Addendum 1: Forum for Injection Technique and Therapy Expert Recommendations, India.

With the emerging complexities in chronic diseases and people's lifestyles, healthcare professionals (HCPs) need to update their methods to manage and educate patients with chronic lifestyle disorders, particularly diabetes. The insulin injection technique (IIT), along with various parameters, must also be updated with newer methods. Forum for Injection Technique and Therapy Expert Recommendations (FITTER), India, has updated its recommendations to cover newer ways of detecting hypoglycaemia and lipohypertrophy, preventing needlestick injuries (NSIs), discouraging the reuse of insulin needles and encouraging good disposal. FITTER, India, is also introducing recommendations to calculate insulin bolus dose. These updated recommendations will help HCPs better manage patients with diabetes and achieve improved outcomes.

Real-World Observational Study of Glimepiride and Metformin Fixed-Dose Combination Along With Insulin in the Management of Type 2 Diabetes Mellitus: Indian Experience.

Background Type 2 diabetes mellitus (T2DM) is associated with a significant burden on both patients and the healthcare system. This study aimed to evaluate the demographics of patients with T2DM receiving different strengths of glimepiride and metformin combination along with insulin. This study also examined the concomitant conditions and therapies, duration of therapies, dosage titration, glycated hemoglobin (HbA1c) levels, hypoglycemic events, and weight changes during the course of therapy. Methods This retrospective, multicenter (347), observational study included adult patients with T2DM who received glimepiride and metformin combination along with insulin. Data related to demographic characteristics, duration of disease, co-morbidities, concomitant medications, and dosage pattern was collected from medical records authenticated by physicians during routine care. Results A total of 7058 patients were included in the study. The median age of included patients was 55 years and around 29% were aged >60 years and 60% were men. The majority of patients (83.3%) had insulin treatment initiation after glimepiride and metformin combination while other patients (16.7%) received glimepiride and metformin combination after insulin initiation. The mean HbA1c levels significantly decreased with a mean change of 1.33%. In one-third of the patients, down-titration of the insulin dose was done, indicating the insulin-sparing effect with the addition of the glimepiride and metformin combination. The most common comorbid condition was hypertension (64.7%). Of 3705 patients, 33.2% patients had weight loss and 66.8% had weight gain. A total of 432 patients reported hypoglycemic events. Physician global evaluation of efficacy and tolerability showed a good to excellent on the scale (97.3% and 96.6%). Conclusion This study presented good HbA1c lowering with glimepiride and metformin combination with insulin, ensuring a positive clinical outcome. Good to excellent efficacy and tolerability were observed in patients with T2DM across the age groups, in early as well as long-standing disease.

Recommendations for in-clinic PoCT for diabetes management in India.

A panel of expert diabetologist clinicians developed consensus standards to address the quality gaps inclinic point of care testing (PoCT) especially pertaining to diabetes care and management in India. The following summarized principles were established- 1. PoCT definition, 2. Advantages and critical aspects of PoCT including guideline recommendations and accreditations, analytical factors (pre &post analytical included) and consensus reached for an ideal PoC analyzer and 3. Key recommendations on in-clinic PoCT implementation by the panel. The experts suggested next steps that included key comparative (PoCT vs NGSP accredited lab) and patient benefit studies on PoCT.

Comparative evaluation of pharmacokinetics and pharmacodynamics of insulin glargine (Glaritus®) and Lantus® in healthy subjects: a double-blind, randomized clamp study.

