First-in-Class Oral Semaglutide: Overcoming Barriers of Incretinisation in the Indian Context.

Despite the availability of multiple therapeutic options and strategies, patients with type 2 diabetes mellitus (T2DM) the world over have inadequate glycaemic control and India is no exception. Patients with T2DM in India have benefitted from glucagon-like peptide-1 analogues similar to that of patients from other parts of the world. However, subcutaneous treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is limited by their injectable mode of administration. The present review highlights barriers to incretinisation with GLP-1RAs and the role of first-in-class oral semaglutide in the Indian context and provides guidance to physicians on its initiation and uses.

The Indian Society for Bone and Mineral Research (ISBMR) position statement for the diagnosis and treatment of osteoporosis in adults.

The Indian Society for Bone and Mineral Research (ISBMR) has herein drafted clinical practice guidelines for the diagnosis and management of osteoporosis for the people of India. Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India. PURPOSE: In India, osteoporosis is a major public health problem. However, in the absence of any robust regional guidelines, the screening, treatment, and follow-up of patients with osteoporosis are lagging behind in the country. METHODS: The Indian Society for Bone and Mineral Research (ISBMR), which is a multidisciplinary group of physicians, researchers, dietitians, and epidemiologists and who study bone and related tissues, in their annual meeting, drafted the guidelines for the diagnosis and management of osteoporosis that would be appropriate in a resource constraint setting like India. RESULTS: Diagnosis of osteoporosis can be made in a patient with minimal trauma fracture without the aid of any other diagnostic tools. In others, bone mineral density measured by dual-energy X-ray absorptiometry remains the modality of choice. Data indicates that osteoporotic fractures occur at an earlier age in Indians than in the West; hence, screening for osteoporosis should begin at an earlier age. FRAX can be used for fracture risk estimation; however, it may underestimate the risk of future fractures in our population and still needs validation. Maintaining optimum serum 25-hydroxyvitamin D levels is essential, which, in most cases, would require regular vitamin D supplementation. Pharmacotherapy should be guided by the presence/absence of vertebral/hip fractures or the severity of risk based on clinical factors, although bisphosphonates remain the first choice in most cases. Regular follow-up is essential to ensure adherence and response to therapy. CONCLUSIONS: Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India.

Judicious use of DXA-BMD in assessing fracture risk by using clinical risk factors in the Indian population.

FRAX scores were significantly higher in patients admitted with fragility fractures than controls and can be useful in choosing the right patients for bone density testing, thus using of an expensive test judiciously. PURPOSE: This study was planned to compare the FRAX scores for the risk for major osteoporotic fracture (FRAX-MOF) and hip fracture (FRAX-HF) in patients with fragility fractures (cases) and those admitted for other indications (controls) in the orthopedic ward in our institute. METHODS: Historical and anthropometric data were prospectively recorded from 500 consecutive patients admitted in the orthopedic ward in in Medanta, the Medicity, Gurgaon, India. The receiver operating characteristic (ROC) curves were constructed for FRAX-MOF and FRAX-HF and the area under the curve (AUC) was calculated between cases and controls. RESULTS: The FRAX-MOF was significantly high in cases as compared to controls (7.34 ± 4.41 versus 5.64 ± 4.3; p = 0.001). The FRAX-HF was also significantly high in cases as compared to controls (2.95 ± 3.13 versus 1.67 ± 2.21; p < 0.001). The areas under the curves were 0.627 for FRAX-MOF and 0.654 for FRAX-HF. For FRAX-MOF, a cutoff of 2 has a 90% sensitivity, but only 15% specificity; whereas a cutoff of 10.5 had a specificity of 90% to differentiate those with and without fractures, but only 23% sensitivity. For FRAX-HF, a cutoff 0.3 had about 90% sensitivity and 20% specificity, whereas a cutoff of 3.5 had 90% specificity and 25% specificity to differentiate cases and controls. CONCLUSIONS: This study compared the FRAX-MOF and FRAX-HF in patients with and without fragility fractures and derived cutoffs for practical clinical use of FRAX-MOF and FRAX-HF to optimize the use of DXA-BMD.

Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial).

OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been shown to reduce liver fat in rodent models. Data regarding the effect of SGLT-2 inhibitors on human liver fat are scarce. This study examined the effect of empagliflozin (an SGLT-2 inhibitor) on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) by using MRI-derived proton density fat fraction (MRI-PDFF). RESEARCH DESIGN AND METHODS: Fifty patients with type 2 diabetes and NAFLD were randomly assigned to either the empagliflozin group (standard treatment for type 2 diabetes plus empagliflozin 10 mg daily) or the control group (standard treatment without empagliflozin) for 20 weeks. Change in liver fat was measured by MRI-PDFF. Secondary outcome measures were change in alanine transaminase (ALT), aspartate transaminase (AST), and γ-glutamyl transferase (GGT) levels. RESULTS: When included in the standard treatment for type 2 diabetes, empagliflozin was significantly better at reducing liver fat (mean MRI-PDFF difference between the empagliflozin and control groups -4.0%; P < 0.0001). Compared with baseline, significant reduction was found in the end-of-treatment MRI-PDFF for the empagliflozin group (16.2% to 11.3%; P < 0.0001) and a nonsignificant change was found in the control group (16.4% to 15.5%; P = 0.057). The two groups showed a significant difference for change in serum ALT level (P = 0.005) and nonsignificant differences for AST (P = 0.212) and GGT (P = 0.057) levels. CONCLUSIONS: When included in the standard treatment for type 2 diabetes, empagliflozin reduces liver fat and improves ALT levels in patients with type 2 diabetes and NAFLD.

Glucocorticoid sparing effect of zoledronic acid in sarcoid hypercalcemia.

INTRODUCTION: Glucocorticoids are regarded as first-line therapy in the management of hypercalcemia associated with sarcoidosis. However, prolonged glucocorticoid therapy leads to metabolic abnormalities, Cushingoid habitus, and impairment of bone health. This study demonstrates the efficacy and glucocorticoid-sparing effect of zoledronic acid in sarcoid hypercalcemia. METHODS: We present three patients with sarcoid hypercalcemia. They were successfully managed with oral glucocorticoids for many months. However, all patients developed adverse effects of glucocorticoids. When tapering of glucocorticoids was attempted, hypercalcemia recurred. Zoledronic acid was administered in order to control hypercalcemia and to allow tapering of glucocorticoids. RESULTS: Following zoledronic acid administration, serum calcium level normalised and glucocorticoids could be discontinued in all the three patients. Normocalcemia was maintained for an average of 18 months after a single infusion. Sarcoidosis remained in remission in all the three patients. CONCLUSION: Zoledronic acid should be studied as a potential first-line agent for sarcoid hypercalcemia. Furthermore, disease-modifying effects of zoledronic acid in sarcoidosis should be investigated.

Pitfalls in interpreting interventional studies for osteoporosis.

After adulthood, changes in the skeleton are slow and takes years for accruing or losing any appreciable amount of bone mass. Proper interpretation of studies that evaluate the effect of nutrients (like calcium, vitamin D) and anti-resorptive agents (like bisphosphonates) on bone mass is important so that the true effect of the agent is measured correctly. In this report, we are highlighting two issues of utmost importance for correctly interpreting interventional studies for osteoporosis. One issue is the bone remodelling transient (BRT). It refers to a transient change in bone mineral density (BMD) by any agent that reduces remodeling space temporarily. This change is, however, not sustained for a long period and can be misinterpreted as a true gain in bone mass. The second issue is difference between calcium balance and bone balance. Calcium balance is the difference between the amount of calcium ingested in a day and the amount of calcium lost in that day. Recommendations for dietary calcium intake are based on calcium balance studies that presume calcium balance as an equivalent for bone balance. However, these are two different entities and need to be distinguished. Dietary calcium requirements should be established by bone balance studies using bone densitometry, not by calcium balance studies.

Hypercalcemia of advanced chronic liver disease: a forgotten clinical entity!

