The Promise of Cilnidipine in Hypertension with Comorbidities: National Consensus Statement: National Consensus Group Comprises Cardiologists, Nephrologists, and Diabetologists from India in a National Meet at New Delhi held on 22nd May 2022.

The rapidly increasing burden of hypertension is responsible for premature deaths from cardiovascular disease (CVD), renal disease, and stroke, with a tremendous public health and financial burden. Hypertension detection, treatment, and control vary worldwide; it is still low, particularly in low- and middle-income countries (LMICs). High blood pressure (BP) and CVD risk have a strong, linear, and independent association. They contribute to alarming numbers of all-cause and CVD deaths. A major culprit for increased hypertension is sympathetic activity, and further complications of hypertension are heart failure, ischemic heart disease (IHD), stroke, and renal failure. Now, antihypertensive interventions have emerged as a global public health priority to reduce BP-related morbidity and mortality. Calcium channel blockers (CCB) are highly effective vasodilators. and the most common drugs used for managing hypertension and CVD. Cilnidipine, with both L- and N-type calcium channel blocking activity, is a promising 4th generation CCB. It causes vasodilation via L-type calcium channel blockade and inhibits the sympathetic nervous system (SNS) via N-type calcium channel blockade. Cilnidipine, which acts as a dual L/N-type CCB, is linked to a reduced occurrence of pedal edema compared to amlodipine, which solely blocks L-type calcium channels. The antihypertensive properties of cilnidipine are very substantial, with low BP variability and long-acting properties. It is beneficial for hypertensive patients to deal with morning hypertension and for patients with abnormal nocturnal BP due to exaggerated sympathetic nerve activation. Besides its BP-lowering effect, it also exhibits organ protection via sympathetic nerve inhibition and renin-angiotensin-aldosterone system inhibition; it controls heart rate and proteinuria. Reno-protective, neuroprotective, and cardioprotective effects of cilnidipine have been well-documented and demonstrated.

Expert Opinion by Clinicians on the Use of Insulin Therapy in People with Hepatic Impairment.

People with type 2 diabetes mellitus (T2DM) have a higher risk of developing chronic liver disease (CLD) and its complications. T2DM, obesity, and insulin resistance are all strongly associated with nonalcoholic fatty liver disease (NAFLD). Conversely, people suffering from cirrhosis have reduced glucose tolerance in approximately 60% of cases, diabetes in 20% of cases, and insulin-mediated glucose clearance is lowered by 50% as compared with those who do not have cirrhosis. An exploratory review was conducted using existing published evidence from clinical studies on dosing and titrations of individual insulin formulations in people with CLD to optimize insulin dosage titration for minimizing hypoglycemia risk.pThis article discusses current hyperglycemia treatment techniques for patients with CLD as well as the consensus recommendations on insulin use in special populations with T2DM and hepatic impairment. Based on available evidence and expert diabetologists' recommendations, careful insulin dose titration, customized glycemic targets, and frequent glucose screening are recommended for optimal glycemic management without hypoglycemia in CLD. Long-acting insulin should be avoided or used when short-acting insulin fails to provide adequate glycemic control with raised fasting blood sugar levels. While the patient's glucose profile is being evaluated, the prandial insulin dose can be lowered by 25% initially. The dose can be titrated based on the patient's postprandial glycemic expression and whether their food intake meets the Child-Pugh scores A and B categories. Titrating premixed insulins is difficult for patients in class C since their appetite and overall health are constantly compromised and in flux.

The Power and Promise of Angiotensin Receptor Neprilysin Inhibitor (ARNI) in Heart Failure Management: National Consensus Statement.

