Once-weekly Insulin Icodec as Compared to Once-daily Basal Insulins: A Meta-analysis.

BACKGROUND: Once-weekly basal insulin icodec has been tested in clinical trials for efficacy and safety over currently available glargine-100 and degludec in different clinical settings for type 2 diabetes. We performed this meta-analysis to evaluate its overall safety and efficacy as compared to glargine-100 and degludec (nonicodec), from all available randomized controlled trials. METHODS: Seven trials comparing once-daily basal insulin analogs to once-weekly basal insulin icodec were included. Based on available information, outcomes in terms of HbA1c, fasting plasma glucose reduction, and increase in time in range (TIR) were compared. Side-effects were compared for overall hypoglycemia, severe hypoglycemia, and weight gain. The pooled effect size for continuously distributed data was measured as a reduction in "estimated differences in mean (with 95% CI)." For categorical data, the pooled effect size was measured as the Mantel-Haenszel risk ratio (with 95% CI). RESULTS: Analyzing against the nonicodec comparators together, the "estimated mean changes" in HbA1c and fasting plasma glucose favoring icodec were -0.22% (-0.35, -0.10) and -1.59 mg% (-9.26, 6.08) respectively. The "estimated mean increment" in weight for icodec was 0.64 kg (0.61, 0.67). The "estimated mean percentage" increment in TIR for icodec was 4.24% (2.99, 5.49). The Mantel-Haenszel risk ratios for all hypoglycemic events and severe hypoglycemia for icodec were 1.24 (1.02, 1.50) (P = .03) and 0.81 (0.31, 2.08) (P is not significant), respectively, suggesting a 24% increased incidence of all hypoglycemia with icodec. CONCLUSION: Once-weekly basal insulin icodec as compared to once-daily basal insulin analogs had a slight increase in the risk of overall hypoglycemia and weight gain, without any difference in severe hypoglycemia, with similar glycemic control (in terms of fasting plasma glucose, HbA1c, and TIR).

Different Sodium-Glucose Cotransporter-2 Inhibitors: Can They Prevent Death?

OBJECTIVE: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) in cardiovascular outcome trials (CVOTs) demonstrate cardiovascular (CV) safety and benefits. Some dedicated randomized controlled trials (RCTs) demonstrate benefit in terms of renal outcomes and hospitalization due to heart failure (HF). RCTs report differences in the secondary outcomes with respect to mortality (CV and/or all-cause). We undertook a meta-analysis of all SGLT2is for which in addition to CVOT, HF outcome/renal outcome studies are available to establish whether individual SGLT2is were able to prevent death. METHODS: We included available event-driven randomized, placebo-controlled CVOTs and dedicated RCTs of SGLT2is exploring renal outcomes and HF. We included 3 trials of empagliflozin, 3 of dapagliflozin, 2 of canagliflozin, and 2 of sotagliflozin. The efficacy outcomes included all-cause mortality and CV mortality. Hazard ratios (HRs) with 95% CIs were pooled for individual molecules. RESULTS: The HR for all-cause mortality including all trials was 0.86 (0.80-0.93). The HRs for all-cause mortality in empagliflozin (N = 16 738), dapagliflozin (N = 26 208), canagliflozin (N = 14 543), and sotagliflozin (N = 11 806) were 0.86 (0.69-1.08), 0.83 (0.72-0.97), 0.86 (0.75-0.97), and 0.95 (0.81-1.11), respectively. The HR for CV mortality including all trials was 0.85 (0.78-0.92). The HRs for CV mortality in empagliflozin, dapagliflozin, sotagliflozin, and canagliflozin were 0.81 (0.63-1.03), 0.88 (0.78-1.00), 0.89 (0.74-1.07), and 0.84 (0.72-0.98), respectively. CONCLUSION: SGLT2is as a class reduce both all-cause mortality and CV mortality. Canagliflozin possibly reduces both all-cause mortality and CV mortality, whereas dapagliflozin may reduce all-cause mortality but not CV mortality. Empagliflozin and sotagliflozin may reduce neither.

Assessment of Insulin Resistance Indices in Individuals with Lean and Obese Metabolic Syndrome Compared to Normal Individuals: A Population Based Study.