Hypercalcemia caused by advanced chronic liver disease (CLD) without hepatic neoplasia is uncommonly reported and poorly understood condition. We are reporting two cases of advanced CLD who developed hypercalcemia in the course of the disease. This diagnosis of exclusion was made only after meticulous ruling out of all causes of hypercalcemia. The unique feature of this type of hypercalcemia is its transient nature that may or may not require treatment. This clinical condition in patients with CLD should be kept in mind while evaluating the cause of hypercalcemia in them.

Prognostic significance of glycemic variability after cardiac surgery.

INTRODUCTION: The prognostic significance of acute glycemic variability (GV) after cardiac surgery is not known. This study was therefore planned to analyze the independent prognostic value of GV after cardiac surgery. MATERIALS AND METHODS: This is a single center prospective observational study in 870 consecutive cardiac surgery patients over a 3-month period at a tertiary care institute in India. RESULTS: In linear regression analysis, GV was a significant predictor of length of stay in intensive care unit (LOS-ICU) (beta 0.102, p=0.007) and rise in creatinine after surgery (beta 0.229, p<0.001). Mean POC-BG was a significant positive predictor of length of stay in hospital (LOS-hospital) (beta 0.1, p=0.004). In multivariable logistic regression analysis, GV predicted prolonged LOS-ICU (p=0.006, OR 1.016) and acute kidney injury (p<0.001, OR 1.034). CONCLUSION: This study showed that GV, as measured by standard deviation, was a predictor of LOS-ICU, rise in creatinine and AKI after cardiac surgery. GV is therefore a new dimension in postoperative glycemic management in cardiac surgery patients, which needs to be explored.

Childhood and Youth Onset Diabetes: A Single Centre Experience.

OBJECTIVES: To identify proportion of various types of diabetes and differences between type 1 and type 2 diabetes in patients with youth onset diabetes (onset below 25 completed years of age). In addition, concurrent autoimmune diseases in type 1 diabetes were studied in a subset of patients. METHODS: A total of 577 patients (192 girls) with diabetes onset at median age of 14 y (range 1 mo-25 y) with median duration of 1 y (range day of diagnosis- 43 y) were included. Clinical details, investigations and complications were recorded in a proforma. Diabetes was classified using clinical criteria supported by laboratory tests of C peptide and anti GAD-65 antibody in a subset of patients. RESULTS: Type 1 diabetes accounted for 368/421 (87.4 %) patients with age of onset <18 y and 99/156 (63.5 %) of patients with onset between 19 and 25 y of age. Proportion of type 2 diabetes was 36/421 (8.5 %) and 41/156 (26.2 %) in these two groups. Older age at onset, diabetes in one or both parents, absence of ketosis /weight loss and presence of acanthosis were significant predictors of type 2 diabetes. Hypothyroidism (TSH >10) and biopsy proven celiac disease was found in 11.6 and 9.7 % of type 1 diabetes patients respectively. CONCLUSIONS: Type 1 diabetes is the most common type of diabetes in youth, however, a significant proportion of youth have type 2 diabetes. In these patients a combination of clinical factors, biochemical parameters and course over few months helps to guide the diagnosis.

Feasibility, efficacy, and safety of a simple insulin infusion protocol in a large volume cardiac surgery unit in India.

AIM: Inpatient hyperglycemia management is essential, but difficult to achieve especially in a large volume cardiac surgery setup, thus necessitating use of nurse-led insulin protocols. A rapid flux of nurses dealing with a huge workload has been a cause for traditionally not using nurse-led protocols in most Indian institutes. The challenges we faced were to have a simple protocol for the nurses to accept it without compromising on glycemic control. Therefore, this observational study was planned to measure the efficacy and safety of the insulin infusion protocol in cardiac surgery patients. MATERIALS AND METHODS: Insulin protocol was implemented, using seven fixed columns of infusion with the nurse making decisions to initiate and titrate doses based on simple rules. Blood glucose (BG) data captured from blood gas analyzers (glucometrics) in the intervention group (i.e., after protocol implementation) were compared to control group (i.e., before the protocol implementation). RESULTS: The mean BG for the first 48 h was lower in the intervention group as compared to control group, without an increase in the episodes of hypoglycemia. The nurses found the protocol easy to understand, less time-consuming and there was no protocol deviation over 8 months after implementation. CONCLUSION: A small change in the process, allowing nurses to titrate insulin doses based on some rules and having seven fixed columns of insulin infusion rates, improved glycemic control and efficiency.