AIMS: The objective of the study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of an insulin glargine formulation, Glaritus® (test) with the innovator's formulation Lantus® (reference) using the euglycemic clamp technique in a single-dose, double-blind, randomized, two sequences, four-period replicate crossover study in healthy volunteers (n = 40). METHODS: Subjects received subcutaneous administration of the insulin glargine (0.4 IU/kg) formulation at two occasions for test and reference and a 20% glucose solution was infused at variable rate to maintain euglycemia for 24 h. RESULTS: Both PK [area under the plasma concentration time curve (AUC0-24 h) and maximum insulin concentration (Cmax)] and PD endpoints [area under glucose infusion rate time curve (AUCGIR0-24) and maximum glucose infusion rate (GIRmax)] demonstrated bioequivalence of Glaritus to Lantus with the 90% confidence interval of geometric mean ratio of test to reference entirely contained within 0.80-1.25. Both formulations showed equivalent geometric least-square mean LSM value (0.08 nmol/L) for Cmax. The geometric LSM AUC0-24 h value for Glaritus® (1.09 h nmol/L) was comparable to Lantus (1.05 h nmol/L). Median Tmax values were also identical (12 h for both), and median t1/2 values were also equal (18 h for both). For GIRTmax, the difference between the means for the two was not statistically significant. No AEs related to study formulations were reported, and both products were well tolerated. CONCLUSIONS: The test product (Glaritus) was found to be bioequivalent to the reference product (Lantus). CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2015/06/005890; http://www.ctri.nic.in/ .

Forum for Injection Technique and Therapy Expert Recommendations, India: The Indian Recommendations for Best Practice in Insulin Injection Technique, 2017.

Health-care professionals in India frequently manage injection or infusion therapies in persons with diabetes (PWD). Patients taking insulin should know the importance of proper needle size, correct injection process, complication avoidance, and all other aspects of injection technique from the first visit onward. To assist health-care practitioners in their clinical practice, Forum for Injection Technique and Therapy Expert Recommendations, India, has updated the practical advice and made it more comprehensive evidence-based best practice information. Adherence to these updated recommendations, learning, and translating them into clinical practice should lead to effective therapies, improved outcomes, and lower costs for PWD.

A review of clinical efficacy and safety of canagliflozin 300 mg in the management of patients with type 2 diabetes mellitus.

Currently available antihyperglycemic agents, despite being effective, provide inadequate glycemic control and/or are associated with side effects or nonadherence. Canagliflozin, a widely used orally active inhibitor of sodium-glucose cotransporter 2 (SGLT2), is a new addition to the therapeutic armamentarium of glucose-lowering drugs. This review summarizes findings from different clinical and observational studies of canagliflozin 300 mg in patients with type 2 diabetes mellitus (T2DM). By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose, thereby increasing urinary glucose excretion in patients with T2DM. Canagliflozin 300 mg has been shown to be effective in lowering glycated hemoglobin, fasting plasma glucose, and postprandial glucose in patients with T2DM. Canagliflozin 300 mg also demonstrated significant reductions in body weight and blood pressure and has a low risk of causing hypoglycemia, when not used in conjunction with insulin and insulin secretagogues. Canagliflozin 300 mg was generally well tolerated in clinical studies. The most frequently reported adverse events include genital mycotic infections, urinary tract infections, osmotic diuresis, and volume depletion-related events.

Cardiac autonomic function and vascular profile in subclinical hypothyroidism: Increased beat-to-beat QT variability.

BACKGROUND: Patients with subclinical hypothyroidism (SH) may have higher incidence of coronary heart disease and autonomic dysfunction. DESIGN OF THE STUDY: Prospective case control study. AIM AND OBJECTIVES: To evaluate beat-to-beat QT variability and vascular stiffness in patients with SH compared to normal controls. MATERIALS AND METHODS: We compared linear and nonlinear measures of cardiac repolarization liability using beat-to-beat QT intervals derived from the surface electrocardiogram during supine posture and vascular indices including pulse wave velocity and ankle-brachial index (ABI) during supine posture between female patients with SH and age- and sex-matched normal controls. Spectral analysis was done at very low frequency (LF) (0.003-0.04 Hz), Low frequency (LF) (0.04-0.15 Hz), and high frequency (HF) (0.15-0.4 Hz). The HF represents vagal regulation (parasympathetic) and LF represents both parasympathetic and sympathetic regulation. RESULTS: We recruited 58 women with a mean age of 31.83 ± 8.9 years and 49 controls with mean age of 32.4 ± 9.9 years (P = NS). QT variability index (QTvi) was higher in cases compared to controls (P = 0.01). The ratio of LF/HF of R-R interval which is an index of sympathovagal tone was significantly more in cases compared to controls (P = 0.02). The difference in the left minus the right ABI was significant between cases and controls (P = 0.03). CONCLUSIONS: The cases had lower parasympathetic activity as compared to controls, and there was a predominance of sympathetic activity in cases. QTvi may be an important noninvasive tool in this group of patients to study the risk of cardiovascular mortality.