;Heart failure (HF) is a huge global public health task due to morbidity, mortality, disturbed quality of life, and major economic burden. It is an area of active research and newer treatment strategies are evolving. Recently angiotensin receptor-neprilysin inhibitor (ARNI), a class of drugs (the first agent in this class, Sacubitril-Valsartan), reduces cardiovascular mortality and morbidity in chronic HF patients with reduced left ventricular ejection fraction (LVEF). Positive therapeutic effects have led to a decrease in cardiovascular mortality and HF hospitalizations (HFH), with a favorable safety profile, and have been documented in several clinical studies with an unquestionable survival benefit with ARNI, Sacubitril-Valsartan. This consensus statement of the Indian group of experts in cardiology, nephrology, and diabetes provides a comprehensive review of the power and promise of ARNI in HF management and an evidence-based appraisal of the use of ARNI as an essential treatment strategy for HF patients in clinical practice. Consensus in this review favors an early utility of Sacubitril-Valsartan in patients with HF with reduced EF (HFrEF), regardless of the previous therapy being given. A lower rate of hospitalizations for HF with Sacubitril-Valsartan in HF patients with preserved EF who are phenotypically heterogeneous suggests possible benefits of ARNI in patients having 40-50% of LVEF, frequent subtle systolic dysfunction, and higher hospitalization risk.

Medical Management of Diabesity.

The intricate relationship between obesity and T2DM is well recognised, as evidenced by the coining of the term 'diabesity' by Dr Ethan Sims that encompasses the two.Most patients with type 2 diabetes are obese and the global rise in obesity largely explains the epidemic rise in incidence and prevalence of type 2 diabetes(T2DM) over the last few decades. Obesity has been linked to insulin resistance and predisposes to metabolic abnormalities including prediabetes, type diabetes and the metabolic syndrome.Weight reduction is an essential component to prevent progression from prediabetes to T2DM in obese individuals and also forms an essential component of all T2DM management strategies in association with other lifestyle modifications, diet and pharmacotherapy. Obesity management today is a high priority preventive as well as treatment intervention for diabetes and various chronic diseases. Achieving effective weight loss and sustaining it is a huge practical challenge for all obese individuals, more so for the obese type 2 diabetic individuals who many times are prescribed various antihyperglycemic therapies that may be associated with weight gain. This chapter focusses on current treatment strategies for patients with coexisting obesity and T2DM and the role of different anti-obesity agents in the medical management of diabesity.

Consensus on "Basal insulin in the management of Type 2 Diabetes: Which, When and How?"

INTRODUCTION: Type 2 diabetes mellitus (T2DM) has attained epidemic proportions and continues to increase despite the availability of a number of oral antidiabetic medications and major advances made in insulin delivery since its discovery nearly a hundred years ago. One, amongst many other reasons responsible for the inability to achieve adequate glycaemic control in a substantial proportion of T2DM patients is the delayed initiation and inappropriate intensification of insulin treatment. Appropriate initiation and intensification of insulin is critical for the successful achievement of tight glycaemic control. OBJECTIVE: To provide simple and easily implementable guidelines to primary care physicians on basal insulin initiation and intensification, along with use of basal insulin in special situations (hepatic failure, renal failure and gestational diabetes mellitus). METHODS: Each consensus statement on basal insulin initiation, intensification and use of basal insulin in special situations was evaluated for dosing and titration based on established guidelines, data from approved pack inserts, prescribing information or summary of product characteristics for each insulin type, and published scientific literature. These evaluations were then factored into the national context based not only on the clinical experience of the expert committee representatives' but also based on the common therapeutic practices followed in India to successfully achieve optimal glucose control. RESULTS: Recommendations on initiation and intensification of basal insulin, and its use in special situations, have been developed. The key recommendations are to initiate basal insulin when 2 or 3 oral antidiabetic medications fail to achieve target glycaemic control, or in symptomatic patients with glycated haemoglobin value greater than 9%. Depending upon patient characteristics, any of the four available basal insulins [Neutral protamine Hagedorn (NPH), Glargine (IGlar), Detemir (IDet), Degludec (IDeg)] can be used. However, IDeg has a longer duration of action, comparatively lesser hypoglycaemia (both overall and nocturnal) and more flexibility in administration timing compared to IGlar) and IDet. Inability to maintain glycaemic control should lead to prompt intensification of basal insulin treatment by adding mealtime insulin, consisting of one to three injections of either rapid-acting insulin analog or regular insulin; depending upon patient characteristics, intensification can also be achieved by transition from basal insulin to twice daily premixed insulin analogs/premixed human insulin/insulin co-formulations. IDeg/IDet can be used in all grades of renal and hepatic impairment; and IDet has been approved for use in gestational diabetes mellitus. CONCLUSIONS: We hope that these consensus based recommendations shall be a useful reference tool for health care practitioners and help them in initiating and intensifying insulin therapy in T2DM patients in order to achieve optimal glycaemic control.