A randomized controlled trial of cholecalciferol supplementation in patients on maintenance hemodialysis.

BACKGROUND: Vitamin D deficiency is common in Indian patients with chronic kidney disease (CKD) on maintenance hemodialysis (MHD), but optimal dose of cholecalciferol is unclear. MATERIALS AND METHODS: A total of 45 consenting patients were randomized to intervention and control groups. In the intervention group, patients (n = 35) with serum 25-hydroxy vitamin D (25(OH)D) < 30 ng/mL (n = 33), received oral cholecalciferol 60,000 units/week for 6 weeks. The serum levels of 25(OH)D, calcium, phosphorus, albumin, and parathyroid hormone (PTH) were measured at 0, 6, and 12 weeks. In the control group (n = 10), these were estimated at 0 and 6 weeks. RESULTS: In the intervention group, 25/35 patients completed the supplementation at 6 weeks and 20/35 were available at 12 weeks. The mean baseline level of 25(OH)D was 9.59 ± 7.59 ng/mL, and after 6 weeks 19.51 ± 4.27 ng/mL, mean increase being 9.99 ± 6.83 ng/mL, which was highly significant (P < 0.0001). After discontinuing supplementation at 6 weeks, serum 25(OH)D level dropped significantly from 6 to 12 weeks [-2.84 ± 6.25 ng/mL (P = 0.04)]. However, it was still significantly higher at 12 weeks (16.08 ± 8.27 ng/mL) as compared with the baseline. PTH and calcium did not change significantly with supplementation. The change in serum 25(OH)D level from baseline to 6 weeks in the intervention group was inversely related to baseline 25(OH)D levels and patient's weight. In the control group, change in 25(OH)D from baseline to 6 weeks was not significant. CONCLUSION: Supplementation with cholecalciferol 60,000 unit/week for 6 weeks was insufficient to achieve optimal levels of 25(OH)D in Indian patients with CKD on MHD.

Medanta insulin protocols in patients undergoing cardiac surgery.

Hyperglycemia is common in patients undergoing cardiac surgery and is associated with poor outcomes. This is a review of the perioperative insulin protocol being used at Medanta, the Medicity, which has a large volume cardiac surgery setup. Preoperatively, patients are usually continued on their preoperative outpatient medications. Intravenous insulin infusion is intiated postoperatively and titrated using a column method with a choice of 7 scales. Insulin dose is calculated as a factor of blood glucose and patient's estimated insulin sensitivity. A comparison of this protocol is presented with other commonly used protocols. Since arterial blood gas analysis is done every 4 hours for first two days after cardiac surgery, automatic data collection from blood gas analyzer to a central database enables collection of glucose data and generating glucometrics. Data auditing has helped in improving performance through protocol modification.

Hypocalcemic cardiomyopathy-different mechanisms in adult and pediatric cases.

BACKGROUND: Hypocalcemic cardiomyopathy (CMP) is a rare but potentially reversible cause of heart failure. However, the mechanism of hypocalcemia seems to differ between infants and adults. Although severe vitamin D deficiency alone is the usual cause of hypocalcemic CMP in infants, in adult patients significant cardiac dysfunction usually occurs as a result of hypoparathyroidism, either isolated or in combination with vitamin D deficiency. We present two cases of hypocalcemic CMP-one adult and one pediatric-to highlight these differences. CASE PRESENTATION: The first patient was a 47-year-old female who presented with progressive dyspnea and fatigue and was found to have severe left ventricular (LV) systolic dysfunction (LV ejection fraction, 25%). Her serum calcium level was 3.5 mg/dL, serum phosphorus level was 5.7 mg/dL, and serum 25-hydroxyvitamin D level was 14.1 ng/mL, along with a serum PTH level of 11.8 pg/mL. Her LV ejection fraction normalized completely over 6 months with calcium and calcitriol treatment. In contrast, the second patient was an infant who had presented in cardiogenic shock. Investigations revealed serum calcium of 4.5 mg/dL, serum phosphorus of 11.9 mg/dL, 25-hydroxyvitamin D of 8.9 ng/mL, and serum PTH level of 670 pg/mL. Calcium and calcitriol supplementation resulted in rapid and complete clinical and hemodynamic recovery. CONCLUSION: Hypocalcemia is a rare but treatable cause of dilated CMP. In infants, hypocalcemia is usually due to maternal vitamin D deficiency and is accompanied by compensatory hyperparathyroidism. In contrast, in adult patients, hypocalcemic CMP is usually a result of hypoparathyroidism, with or without concomitant vitamin D deficiency.