Evaluation of accuracy of ambulatory glucose profile in an outpatient setting in children with type 1 diabetes.

BACKGROUND: In children with type 1 diabetes, intensive diabetes management has been demonstrated to reduce long-term microvascular complications. At present, self-monitoring of blood glucose (SMBG) by patients at home and glycated hemoglobin estimation every 3 months are used to monitor glycemic control in children. Recently, ambulatory glucose profile (AGP) is increasingly being used to study the glycemic patterns in adults. However, accuracy and reliability of AGP in children have not been evaluated yet. OBJECTIVES: To assess the accuracy of AGP data in children with type 1 diabetes mellitus when compared with laboratory random blood sugar (RBS) levels, capillary blood glucose (CBG) measured by glucometer in the hospital, and SMBG monitored at home. METHODS: Paired RBS, CBG, and AGP data were analyzed for 51 patients who wore AGP sensors for 2 weeks. Simultaneous venous and CBG samples were collected on day 1 and day 14. SMBG at home was checked and recorded by the patients for optimizing insulin doses. Accuracy measures (mean absolute deviation, mean absolute relative difference (MARD), and coefficient of linear regression of AGP on RBS, CBG, and home-monitored SMBG were calculated. RESULTS: Seventy paired RBS, CBG, and AGP data and 362 paired home-monitored SMBG and AGP data were available. The MARD was 9.56% for AGP over RBS and 15.07% for AGP over CBG. The linear regression coefficient of AGP over RBS was 0.93 and that of AGP over CBG was 0.89 (P < 0.001). The accuracy of AGP over SMBG was evaluated over four ranges: <75, 76-140, 141-200, and >200 mg/dl. CONCLUSION: In this study, AGP data significantly correlate with RBS and CBG data in children with type 1 diabetes. However, a large number of samples in a research setting would help to document reproducibility of our results.

Effectiveness of vildagliptin versus other oral antidiabetes drugs as add-on to sulphonylurea monotherapy: Post hoc analysis from the EDGE study.

AIM: In this post hoc analysis of the EDGE study, we assessed the effectiveness and safety of vildagliptin versus other oral antidiabetes drugs (OADs) as add-on to first-line sulphonylurea (SU) therapy in patients who did not receive metformin in a real-life setting. METHODS: The primary endpoint was odds of achieving an HbA1c reduction of >0.3% without tolerability issues. Secondary endpoint was odds of achieving HbA1c <7.0% without hypoglycaemia or weight gain. Changes in HbA1c, body weight; and safety were also assessed. RESULTS: 2936 patients received vildagliptin and 820 received comparator OADs (any α-GI, TZD, glinide) as add-on to first-line SU therapy. Overall, the mean age, disease duration, HbA1c, and BMI at baseline were 57.1 years, 6.3 years, 8.5%, and 27.7kg/m2, respectively. The odds ratios for achieving primary and secondary endpoints were 1.6 (95% CI: 1.36, 1.86; p<0.0001) and 1.8 (1.45, 2.21; p<0.0001), respectively, in favour of vildagliptin. The between-treatment differences (vildagliptin vs. comparator OAD) for the mean change in HbA1c and body weight were -0.2±0.04% (p<0.0001) and -0.8±0.16kg (p<0.0001), respectively. Overall, the incidence of adverse events was low (vildagliptin, 7% vs. comparator, 8.2%) in both groups. Similar results were observed in a subset of patients enrolled from India and patients who received TZDs as a comparator OAD. CONCLUSION: Under real-life settings, vildagliptin as add-on to SU monotherapy showed better glycaemic response without tolerability issues compared with other OADs.