Management of Sitagliptin and Metformin Combination Toxic Overdose.

Metformin and Sitagliptin are often used in combination in the management of non-insulin dependent diabetes mellitus. Though toxicity is rare, but occurs more frequently in cases of intentional or unintentional overdose of these drugs. Here, we present a case of an intentional overdose of a metformin- sitagliptin combination (70g metformin and 3500mg sitagliptin) in a suicide attempt by a young non-diabetic female who presented with severe lactic acidosis and was successfully treated with prompt hemodialysis and bicarbonate therapy.

Time to reposition sulfonylureas in type 2 diabetes management in Indian context: A pragmatic practical approach.

Sulfonylureas (SU) continue to be a vital therapeutic category of oral hypoglycemic agents (OHAs) for the management of type 2 diabetes mellitus (T2DM). Physicians consider modern SU (gliclazide and glimepiride) as "safe and smart" choices for T2DM management. The presence of multiple international guidelines and scarcity of a national guideline may contribute to the challenges faced by few physicians in choosing the right therapeutic strategy. The role of SU in diabetes management is explicit, and the present consensus aims to emphasize the benefits and reposition SU in India. This pragmatic, practical approach aims to define expert recommendations for the physicians to improve caregivers' knowledge of the management of T2DM, leading to superior patient outcomes.

Clinical Utility of a Digital Therapeutic Intervention in Indian Patients With Type 2 Diabetes Mellitus: 12-Week Prospective Single-Arm Intervention Study.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) having elevated levels of blood glucose and glycated hemoglobin (HbA1c) are at higher risk of macro- and microvascular complications. Nonetheless, the goal of achieving glycemic control cannot be met with the use of pharmacotherapy alone. The recent emergence of digital therapeutic tools has shown the possibility of improving the modifiable risk factors and self-management of diabetes. OBJECTIVE: The aim of this study was to examine the clinical utility of a digital therapeutic intervention as an add-on therapy to achieve glycemic control in patients with T2DM. METHODS: This was a 12-week prospective, single-arm digital intervention study in patients with T2DM receiving regular antidiabetic treatment. The eligibility criteria included male and female patients with HbA1c≥6.5%, functional English literacy, and a mobile phone capable of running the intervention app. Outcome measures of the study were mean changes in HbA1c, fasting blood glucose (FBG), postprandial blood glucose (PPBG), BMI, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index at the end of 12 weeks. RESULTS: A total of 128 participants completed the study period of 12 weeks. There were 54.7% (70/128) men and 45.3% (58/128) women with a mean age of 48.48 years (SD 10.27). At the end of 12 weeks, the mean change in HbA1c, FBG, PPBG, and BMI for the overall study population was -0.84% (P<.001), -8.39 mg/dl (P=.02), -14.97 mg/dl (P<.001), and -0.24 kg/m2 (P=.06), respectively. Among the participants showing improvement in the HbA1c value at the end of 12 weeks (responders), the mean change in HbA1c, FBG, PPBG, and BMI was -1.24% (P<.001), -12.42 mg/dl (P=.003), -21.45 mg/dl (P<.001), and -0.34 kg/m2 (P=.007), respectively. There was an increase in HOMA-IR values for the overall study population (0.54, P=.29). HbA1c response showed a significant association with a baseline HbA1c level ≥7.5%, no prior history of smoking, and no prior COVID-19 infection, as well as with higher levels of program engagement. CONCLUSIONS: A digital therapeutic intervention when used alongside standard medications significantly reduces HbA1c, FBG, and PPBG levels in patients with T2DM.

Relationship between diabetic retinopathy microalbuminuria and other modifiable risk factors.

