The Role of Real-World Evidence in Treatment Decision-Making, Regulatory Assessment, and Understanding the Perspectives of People with Type 2 Diabetes: Examples with Gliclazide MR.

Real-world evidence (RWE) plays an important role in the management of type 2 diabetes (T2D). It provides data about the effectiveness and safety of an intervention from outside the randomised controlled trial (RCT) setting and allows healthcare professionals (HCPs) to determine if RCT data are applicable to their patients in routine clinical practice. This review provides a discussion of the value of RWE in T2D management in day-to-day clinical practice, with a focus on RWE with sulfonylureas (SUs), and presents two examples of a new generation of international real-world studies in people with T2D managed in routine clinical practice. RWE plays a valuable role in advising HCPs in the day-to-day management of T2D, informing regulatory authorities with regard to pharmacovigilance and post-approval updates, and providing insights with regard to patients' treatment adherence and preference. RWE should be used alongside RCTs to increase HCP awareness and understanding of their patients' perspectives, potentially allowing for improvements in treatment adherence, glycaemic control and health-related quality of life (HRQoL). In addition, real-world studies must be conducted in a way that generates robust RWE by limiting the risks of bias and confounding as much as possible. A growing body of RWE is emerging from Asia. For example, in a preliminary HRQoL analysis of the Joint Asia Diabetes Evaluation (JADE) Register, Asian people with T2D had better HRQoL with gliclazide-based treatment than with other SU agents, despite being older and having more diabetes-related complications.

Management of Diabetes and Hypertension within the Gulf Region: Updates on Treatment Practices and Therapies.

Cardiovascular disease (CVD) is a leading cause of death globally, driven by the high rates of risk factors, such as diabetes and hypertension. As the prevalence of these risk factors is particularly high in the Gulf region, better diagnosis and management of type 2 diabetes (T2D) and hypertension has the potential to dramatically reduce adverse cardiovascular outcomes for individuals in that part of the world. This article provides a summary of presentations made during the EVIDENT summit, a virtual symposium on Evidence in Diabetes and Hypertension, held in September 2021, including a review of the various guidelines for both T2D and hypertension, as well as recent findings relevant to the safety and efficacy for therapies relating to these conditions. Of relevance to the Gulf region, the risk of hypoglycaemia with sulfonylureas during Ramadan was reviewed. For the management of T2D, sulfonylureas have been a long-standing medication used to achieve glycaemic control; however, differences have emerged between early and later generations, with recent studies suggesting improvements in the safety profiles of late-generation sulfonylureas. For patients with hypertension, incremental therapy changes are recommended to reduce the risk of cardiovascular complications that are associated with increasing blood pressure. For first-line therapy, angiotensin-converting enzyme inhibitors (ACEi), such as perindopril, have been demonstrated to reduce the risk of cardiovascular and all-cause mortality. The addition of calcium channel blockers and diuretics to ACEi has been shown to be effective in patients with poorly controlled hypertension. The different renin-angiotensin-aldosterone system inhibitors are reviewed, and the benefit of combination therapies, including amlodipine and indapamide in patients with difficult-to-control hypertension, is investigated. The benefits of lifestyle modifications for these patients are also discussed, with important clinical considerations that are expected to inform patient management in daily clinical practice.

Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by GLP-1RA treatment: A subgroup analysis from the FIDELIO-DKD trial.

AIMS: Finerenone significantly reduced the risk of kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease and type 2 diabetes in the FIDELIO-DKD trial (NCT02540993). This exploratory subgroup analysis investigates the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on the treatment effect of finerenone. MATERIALS AND METHODS: Patients with type 2 diabetes, urine albumin-to-creatinine ratio (UACR) 30-5000 mg/g and estimated glomerular filtration rate 25-<75 ml/min per 1.73 m2 receiving optimized renin-angiotensin system blockade were randomized to finerenone or placebo. RESULTS: Of the 5674 patients analysed, overall, 394 (6.9%) received GLP-1RAs at baseline. A reduction in UACR with finerenone was observed with or without baseline GLP-1RA use; ratio of least-squares means 0.63 (95% confidence interval 0.56, 0.70) with GLP-1RA use and 0.69 (95% confidence interval 0.67, 0.72) without GLP-1RA use (p value for interaction .20). Finerenone also significantly reduced the primary kidney (time to kidney failure, sustained decrease in estimated glomerular filtration rate ≥40% from baseline, or renal death) and key secondary CV outcomes (time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) versus placebo, with no clear difference because of GLP-1RA use at baseline (p value for interaction .15 and .51 respectively) or any time during the trial. The safety profile of finerenone was similar between subgroups. CONCLUSIONS: This exploratory subgroup analysis suggests that finerenone reduces UACR in patients with or without GLP-1RA use at baseline, and the effects on kidney and CV outcomes are consistent irrespective of GLP-1RA use.