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from India.

BACKGROUND: This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from India. METHODS: Changes from baseline in HbA1c, fasting plasma glucose (FPG), body weight, and blood pressure (BP) with canagliflozin 100 and 300 mg were evaluated in a subgroup of patients from India (n = 124) from 4 randomized, double-blind, placebo- and active-controlled, Phase 3 studies (N = 2313; Population 1). Safety was assessed based on adverse event (AE) reports in these patients and in a broader subgroup of patients from India (n = 1038) from 8 randomized, double-blind, placebo- and active-controlled, Phase 3 studies (N = 9439; Population 2). RESULTS: Reductions in HbA1c with canagliflozin 100 and 300 mg were -0.74% and -0.88%, respectively, in patients from India, and -0.81% and -1.00%, respectively, in the 4 pooled Phase 3 studies. In the Indian subgroup, both canagliflozin doses provided reductions in FPG, body weight, and BP that were consistent with findings in the overall population. The incidence of overall AEs in patients from India was generally similar with canagliflozin 100 and 300 mg and noncanagliflozin. The AE profile in patients from India was generally similar to the overall population, with higher rates of genital mycotic infections and osmotic diuresis-related and volume depletion-related AEs with canagliflozin versus noncanagliflozin. CONCLUSION: Canagliflozin provided glycemic control, body weight reduction, and was generally well tolerated in patients with T2DM from India.

The seroprevalence of immunoglobulin A transglutaminase in type 1 diabetic patients of South Indian origin.

CONTEXT: Celiac disease (CD) is a commonly encountered autoimmune condition in patients with type 1 diabetes (T1D). There is sparse data on the seroprevalence of immunoglobulin A (IgA) transglutaminase (tTG) in T1D patients of South Indian origin. AIMS: To detect the prevalence of IgA tTG in T1D patients of South Indian origin. To evaluate the relation between the presence of autoimmunity and metabolic control and complications of diabetes. MATERIALS AND METHODS: We conducted a cross-sectional study on 258 T1D patients. All the patients were subjected to biochemical tests and evaluated for microvascular complications. IgA tTG was estimated by ELISA. IgA tTG levels >40 AU/ml was considered positive. RESULTS: Of the 258 participants, 12 (4.65%) were found to be positive for IgA tTG antibodies. Distribution of IgA positivity was equal in both sexes. There was a significant negative correlation of IgA tTG positivity with hemoglobin and glycated hemoglobin (HbA1c). CONCLUSIONS: The seropositivity of CD in South Indian patients with T1D has been observed to be 4.68%. This is much lower compared to studies from North India. This can be explained by both the genetic and dietary factors. The seropositivity correlated negatively with hemoglobin and HbA1c.

Long-term carbimazole pretreatment reduces the efficacy of radioiodine therapy.

INTRODUCTION: Data from several studies suggest that pretreatment with antithyroid drugs (ATD) before (131)I increases the risk of treatment failure. This effect has been demonstrated more consistently with propylthiouracil than with carbimazole (CMZ) or methimazole (MMI). Men with Graves' disease (GD) have a lower rate of remission with (131)I compared to women and the impact of long-term ATD pretreatment on the success of (131)I is unknown. The objective of our study was to compare the efficacy of fixed doses of radioiodine between patients with and without long-term CMZ pretreatment. MATERIALS AND METHODS: We performed a retrospective study on 335 male patients with GD treated with (131)I from 1998 to 2008. 148 patients had been pretreated with CMZ, and the remaining 187 patients received (131)I without pretreatment. We compared the success rate of a single dose of (131)I, between patients with and without long-term CMZ pretreatment. RESULTS: The success rate of a single dose of (131)I was significantly higher in patients without pretreatment than in patients who were pretreated with CMZ (91.4% vs. 82.3%, P = 0.01). The rate of hypothyroidism in the first 6 months after (131)I therapy was significantly higher in patients without pretreatment (55.1% vs. 44.6%, P = 0.05). There was also a trend for higher cumulative rate of hypothyroidism at last follow-up in nonpretreated patients (78.1% vs. 69.7%). CONCLUSION: Male patients with Graves' hyperthyroidism pretreated with CMZ have lower efficacy with 131I therapy compared to nonpretreated patients. CMZ pretreatment given for a prolonged period reduces the efficacy of (131)I therapy.

