IV studies.

Depression in heart failure: Intricate relationship, pathophysiology and most updated evidence of interventions from recent clinical studies

Heart failure (HF) is a burgeoning chronic health condition affecting more than 20million people worldwide. Patients with HF have a significant (17.1%) 30-day readmission rate, which invites substantial penalty in payment to hospitals from Centers for Medicare and Medicaid Services, as per the newly introduced Hospital Readmissions Reduction Program. Depression is one of the important risk factors for readmission in HF patients. It has a significant prevalence in patients with HF and contributes to the overall poor quality of life in them. Several behavioral (smoking, obesity, lack of exercise and medication noncompliance) and pathophysiological factors (hypercortisolism, elevated inflammatory biomarkers, fibrinogen, and atherosclerosis) have been found responsible for the adverse outcome in patients with HF and concomitant depression. Hippocampal volume loss noted in patients with acute HF exacerbations may contribute to the development of depressive symptoms in them. Screening for depression in HF patients continues to be challenging due to a considerable overlap in symptoms. Published trials on the use of antidepressants and cognitive behavioral therapy (CBT) have shown variable outcomes. Newer modalities like internet-based CBT have been tried in small studies, with promising results. A recent meta-analysis observed the beneficial role of aerobic exercise training in patients with HFrEF. Future long-term prospective studies may contribute to the formulation of a detailed screening and management guideline for patients with HF and depression. Our review is aimed to summarize the intricate relationship between depression and heart failure, with respect to their epidemiology, pathophysiological aspects, and optimal management approach.

Effect of addition of either sitagliptin or pioglitazone in patients with uncontrolled type 2 diabetes mellitus on metformin: A randomized controlled trial

Objective: To compare and study the dipeptidy1 peptidase-4 (DPP-4) inhibitors in combination with metformin against established combination therapies. Materials and Methods: This 16-week study was designed to compare sitagliptin versus pioglitazone as add-on therapy in patients of type 2 diabetes mellitus inadequately controlled with metformin alone. Fifty-two patients were randomized into two groups to receive either sitagliptin 100 mg (group 1) or pioglitazone 30 mg (group 2) in addition to metformin. The primary efficacy end point was change in HbA1c. Secondary end points included change in fasting plasma glucose (FPG), body weight and lipid profile. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire. Both the groups had a significant decrease in HbA1c. Results: There was no significant difference between mean reductions in FPG in both the groups. There was a significant decrease in the mean body weight and body mass index in group 1 in contrast to the significant increase in the same in group 2. Both the treatment groups reported a significant decrease in High-density lipoprotein (HDL-C) and Triglyceride. Conclusion: Sitagliptin was well tolerated without any incidence of hypoglycemia. It was concluded that sitagliptin as an add-on to metformin is as effective and well tolerated as pioglitazone.

Perception, attitude and usage of complementary and alternative medicine among doctors and patients in a tertiary care hospital in India

Aim: Complementary and alternative medicine (CAM) has been practiced in India for thousands of years. The aim of this study was to determine the extent of use, perception and attitude of doctors and patients utilizing the same healthcare facility. Methods: This study was conducted among 200 doctors working at a tertiary care teaching Hospital, India and 403 patients attending the same, to determine the extent of usage, attitude and perception toward CAM. Results: The use of CAM was more among doctors (58%) when compared with the patients (28%). Among doctors, those who had utilized CAM themselves, recommended CAM as a therapy to their patients (52%) and enquired about its use from patients (37%) to a greater extent. CAM was used concomitantly with allopathic medicine by 60% patients. Very few patients (7%) were asked by their doctors about CAM use, and only 19% patients voluntarily informed their doctors about the CAM they were using. Most patients who used CAM felt it to be more effective, safer, less costly and easily available in comparison to allopathic medicines. Conclusion: CAM is used commonly by both doctors and patients. There is a lack of communication between doctors and patients regarding CAM, which may be improved by sensitization of doctors and inclusion of CAM in the medical curriculum

Current status of CETP inhibitors in the treatment of hyperlipidemia: an update.

INTRODUCTION The inverse relationship between HDL-C and cardiovascular disease risk suggests that increasing HDL-C could potentially reduce the disease risk. Reverse cholesterol transport is considered to be the primary mechanism by which HDL-C exerts its anti-atherogenic effects. A key regulator of RCT is cholesteryl ester transfer protein (CETP). AREAS COVERED Inhibition of CETP has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy in preliminary clinical trials. The development of this novel class suffered a major setback when the major phase 3 trial of torcetrapib, the first CETP inhibitior was prematurely terminated due to an increase in cardiovascular and noncardiovascular mortality. Subsequent animal and clinical studies have shown that the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect. The other two CETP inhibitors i.e. dalcetrapib and anacetrapib were well tolerated in phase I and II clinical trials and unlike torcetrapib, did not affect blood pressure and aldosterone levels. In this review article the authors have discussed the lessons learned from torcetrapib failure and important preclinical and clinical developments of CETP inhibitors and their role in management of hyperlipidemia and cardiovascular risk reduction.

Role of Ranolazine in cardiovascular disease and diabetes: Exploring beyond angina

Ranolazine was FDA approved for chronic angina in 2006. Since then, there has been extensive research involving this drug. The mechanism of action, debatable at the time of approval, has been demonstrated. Ranolazine acts via inhibition of late sodium channel current in the myocardium. This acts by lowering abnormally high cytosolic calcium levels. Other possible clinical applications of Ranolazine have also been explored. Out of many lines of investigation, its effects in atrial fibrillation, especially post-CABG and recurrent atrial fibrillation show promise. It has also shown definite HbA1c lowering effects when used in diabetics with coronary artery disease. Other possible indications for the drug include pulmonary arterial hypertension, diastolic dysfunction and chemotherapy-induced cardiotoxicity. This review aims to summarize major research regarding Ranolazine in potential applications beyond chronic angina. There are few dedicated large, randomized, phase III trials exploring the newer effects of Ranolazine. There are a few such trials underway, but more are needed.

Selexipag in Pulmonary Arterial Hypertension: Most Updated Evidence From Recent Preclinical and Clinical Studies

Pulmonary arterial hypertension (PAH) is a relatively rare disease that, due to its chronic nature, has always been difficult to treat effectively. Selexipag is an oral prostacyclin (PGI2) agonist that was approved by US Food and Drug Administration (US FDA) in December 2015 for the treatment of PAH. After its success in phase 1 and phase 2 clinical trials regarding the convenient oral twice‐daily dosing and low side‐effect profile, selexipag raised the hope of controlling the disease progression in PAH patients. In the recently completed multicentered phase 3 study (GRIPHON), selexipag has been shown to reduce death and hospitalization due to PAH significantly, an effect that was consistent across different ranges of maintenance dose. In the same study selexipag use was also associated with an increase in 6‐minute walk distance (a measure of symptom severity) from baseline, but no significant improvement in all‐cause mortality could be observed. The results of the ongoing phase 3 studies (TRITON and TRANSIT‐1) are expected to throw some more light on the safety and efficacy of this novel molecule across various treatment scenarios. Hence, our article aims to summarize all the available information from preclinical and clinical studies published to date on the pharmacodynamics, pharmacokinetics, efficacy, safety (in general and in scenarios such as hepatic and renal function impairment), significant drug interactions (with warfarin and antiretroviral drugs), and clinical significance of oral selexipag in patients with PAH.