BACKGROUND: Diabetic Retinopathy (DR) is an important microvascular complication of diabetes that can lead to irreversible blindness. Microalbuminuria is strongly associated with diabetic retinopathy and can be used as a reliable marker of diabetic retinopathy. AIM: To assess the association between DR, microalbuminuria, and other modifiable risk factors in patients with type 2 diabetes. METHODOLOGY: 3090 patients with T2DM visiting North Delhi Diabetes Centre, New Delhi between July 2016 to October 2019 were evaluated for the clinical and biochemical parameters that included urinary albumin, HbA1C, lipid profiles, serum creatinine estimation and underwent biothesiometry. RESULTS: 3090 patients (1350 females and 1740 males), with mean age of 52.7 ± 9.2 years and diabetes duration ranging from 1 to 19 years (mean 9.4 ± 6), duration of less than 5 years, 6-10 years and more than 10 years in 52%, 26% and in 22%, respectively. Duration of diabetes was strong predictor of retinopathy (p = 0.001). The HbA1c and BMI in patients with DR was significantly higher than in those without DR. 18.2% patients were diagnosed to have retinopathy. Peripheral neuropathy was observed in 24.2% and was positively associated with DR (p = 0.002). 33.9% and 4.5% patients had microalbuminuria macroalbuminuria, respectively and 9.7% patients had creatinine >1.3 mg/dL. There was significant positive relationship between different grades of retinopathy and albuminuria. CONCLUSIONS: Our study is a large real-world study that demonstrates that HbA1c, BMI, duration of diabetes, microalbuminuria and peripheral neuropathy are relatively, yet cohesively contributing factors towards varying grade of retinopathy.

Optimizing the treatment of newly diagnosed type 2 diabetes mellitus with combination of dipeptidyl peptidase-4 inhibitors and metformin: An expert opinion.

The expanding burden of Type 2 Diabetes Mellitus (T2DM) in today's world, with respect to incidence, prevalence, and cost incurred, is an existential risk to society. Various guidelines recommend individualization of treatment. This expert opinion aims to review the recent evidences and reach a consensus on the preferable combination therapy for use in newly diagnosed Indian T2DM patients with HbA1C >7.5%. The core committee included seventeen diabetes specialists. Three statements were developed, discussed, and rated by specialists and recommendations were noted. Specialists were requested to rate the statements using a 9-point Likert's scale with score of 1 being "Strongly Disagree" and 9 being "Strongly Agree". Statement-specific scores of all the specialists were added and mean score of ≥7.00 was considered to have achieved a consensus. Statements used to meet the consensus were: Statement 1. Majority of newly-diagnosed Indian diabetics have HbA1C >7.5%; Statement 2. Patients with HbA1C >7.5% may be initiated with dual therapy of dipeptidyl peptidase-4 inhibitors (DPP4Is) + Metformin; and Statement 3. In Indian patients with HbA1C >7.5% at diagnosis, DPP4Is + Metformin may be considered as a first-line therapy. Literature review revealed that HbA1C level at the time of diagnosis in majority of Indian T2DM patients is >7.5%. Consensus was reached that dual anti-diabetic therapy should be initiated in patients with HbA1C >7.5%. DPP4Is + Metformin is the preferred cost-effective option and may be considered as a first-line therapy in Indian T2DM patients with HbA1C >7.5% at diagnosis.

Teneligliptin Real-World Effectiveness Assessment in Patients with Type 2 Diabetes Mellitus in India: A Retrospective Analysis (TREAT-INDIA 2).