Risk factors for kidney disorders in patients with type 2 diabetes at high cardiovascular risk: An exploratory analysis (DEVOTE 12).

AIM: To investigate risk factors associated with kidney disorders in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk. METHODS: In DEVOTE, a cardiovascular outcomes trial, 7637 patients were randomised to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100), with standard of care. In these exploratory post hoc analyses, serious adverse event reports were searched using Standardised MedDRA® Queries related to chronic kidney disease (CKD) or acute kidney injury (AKI). Baseline predictors of CKD, AKI and change in estimated glomerular filtration rate (eGFR) were identified using stepwise selection and Cox or linear regression. RESULTS: Over 2 years, eGFR (mL/min/1.73 m2) decline was small and similar between treatments (degludec: 2.70; glargine U100: 2.92). Overall, 97 and 208 patients experienced CKD and AKI events, respectively. A history of heart failure was a risk factor for CKD (hazard ratio [HR] 1.97 [95% confidence interval [CI] 1.41; 2.75]) and AKI (HR 2.28 [95% CI 1.64; 3.17]). A history of hepatic impairment was a significant predictor of CKD (HR 3.28 [95% CI 2.12; 5.07]) and change in eGFR (estimate: -8.59 [95% CI -10.20; -7.00]). CONCLUSION: Our findings indicate that traditional, non-modifiable risk factors for kidney disorders apply to insulin-treated patients with T2D at high CV risk. TRIAL REGISTRATION: NCT01959529 (ClinicalTrials.gov).

Role of Gliclazide MR in the Management of Type 2 Diabetes: Report of a Symposium on Real-World Evidence and New Perspectives.

In patients with type 2 diabetes mellitus (T2DM) who require additional glucose-lowering on top of first-line metformin monotherapy, sulfonylureas are the most common choice for second-line therapy followed by dipeptidyl peptidase inhibitors (DPP-4i). This article summarises presentations at a symposium entitled "Real-World Evidence and New Perspectives with Gliclazide MR" held at the International Diabetes Federation Congress in Busan, South Korea on 4 December 2019. Although guideline recommendations vary between countries, the guidelines with the highest quality ratings include sulfonylureas as one of the preferred choices as second-line therapy for T2DM. Data from randomised controlled trials (RCTs) have consistently demonstrated that sulfonylureas are effective glucose-lowering agents and that the risk of severe hypoglycaemia with these agents is low. In addition, both RCTs and real-world observational studies have shown no increased risk of mortality or cardiovascular disease with the use of newer-generation sulfonylureas compared with other classes of glucose-lowering treatments. However, differences between sulfonylureas do exist, with gliclazide being associated with a significantly lower risk of mortality or cardiovascular mortality compared with glibenclamide, as well as the lowest incidence of severe hypoglycaemia compared with other agents in this class. Recent real-world studies into the effectiveness and safety of gliclazide appear to confirm these findings, and publication of new data from these studies in patients with T2DM in the UK, and in Muslim patients who are fasting during Ramadan, are awaited with interest. Another study being undertaken with gliclazide is a pan-India study in patients with maturity-onset diabetes of the young (MODY) subtypes 1, 3 and 12. Patients with these MODY subtypes respond particularly well to sulfonylurea treatment, and sulfonylureas are the first-line agents of choice in these patients. These new and ongoing studies will add to the cumulative data on the efficacy and safety of certain sulfonylureas in patients with diabetes.

The Place of Sulfonylureas in Guidelines: Why Are There Differences?