Usage of pioglitazone at Medanta, the Medicity.

Pioglitazone improves glycemic control by acting as an insulin sensitizer and is used in the management of Type 2 diabetes mellitus. Pioglitazone has recently been at the center of a controversy with regards to its safety. There is no clear consensus on how, when and in what dose the drug should be used in the management of diabetes. We have summarized our strategy on pioglitazone use in Type 2 diabetes in a large private tertiary care center - Medanta, the Medicity- which may help in generating further thought about positioning of this anti-diabetic molecule. We use pioglitazone as the fourth in the pecking order of oral anti-diabetic agents. We typically use pioglitazone in a dose of 15 mg/day. We avoid using pioglitazone with insulin. We do not use pioglitazone under following situations: In the presence of significant or proven cardiac disease, in patients who are struggling with their weight or need to lose weight, in patients at high risk for osteoporotic fractures, in patients with macular edema, in patients with pre-existing bladder cancer and would discontinue in case hematuria or any other symptom of bladder cancer develops. We continue to use the drug in patients well controlled on it without any evident side-effects or contraindications.

Vitamin D deficiency in hemodialysis patients.

BACKGROUND: Vitamin D [(25(OH)D] deficiency and insufficiency is common in patients with chronic kidney disease (CKD). 25(OH)D has been found to have beneficial effects on bone, cardiovascular and immune functions. There are little data about vitamin D levels in Indian patients on dialysis. This study was undertaken to determine the vitamin D status of Indian CKD patients on hemodialysis. MATERIALS AND METHODS: We included 45 patients on maintenance hemodialysis coming to Medanta, Medicity, Gurgaon. 25(OH)D levels were measured with radioimmunoassay (Diasorin) method and parathyroid hormone (PTH) was measured using electrochemiluminiscence immunoassay (ECLIA). RESULTS: The mean age of patients was 55 ± 13 years. 32/45 (71%) were males. 23/45 (51%) were diabetics. The median duration of hemodialysis was 5.5 months (range 1-74 months). 33/45 (74%) patients were on thrice weekly hemodialysis. The mean level of vitamin D was 10.14 ± 8.7 ng/ml. Majority of the patients [43/45 (95.5%)] were either vitamin D deficient or had insufficient levels. 40/45 (88.9%) were vitamin D deficient (levels <20 ng/ml); of these, 29/40 (64.4%) had severe vitamin D deficiency (levels <10 ng/ml) and 3/45 (6.7%) had insufficient levels (20-30 ng/ml) of vitamin D. Only 2/45 (4.4%) patients had normal levels of vitamin D. 23/45 (51%) of patients were receiving calcitriol. The mean levels of serum calcium, phosphorus, alkaline phosphatase, and albumin were 8.8 ± 0.64 mg/dl, 5.0 ± 0.7 mg/dl, 126 ± 10.3 IU/l and 3.6 ± 0.62 g/dl, respectively. PTH levels ranged from 37 to 1066 pg/ml, and the median was 195.8 pg/ml. There was a weak correlation between 25(OH)D levels and weight, sex, hemoglobin, albumin, alkaline phosphatase, and presence of diabetes. There was, however, no correlation with duration of dialysis or PTH levels. CONCLUSION: Vitamin D deficiency and insufficiency are universal in our hemodialysis patients, with severe vitamin D deficiency in two-third of patients.

Abdominal fat distribution and insulin resistance in Indian women with polycystic ovarian syndrome.

The relationship between insulin resistance and abdominal fat distribution was studied in Indian patients with PCOS. Subcutaneous fat, together with a family history of type 2 diabetes mellitus, was the best marker of insulin resistance.