INTRODUCTION: Teneligliptin is an antidiabetic medication that has been approved for the management of type 2 diabetes mellitus (T2DM) in Japan, South Korea and India. It is one of the most commonly prescribed antihyperglycaemic agents. The aim of this study was to assess the effectiveness of teneligliptin in improving glycemic control amongst Indian patients with T2DM in a real-world setting. METHODS: This was a retrospective observational study in which a predesigned structured proforma was used to collect information from hospital records of 18 medical centres across India. All participating centres were established primary care hospitals with adequate record keeping, a pre-determined condition in the study design. Data were collected during the period of January 2019 to June 2019. Data extracted from patient records, including glycaemic parameters, concomitant drugs, drug dosage and duration, were collated. The effectiveness of teneligliptin was assessed by analyzing the mean change in glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG) and post-prandial plasma glucose (PPG) at 12 weeks after initiation of teneligliptin. RESULTS: Data from 10,623 patients were available for analysis. The mean age of the enrolled patients was 51.86 ± 11.76 years. At 12 weeks after initiation of teneligliptin as monotherapy or add-on to other medications (combination therapy), the patients showed a signficant decrease from baseline in mean HbA1c, FPG and PPG. Mean HbA1c dropped from 8.66 ± 1.15% at baseline to 7.67 ± 1.28% at 12 weeks (71 ± 12.6 to 60 ± 14 mmol/mol), with a difference of - 0.99% (95% confidence interval [CI] 0.96-1.02) or - 10.8 (95% CI 10.5-11.1) mmol/mol (p < 0.0001). The mean reductions in FPG and PPG were 43.12 mg/dL (2.39 mmol/L) and 87.73 mg/dL (4.87 mmol/L) (both p < 0.0001) respectively. HbA1c (%) reductions with teneligliptin when used as add-on to metformin, add-on to metformin + sulfonylurea combination and add-on to metformin + sulfonylurea + alpha glucosidase inhibitor combination were 0.76% (8.3 mmol/mol), 1.24% (13.6 mmol/mol) and 1.04% (11.4 mmol/mol), respectively. Teneligliptin also significantly reduced HbA1c (1.13% or 12.4 mmol/mol, p < 0.0001) in patients with impaired renal function, without worsening the estimated glomerular filtration rate. Teneligliptin consistently reduced HbA1c across all three age categories tested-by 1% (10.9 mmol/mol) in patients aged < 60 years, by 1.15% (12.6 mmol/mol) in patients aged 60-75 years and by 0.88% (9.6 mmol/mol) in patients aged > 75 years. CONCLUSION: Teneligliptin significantly improved glycaemic parameters in Indian patients with T2DM when prescribed either as monotherapy or as an add-on to one or more other commonly prescribed antihyperglycaemic agents.

Insights on Medical Nutrition Therapy for Type 2 Diabetes Mellitus: An Indian Perspective.

It is critical to integrate medical nutrition therapy (MNT) provided by a registered dietician (RD) into primary care of type 2 diabetes mellitus (T2DM). This is necessary to achieve the goals of improving overall metabolic measures beyond calorie restriction and weight loss. Misconceptions about nutrition in T2DM add to the challenges of executing MNT in a culturally sensitive population. The current review provides insights into MNT for the prevention and management of T2DM in India, based on both evidence and experience. It revisits historical Indian studies and provides information on appropriate dietary intake of carbohydrates (60-70%), proteins (~ 20%) and fats (10%) that will be acceptable and beneficial in an Indian T2DM population. It discusses nuances of types of carbohydrates and fats and explains associations of increased dietary fiber intake, balanced intake of low and high glycemic index foods and substitution of saturated fats with plant-based polyunsaturated fats in improving outcomes of T2DM and attenuating risk factors. The article also deliberates upon special patient populations with comorbid conditions and diseases and the necessary adjustments needed in their nutritional care. It outlines a step-wise approach to MNT involving a careful interplay of nutrition assessment, diagnosis, individualization and patient counseling. Overall, the success of MNT relies on providing accurate, acceptable and appropriate dietary choices for continued patient adherence. Collaborative efforts from diabetologists, endocrinologists, internists and RDs are required to prioritize and implement MNT in diabetes practice in India.Funding: Signutra Inc.

Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum?

Diabetes and related complications are associated with long-term damage and failure of various organ systems. The line of demarcation between the pathogenic mechanisms of microvascular and macrovascular complications of diabetes and differing responses to therapeutic interventions is blurred. Diabetes induces changes in the microvasculature, causing extracellular matrix protein synthesis, and capillary basement membrane thickening which are the pathognomic features of diabetic microangiopathy. These changes in conjunction with advanced glycation end products, oxidative stress, low grade inflammation, and neovascularization of vasa vasorum can lead to macrovascular complications. Hyperglycemia is the principal cause of microvasculopathy but also appears to play an important role in causation of macrovasculopathy. There is thought to be an intersection between micro and macro vascular complications, but the two disorders seem to be strongly interconnected, with micro vascular diseases promoting atherosclerosis through processes such as hypoxia and changes in vasa vasorum. It is thus imperative to understand whether microvascular complications distinctly precede macrovascular complications or do both of them progress simultaneously as a continuum. This will allow re-focusing on the clinical issues with a unifying perspective which can improve type 2 diabetes mellitus outcomes.