This review describes a presentation at a recent symposium entitled "SUs in the treatment of T2DM: a fresh look and new insights" on Wednesday September 18, 2019 at the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Barcelona, Spain. It examines the current role of sulfonylureas (SUs) in the management of type 2 diabetes mellitus (T2DM) and gives the author's personal perspective of how this therapeutic class has performed in both local and international guidelines. The place of SUs within current guidelines is highlighted, and a critical appraisal of the reasons for the differences between guidelines given. Finally, comparison of evidence-based guidelines and consensus reports is discussed.

A Practitioner's Toolkit for Insulin Motivation in Adults with Type 1 and Type 2 Diabetes Mellitus: Evidence-Based Recommendations from an International Expert Panel.

AIM: To develop an evidence-based expert group opinion on the role of insulin motivation to overcome insulin distress during different stages of insulin therapy and to propose a practitioner's toolkit for insulin motivation in the management of diabetes mellitus (DM). BACKGROUND: Insulin distress, an emotional response of the patient to the suggested use of insulin, acts as a major barrier to insulin therapy in the management of DM. Addressing patient-, physician- and drug-related factors is important to overcome insulin distress. Strengthening of communication between physicians and patients with diabetes and enhancing the patients' coping skills are prerequisites to create a sense of comfort with the use of insulin. Insulin motivation is key to achieving targeted goals in diabetes care. A group of endocrinologists came together at an international meeting held in India to develop tool kits that would aid a practitioner in implementing insulin motivation strategies at different stages of the journey through insulin therapy, including pre-initiation, initiation, titration and intensification. During the meeting, emphasis was placed on the challenges and limitations faced by both physicians and patients with diabetes during each stage of the journey through insulinization. REVIEW RESULTS: After review of evidence and discussions, the expert group provided recommendations on strategies for improved insulin acceptance, empowering behavior change in patients with DM, approaches for motivating patients to initiate and maintain insulin therapy and best practices for insulin motivation at the pre-initiation, initiation, titration and intensification stages of insulin therapy. CONCLUSIONS: In the management of DM, bringing in positive behavioral change by motivating the patient to improve treatment adherence helps overcome insulin distress and achieve treatment goals.

Glomerular Filtration Rate and Associated Risks of Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes: Secondary Analysis (DEVOTE 11).

INTRODUCTION: The associations of chronic kidney disease (CKD) severity, cardiovascular disease (CVD), and insulin with the risks of major adverse cardiovascular events (MACE), mortality, and severe hypoglycemia in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk are not known. This secondary, pooled analysis of data from the DEVOTE trial examined whether baseline glomerular filtration rate (GFR) categories were associated with a higher risk of these outcomes. METHODS: DEVOTE was a treat-to-target, double-blind trial involving 7637 patients with T2D at high CV risk who were randomized to once-daily treatment with either insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). Patients with estimated GFR data at baseline (n = 7522) were analyzed following stratification into four GFR categories. RESULTS: The risks of MACE, CV death, and all-cause mortality increased with worsening baseline GFR category (P < 0.05), with a trend towards higher rates of severe hypoglycemia. Patients with prior CVD, CKD (estimated GFR < 60 mL/min/m2), or both were at higher risk of MACE, CV death, and all-cause mortality. Only CKD was associated with a higher rate of severe hypoglycemia, and the risk of MACE was higher in patients with CVD than in those with CKD (P  = 0.0003). There were no significant interactions between randomized treatment and GFR category. CONCLUSION: The risks of MACE, CV death, and all-cause mortality were higher with lower baseline GFR and with prior CVD, CKD, or both. The relative effects of degludec versus glargine U100 on outcomes were consistent across baseline GFR categories, suggesting that the lower rate of severe hypoglycemia associated with degludec use versus glargine U100 use was independent of baseline GFR category. FUNDING: Novo Nordisk.

Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 diabetes, lowering glycated haemoglobin (HbA1c) and weight, but are currently only approved for use as subcutaneous injections. Oral semaglutide, a novel GLP-1 agonist, was compared with subcutaneous liraglutide and placebo in patients with type 2 diabetes. METHODS: In this randomised, double-blind, double-dummy, phase 3a trial, we recruited patients with type 2 diabetes from 100 sites in 12 countries. Eligible patients were aged 18 years or older, with HbA1c of 7·0-9·5% (53-80·3 mmol/mol), on a stable dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhibitor. Participants were randomly assigned (2:2:1) with an interactive web-response system and stratified by background glucose-lowering medication and country of origin, to once-daily oral semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1·8 mg), or placebo for 52 weeks. Two estimands were defined: treatment policy (regardless of study drug discontinuation or rescue medication) and trial product (assumed all participants were on study drug without rescue medication) in all participants who were randomly assigned. The treatment policy estimand was the primary estimand. The primary endpoint was change from baseline to week 26 in HbA1c (oral semaglutide superiority vs placebo and non-inferiority [margin: 0·4%] and superiority vs subcutaneous liraglutide) and the confirmatory secondary endpoint was change from baseline to week 26 in bodyweight (oral semaglutide superiority vs placebo and liraglutide). Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on Clinicaltrials.gov, number NCT02863419, and the European Clinical Trials registry, number EudraCT 2015-005210-30. FINDINGS: Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened, of whom 711 were eligible and randomly assigned to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). 341 (48%) of 711 participants were female and the mean age was 56 years (SD 10). All participants were given at least one dose of study drug, and 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group completed the 52-week trial period. Mean change from baseline in HbA1c at week 26 was -1·2% (SE 0·1) with oral semaglutide, -1·1% (SE 0·1) with subcutaneous liraglutide, and -0·2% (SE 0·1) with placebo. Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA1c (estimated treatment difference [ETD] -0·1%, 95% CI -0·3 to 0·0; p<0·0001) and superior to placebo (ETD -1·1%, -1·2 to -0·9; p<0·0001) by use of the treatment policy estimand. By use of the trial product estimand, oral semaglutide had significantly greater decreases in HbA1c than both subcutaneous liraglutide (ETD -0·2%, 95% CI -0·3 to -0·1; p=0·0056) and placebo (ETD -1·2%, -1·4 to -1·0; p<0·0001) at week 26. Oral semaglutide resulted in superior weight loss (-4·4 kg [SE 0·2]) compared with liraglutide (-3·1 kg [SE 0·2]; ETD -1·2 kg, 95% CI -1·9 to -0·6; p=0·0003) and placebo (-0·5 kg [SE 0·3]; ETD -3·8 kg, -4·7 to -3·0; p<0·0001) at week 26 (treatment policy). By use of the trial product estimand, weight loss at week 26 was significantly greater with oral semaglutide than with subcutaneous liraglutide (-1·5 kg, 95% CI -2·2 to -0·9; p<0·0001) and placebo (ETD -4·0 kg, -4·8 to -3·2; p<0·0001). Adverse events were more frequent with oral semaglutide (n=229 [80%]) and subcutaneous liraglutide (n=211 [74%]) than with placebo (n=95 [67%]). INTERPRETATION: Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing bodyweight compared with both liraglutide and placebo at week 26. Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide. Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care. FUNDING: Novo Nordisk A/S.

Management of low-density lipoprotein cholesterol levels in South Africa: the International ChoLesterol management Practice Study (ICLPS).

The International Cholesterol Management Practice Study (ICLPS) South Africa investigated achievement of European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline low-density lipoprotein cholesterol (LDL-C) targets in real-world clinical practice. Demographic data, clinical characteristics, cardiovascular risk factors, lipid-modifying medications, lipid values and investigator's assessment of cardiovascular risk were recorded for 396 patients on stable lipid-modifying therapy. Most (98.7%) patients received statins; 25.1% of statin-treated patients were receiving high-intensity statins. Overall, 41.4% of patients achieved their LDL-C target; among 354 (89.4%) patients in whom cardiovascular disease risk, based on ESC Systematic Coronary Risk Estimation (SCORE) was calculated, achievement rate was 14.3% for moderate-risk (n = 7), 59.3% for high-risk (n = 123) and 32.3% for very high-risk patients (n = 223). Half of Asian (54.7%) and black African (53.2%) patients were at LDL-C target compared with 29.8% of European/Caucasian and 27.3% of 'other' patients. Improved guideline adherence and greater use of combination therapy may increase LDL-C goal achievement.