INTRODUCTION: Obesity is associated with insulin resistance and measuring it in an apparently healthy population and correlating them with established risk parameters may identify predisposed individuals who may later develop diabetes or cardiovascular diseases. MATERIAL AND METHODS: 405 participants from a rural area were investigated for various metabolic parameters and indices of insulin resistance. Insulin resistance indices were evaluated in the 3 different groups [Obese Metabolic Syndrome (MetS), Lean MetS and those without MetS]. Various anthropometric and metabolic parameters were compared. Lean MetS is defined as those having waist criteria below the region specific waist criteria and even then satisfying the definition of MetS as per the NCEP ATP-III criteria. RESULTS: The mean fasting insulin level was 7.69+4.38 uIU/ml in normal population, 10.40+5.65 uIU/ml in Lean MetS population and 13.71+6.63 uIU/ml in Obese MetS population (P<0.05). The HOMA-IR2 measured was 2.39+ 1.69 in normal population, while in the Lean MetS and Obese Mets were 3.99+3.40 and 4.04+2.53, respectively (P<0.05). The QUICKI level measured was 0.358+0.041 in normal population and 0.334+0.037 and 0.316+0.026 respectively in the Lean MetS and Obese MetS (P<0.05). McAuley index measured in normal population was 0.49+0.26 and 0.75+0.25 and 0.79+0.17 in the Lean MetS and Obese MetS population (P<0.05).TyG index measured was 8.51+0.46 in normal population and 9.27+0.56 and 9.06+0.49 respectively in the Lean MetS and Obese MetS (P<0.05). CONCLUSION: Insulin resistance indices are elevated in MetS compared to the normal population but the indices in Lean MetS are not different from Obese MetS. The relevance of ethnicity specific waist circumference may need re-evaluation considering its little impact in influencing the level of insulin resistance.

SGLT2 Inhibitors: Effect on Myocardial Infarction and Stroke in Type 2 Diabetes.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have recently been recommended as preferred agents for management of hyperglycemia in type 2 diabetes, primarily based on their ability to reduce a composite of major cardiovascular adverse events (3-point major adverse cardiovascular events [MACE]), predominantly by reducing cardiovascular death. However, reduction of the individual components, myocardial infarction (MI), or stroke (fatal and nonfatal) events have not been well explored. METHODS: In this meta-analysis, we included data available from cardiovascular outcome trials only, which were event-driven, randomized, and placebo-controlled. Pooled efficacy outcomes included Mantel Haenszel (MH) risk ratio using fixed model (with 95% CI) for fatal and nonfatal MI, stroke, and total MI and stroke. FINDINGS: Data from 4 eligible trials included 42,568 subjects. Total MACE, MI, and stroke were reported in 4176, 2157, and 1288 subjects, respectively. SGLT2is did not significantly reduce either MI or stroke individually or in totality. The MH risk ratio (95% CI) for fatal and nonfatal MI and stroke with different SGLT2is was found to be 0.93 (95% CI, 0.85-1.01) and 1.00 (95% CI, 0.89-1.11), respectively. For total atherosclerotic cardiovascular disease (ASCVD) events, MH risk ratio (95% CI) was 0.95 (95% CI, 0.89-1.02). For all nonfatal ASCVD (combined nonfatal MI and nonfatal stroke), MH risk ratio (95% CI) was 0.94 (95% CI, 0.88-1.02). INTERPRETATION: SGLT2is reduce MACE without any discernable significant reduction of the incidence of MI or stroke (fatal and nonfatal), probably implicating mechanisms unrelated to anti-atherogenic effects.

Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.

OBJECTIVES: 46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of underandrogenization of male genitalia. Such patients should be approached systematically to reach an aetiological diagnosis. However, we lack, at present, a clinical practice guideline on diagnostic approach in 46, XY DSD from this part of the globe. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests, performed in these cases. The consensus committee consisting of 34 highly experienced endocrinologists with interest and experience in managing DSD discussed and drafted a consensus statement on the diagnostic approach to 46, XY DSD focussing on relevant history, clinical examination, biochemical evaluation, imaging and genetic analysis. CONTENT: The consensus was guided by systematic reviews of existing literature followed by discussion. An initial draft was prepared and distributed among the members. The members provided their scientific inputs, and all the relevant suggestions were incorporated. The final draft was approved by the committee members. SUMMARY: The diagnostic approach in 46, XY DSD should be multidisciplinary although coordinated by an experienced endocrinologist. We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods. Meticulous history taking and thorough head-to-toe examination should initially be performed with focus on external genitalia, including location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to the age and interpreted according to age-appropriate norms Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, are acceptable alternatives. All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may be used to demonstrate the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings. OUTLOOK: The members of the committee believe that patients with 46, XY DSD need to be approached systematically. The proposed diagnostic algorithm, provided in the consensus statement, is cost effective and when supplemented with appropriate genetic studies, may help to reach an aetiological diagnosis in majority of such cases.

Lipid Profile in Infant.