Insulinoma case series: Experience of a tertiary care center.

BACKGROUND: Insulinomas are usually solitary; benign and encapsulated small lesions and majority of them measure <2 cm in diameter. They pose a challenge for pre-operative localization. Definitive treatment is surgical excision of the tumor. Intra-operative ultrasonography (IOUS), transhepatic portal venous sampling (THPVS) and positron emission tomography (PET) scan can be done for tumors not localized by conventional imaging modalities. MATERIALS AND METHODS: A retrospective study of patients diagnosed with insulinoma during the period 2004-2012 (8 years) was done. Biochemical diagnostic criteria used were plasma concentrations of glucose <55 mg/dl with corresponding insulin level >3.0 µU/ml (18 pmol/L) and C-peptide of >0.6 ng/ml (0.2 nmol/L). The localization of the tumor was done by various modalities namely computed tomography (CT), magnetic resonance imaging (MRI), IOUS, PET and portal venous sampling. The initial localizing technique in most of these patients were CT or MRI imaging, or both and those who were not localized by the above modalities were subjected to PET CT or THPVS or intra-operative ultrasound depending on the initial imaging results and patient's consent. All the modalities were not used in the same patient, but the modalities were decided as per the imaging results, patient's consent and affordability for the procedure. RESULTS: Ninteen cases of insulinoma aged between 10 and 66 years, with a median age of 47 years were included in the analysis. There were 10 males and nine females. Eighty-three percent of patients presented with pre-prandial hypoglycemia (n = 15). Different modalities were employed for pre-operative localization of these patients out of which 5 (26.31%) cases were localized with CT, 5 (26.31) cases with MRI, 5 (26.31%) with THPVS, 1 (5.26%) case with PET CT, 3 (15.78%) of them could not be localized out of which 2 (10.52%) were localized by IOUS and 1 (5.26%) case the lesion could not be localized. Among 19 cases, 12 underwent surgery out of which one patient underwent distal pancreatectomy as tumor was not localized; eight underwent laparoscopic enucleation; three of them required intra-operative exploration and seven of them were not operated, as they did not give consent for surgery. In all the cases, the size of the insulinoma ranged between 1 and 2 cm. CONCLUSION: We report our experience with 19 cases of insulinoma and analyze the role of pre- and intra-operative imaging modalities in the surgical management of insulinomas. Most of our cases were symptomatic, and the most common presentation was with pre-prandial hypoglycemia. THPVS, PET scan and intra-operative ultrasound added to diagnostic sensitivity in some cases not localized by CT or MRI.

Consensus statement on diabetes in children.

While T1DM has been traditionally seen as a minor concern in the larger picture of pediatric ailments, new data reveals that the incidence of T1DM has assumed alarming proportions. It has long been clear that while the disease may be diagnosed at an early age, its impact is not isolated to afflicted children. The direct impact of the disease on the patient is debilitating due to the nature of the disease and lack of proper access to treatment in India. But this impact is further compounded by the utter apathy and often times antipathy, which patients withT1DM have to face. Lack of awareness of the issue in all stakeholders, low access to quality healthcare, patient, physician, and system level barriers to the delivery of optimal diabetes care are some of the factors which hinder successful management of T1DM. The first international consensus meet on diabetes in children was convened with the aim of providing a common platform to all the stakeholders in the management of T1DM, to discuss the academic, administrative and healthcare system related issues. The ultimate aim was to articulate the problems faced by children with diabetes in a way that centralized their position and focused on creating modalities of management sensitive to their needs and aspirations. It was conceptualized to raise a strong voice of advocacy for improving the management of T1DM and ensuring that "No child should die of diabetes". The unique clinical presentations of T1DM coupled with ignorance on the part of the medical community and society in general results in outcomes that are far worse than that seen with T2DM. So there is a need to substantially improve training of HCPs at all levels on this neglected aspect of healthcare.