Incidence of hypoglycaemia in the South African population with diabetes: results from the IDMPS Wave 7 study

Objectives: Management of diabetes is a balancing act of preventing a state of hyperglycaemia while avoiding episodes of hypoglycaemia. Limited information is currently available on the incidence of hypoglycaemia in South African people diagnosed with diabetes. Data regarding the management of diabetes and incidence of hypoglycaemia in the South African population was collected as part of Wave 7 of the International Diabetes Management Practices Study (IDMPS). Design and methods: During this observational study the first 10 adult individuals with type 2 diabetes and the first five adult individuals with type 1 diabetes presenting to a study site during the two-week study period were enrolled. Setting:Patients were enrolled from the private healthcare sector in South Africa only. Subjects:A total of 445 individuals (49 diagnosed with T1D, 396 diagnosed with T2D) were included. Outcome measures:Glycated haemoglobin and hypoglycaemia data were recorded for each patient. Results:Of the patients who reported experiencing hypoglycaemia, 48.6% (17/35) among T1D individuals and 67.8% (40/71) among T2D individuals experienced hypoglycaemia over a four-week period. Furthermore, in patients who discontinued insulin treatment (n= 11), fear of hypoglycaemia was reported to influence adherence to insulin treatment by 27.3% in T1D and T2D individuals. Of the 148 patients not achieving their HbA1c target, 23.0% reported fear of hypoglycaemia as a reason. Conclusions: This report demonstrates the need to address hypoglycaemia and fear of hypoglycaemia in the South African diabetes population

A 24-week, prospective, randomized, open-label, treat-to-target pilot study of obese type 2 diabetes patients with severe insulin resistance to assess the addition of exenatide on the efficacy of u-500 regular insulin plus metformin.

OBJECTIVE: To compare the efficacy of 500 U/mL (U-500) regular insulin + metformin with U-500 regular insulin + metformin + exenatide in improving glycemic control in patients with severely insulin-resistant type 2 diabetes mellitus (T2DM). METHODS: Thirty patients with T2DM and severe insulin resistance were screened, and 28 were randomized to regular insulin U-500 + metformin or the GLP-1 analog exenatide, U-500, and metformin. Glycated hemoglobin (HbA1c) levels, body weight, and insulin doses were documented at baseline and at 3 and 6 months. The number and severity hypoglycemic episodes were noted. RESULTS: There were 7 males and 7 females in each group (U-500 + metformin and U-500 + metformin + exenatide). Overall, U-500 insulin + metformin, either alone or with the addition of exenatide, resulted in a significant improvement in HbA1c in both groups, with no significant difference between the 2 groups. There was no meaningful weight change in those utilizing exenatide. Those on U-500 insulin and metformin alone had a tendency toward some weight gain. No severe hypoglycemia occurred during the study period. Symptomatic hypoglycemia was more common in the group on exenatide, but this occurred in only 5 patients, and the clinical significance of this is uncertain. Insulin dosage changes on U-500 regular insulin were variable but tended to be lower in those subjects on exenatide. CONCLUSIONS: U-500 regular insulin + metformin is effective for the treatment of T2DM patients with severe insulin resistance. The addition of exenatide may ameliorate potential weight gain but provides no additional improvement in glycemia.

Effect of rimonabant on glycemic control in insulin-treated type 2 diabetes: the ARPEGGIO trial.

OBJECTIVE To examine the efficacy and safety of rimonabant, a selective cannabinoid receptor type-1 antagonist, in patients with type 2 diabetes receiving insulin monotherapy. RESEARCH DESIGN AND METHODS Patients (n = 368; A1C > or =7%) were randomized to 20 mg/day rimonabant or placebo in this 48-week, double-blind, placebo-controlled multicenter trial. Change in baseline A1C to week 48 (primary outcome) and changes in body weight, waist circumference, and lipid levels (secondary outcomes) were assessed. RESULTS Rimonabant significantly reduced baseline A1C versus placebo (-0.89 vs. -0.24%; P < 0.0001), and significantly greater improvements were observed in cardiometabolic risk factors. More rimonabant patients achieved >10% reduction in mean total daily insulin dose versus placebo (P = 0.0012), and fewer required rescue medication (P < 0.0001). Hypoglycemia, nausea, dizziness, anxiety, and depression were more frequent with rimonabant. CONCLUSIONS Rimonabant improved glycemic control and cardiometabolic risk factors in patients with type 2 diabetes receiving insulin.