INTRODUCTION: Alteration in lipid parameters at birth has a strong association with the development of cardiovascular disease in later life. MATERIAL AND METHODS: Sixty-one infants below the age of 6 months underwent evaluation of lipid parameters. The infants studied were categorized into two groups of ≤4 and >4 weeks of age, wherein their lipid parameters were compared. RESULTS: The normal distribution of lipid parameters of infants <6 months was generated. The mean total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol was 126.2 ± 26.5, 149.1 ± 48.6, 40.7 ± 14.6, and 69.4 ± 19.4 mg/dl, respectively. The total cholesterol and LDL-cholesterol measured in ≤4 and >4 weeks of age groups were statistically not different (total cholesterol 125.0 ± 30.1 mg/dl vs 127.4 ± 23.4 mg/dl, P = 0.727, and LDL-cholesterol 66.0 ± 19.2 mg/dl vs 75.4 ± 21.2 mg/dl, P = 0.780). However, the HDL-cholesterol and triglycerides measured at ≤4 weeks versus >4 weeks age groups were statistically different (HDL-cholesterol 44.9 ± 17.2 mg/dl vs 36.9 ± 10.8 mg/dl, P = 0.031, and triglyceride 147.4 ± 60.2 mg/dl vs 186.5 ± 75.7 mg/dl, P = 0.030). CONCLUSION: The mean lipid parameters were significantly more atherogenic compared to the Western population. Triglyceride levels and HDL-cholesterol levels change significantly after 4 weeks of age compared to that observed before 4 weeks of age.

Cardiovascular safety of Glimepiride: An indirect comparison from CAROLINA and CARMELINA.

BACKGROUND: Despite having unquestionable glucose lowering efficacy, current guidelines no more favour the uses of sulphonylureas for CV safety concern, except when cost is an issue. However, formal cardiovascular outcome trial (CVOT) is not available. MATERIALS AND METHODS: We performed an indirect treatment comparison to find the hazard ratio for 3-point MACE, all-cause death, CV death and non-CV death between glimepiride and placebo based on two large CVOTs which established the CV safety of linagliptin (CARMELINA and CAROLINA). RESULTS: Glimepiride was shown to have a non-inferior risk compared to placebo for 3-point MACE (HR 1.04, 95% CI 0.850, 1.274), all-cause mortality (HR 1.08, 95% CI 0.880, 1.317), CV death (HR 0.96, 95% CI 0.732, 1.259), and non-CV death (HR 1.24, 95% CI 0.893, 1.733). CONCLUSION: Cardiovascular safety of glimepiride is re-assuring and may help patients with type 2 diabetes world-over to avail the benefit of this affordable efficacious medication.

Kidney Disease in Type 2 Diabetes Mellitus and Benefits of Sodium-Glucose Cotransporter 2 Inhibitors: A Consensus Statement.

Diabetic kidney disease (DKD) occurs in approximately 20-40% of patients with type 2 diabetes mellitus. Patients with DKD have a higher risk of cardiovascular and all-cause mortality. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antihyperglycemic drugs form the mainstay of DKD management and aim to restrict progression to more severe stages of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) control hyperglycemia by blocking renal glucose reabsorption in addition to preventing inflammation, thereby improving endothelial function and reducing oxidative stress; consequently, this class of prescription medicines is emerging as an important addition to the therapeutic armamentarium. The EMPA-REG OUTCOME, DECLARE TIMI 58, and CANVAS trials demonstrated the renoprotective effects of SGLT2i, such as restricting decline in glomerular filtration rate, in the progression of albuminuria, and in death due to renal causes. The renoprotection provided by SGLT2i was further confirmed in the CREDENCE study, which showed a 30% reduction in progression of chronic kidney disease, and in the DELIGHT study, which demonstrated a reduction in albuminuria with dapagliflozin compared with placebo (- 21.0%, confidence interval [CI] - 34.1 to - 5.2, p = 0.011). Furthermore, a meta-analysis demonstrated a reduced risk of dialysis, transplantation, or death due to kidney disease (relative risk 0.67; 95% CI 0.52-0.86; p = 0.0019) and a 45% risk reduction in worsening of renal function, end-stage renal disease, or renal death (hazard ratio 0.55, CI 0.48-0.64, p < 0.0001) with SGLT2i, irrespective of baseline estimated glomerular filtration rate. Thus, there is emerging evidence that SGLT2i may be used to curb the mortality and improve the quality of life in patients with DKD. However, clinicians need to effectively select candidates for SGLT2i therapy. In this consensus statement, we have qualitatively synthesized evidence demonstrating the renal effects of SGLT2i and proposed recommendations for optimal use of SGLT2i to effectively manage and delay progression of DKD.

Uric Acid and Its Correlation with Various Metabolic Parameters: A Population-Based Study.