Chronic complications in newly diagnosed patients with Type 2 diabetes mellitus in India.

BACKGROUND: Prevalence of diabetes is on an increase in India, currently there is limited nation-wide data regarding the prevalence of chronic complications in diabetic patients at diagnosis. This information will help health-care professionals approach management more aggressively to prevent complications. OBJECTIVE: To determine the prevalence of chronic complications in newly-diagnosed Type 2 diabetic (T2D) patients in India. DESIGN AND METHODS: This was a cross-sectional survey of T2D patients, diagnosed within 3 months of their first visit to the centers doing the survey. Each patient was screened for diabetic complications, hypertension, dyslipidemia, and body mass index. Family history was recorded. Standard protocols were used to make the diagnosis of retinopathy, neuropathy and nephropathy. Data analysis was carried out using the standard statistical techniques. RESULTS: Of the total 4,600 (males 67%, females 33%) newly diagnosed patients with T2D, majority were from the age group 41-50 years (40%). 13.15% of newly detected India T2D had neuropathy 6.1% had retinopathy and 1.06% had nephropathy. Risk factors of macro vascular complication such as hypertension, obesity, and dyslipidemia were observed in 23.3%, 26%, and 27% of patients respectively. Ischemic heart disease was noticed in 6%. CONCLUSION: High prevalence of micro vascular complications was present at diagnosis along with association of CV cardiovascular risk factors among Indian T2D. In view of this, screening must be instituted for all diabetics for complications at the time of diagnosis itself.

National recommendations: Psychosocial management of diabetes in India.

Although several evidence-based guidelines for managing diabetes are available, few, if any, focus on the psychosocial aspects of this challenging condition. It is increasingly evident that psychosocial treatment is integral to a holistic approach of managing diabetes; it forms the key to realizing appropriate biomedical outcomes. Dearth of attention is as much due to lack of awareness as due to lack of guidelines. This lacuna results in diversity among the standards of clinical practice, which, in India, is also due to the size and complexity of psychosocial care itself. This article aims to highlight evidence- and experience-based Indian guidelines for the psychosocial management of diabetes. A systemic literature was conducted for peer-reviewed studies and publications covering psychosocial aspects in diabetes. Recommendations are classified into three domains: General, psychological and social, and graded by the weight they should have in clinical practice and by the degree of support from the literature. Ninety-four recommendations of varying strength are made to help professionals identify the psychosocial interventions needed to support patients and their families and explore their role in devising support strategies. They also aid in developing core skills needed for effective diabetes management. These recommendations provide practical guidelines to fulfill unmet needs in diabetes management, and help achieve a qualitative improvement in the way physicians manage patients. The guidelines, while maintaining an India-specific character, have global relevance, which is bound to grow as the diabetes pandemic throws up new challenges.

Evaluation of high sensitivity C-reactive protein and glycated hemoglobin levels in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the major long-term complications of diabetes mellitus (DM). Type 2 DM is frequently associated with an inflammatory status, but limited information is available on the relationship between low-grade inflammation and DN. The aim of the study is to determine the serum level of high sensitivity C-reactive protein (hsCRP) in DN patients and to compare with that of normal subjects and to study the association between serum hsCRP levels and glycated hemoglobin (HbA1c) levels. Fifty DN patients in the age group of 50- 60 years with more than ten years of duration of diabetes were recruited for this study and 25 age-and sex-matched healthy subjects were included in this study as controls. Serum hsCRP levels were measured by turbidometry method. There was a statistically significant increase in serum hsCRP levels in DN cases as compared to normal controls. The hsCRP levels showed a positive correlation with HbA1c in DN. These results suggest that estimation of serum hsCRP levels and aiming at good glycemic control help in early intervention and prevention of further com-plications in diabetic patients.