INTRODUCTION: Uric acid, apparently an inert waste product, was found to have association with various metabolic disorders. The data regarding prevalence of serum uric acid (SUA) abnormalities and its correlation with other anthropo-metabolic parameters, however, are scanty. MATERIALS AND METHODS: In all, 405 participants from a rural area were investigated for various metabolic parameters including uric acid. SUA level was evaluated for having any correlation with other anthropometric and metabolic disorders like obesity, dyslipidemia, metabolic syndrome (MetS), hypertension, calcium and vitamin D abnormalities, liver function, and glycemic alterations. Lean MetS is defined as those having waist criteria below the region specific waist criteria and even then satisfying the definition of MetS as per the National Cholesterol Education Program (NCEP) ATP-III (Adult Treatment Panel) criteria. RESULTS: The mean uric acid was 4.2 mg/dL (±1.35), with 4.9 mg/dL (±1.28) for males and 3.7 mg/dL (±1.14) for females. Thirteen of 405 people (3.2%) found to have uric acid level of more than 7.0 mg/dL, and eight people out of 405 (2.0%) had hypouricemia. SUA showed correlation with age, blood pressure, and the anthropometric parameters for obesity, for example, weight, body mass index, waist circumference, waist hip ratio, waist height ratio, fasting insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides. However, fasting glucose, calcium, phosphate, 25-hydroxy vitamin D3, and iPTH did not show any correlation with the SUA level. Compared to the healthy population, SUA level was elevated in MetS as defined by International Diabetes Federation (IDF) criteria. However, the SUA in healthy population was not significantly different from the Lean MetS, and SUA of Lean MetS was not significantly different from Obese MetS. CONCLUSION: SUA is elevated in MetS compared to the normal population. However, SUA in Lean MetS is not different from Obese MetS.

Pandemic of Vitamin D Deficiency: Cardiometabolic Concern or Skeletal Biochemical Abnormality?

CONTEXT: Biochemical Vitamin D deficiency is said to be present universally in recent times. However, its effect is more profound in modulation of anthropometric and biochemical risk factors of various chronic metabolic disorders rather than its influence on bone mineral abnormalities. The present study was undertaken to compare various anthropometric and biochemical parameters including basic bone mineral biochemistry in various strata of Vitamin D status. MATERIALS AND METHODS: A population based study was done in the rural area of West Bengal comprising 405 people (initially targeted 400) to look for various anthropometric and biochemical parameters. RESULTS: Anthropometric metabolic markers like BMI, WC, waist to height ratio and biochemical parameters like total cholesterol, LDL, TG, insulin, ALT, FPG were statistically significantly higher in vitamin D deficient (<20 ng/ml) (n = 228) subjects compared to Vitamin D non-deficient subjects (≥20 ng/ml) (n = 177) which persisted even after adjustment for BMI except for FPG. The difference was similarly present when severely Vitamin D deficient (<10 ng/ml) (n = 39) subjects were compared to Vitamin D sufficient subjects (≥30 ng/ml) (n = 38) and persisted after adjustment for BMI except for FPG. However, WHR, blood pressure (both systolic and diastolic), HbA1c, HDL, AST, Uric acid, freeT4, TSH, HOMA-IR were not different in both the above-mentioned comparisons. Metabolic syndrome was statistically significantly lower in vitamin D non-deficient subjects. Though iPTH was statistically significantly higher in the low vitamin D cohorts in both the comparisons, bone mineral markers like serum calcium, phosphorus and alkaline phosphatase were not different even when severely vitamin D deficient subjects were compared to vitamin D sufficient subjects. CONCLUSION: Pandemic of vitamin D deficiency is more likely to be associated with cardio-metabolic risk factors than biochemical bone mineral abnormality.

Growth hormone deficiency in children: an approach to a child with short stature.

The importance of recognition of short stature in a child is very important as it allows one to identify important medical conditions where physical shortness is only one manifestation. Causes of short stature are: Familial, idiopathic, delay in growth and maturation, chronic systemic illnesses, endocrinopathies, rickets, skeletal dysplasia, chromosomal disorders and emotional deprivation. Proper history, physical examination, endocrine and non-endocrine investigations are crucial for arriving at the diagnosis of short stature. The cardinal manifestation of growth hormone deficiency in children obviously interferes physical growth. Causes of growth hormone deficiency may be congenital or acquired. A peak growth hormone level of < 10 microg/l in response to stimulation tests along with some clinical features is generally considered sufficient to diagnose growth hormone deficiency. Growth hormone in a dose of 25-50 microg/kg/day should be administered subcutaneously once daily at bed time for growth hormone deficiency state.