Ronald Goldenberg

Association Between Plasma Triglycerides and High-Density Lipoprotein Cholesterol and Microvascular Kidney Disease and Retinopathy in Type 2 Diabetes Mellitus A Global Case–Control Study in 13 Countries

Background— Microvascular renal and retinal diseases are common major complications of type 2 diabetes mellitus. The relation between plasma lipids and microvascular disease is not well established. Methods and Results— The case subjects were 2535 patients with type 2 diabetes mellitus with an average duration of 14 years, 1891 of whom had kidney disease and 1218 with retinopathy. The case subjects were matched for diabetes mellitus duration, age, sex, and low-density lipoprotein cholesterol to 3683 control subjects with type 2 diabetes mellitus who did not have kidney disease or retinopathy. The study was conducted in 24 sites in 13 countries. The primary analysis included kidney disease and retinopathy cases. Matched analysis was performed by use of site-specific conditional logistic regression in multivariable models that adjusted for hemoglobin A1c, hypertension, and statin treatment. Mean low-density lipoprotein cholesterol concentration was 2.3 mmol/L. The microvascular disease odds ratio increased by a factor of 1.16 (95% confidence interval, 1.11–1.22) for every 0.5 mmol/L (≈1 quintile) increase in triglycerides or decreased by a factor of 0.92 (0.88–0.96) for every 0.2 mmol/L (≈1 quintile) increase in high-density lipoprotein cholesterol. For kidney disease, the odds ratio increased by 1.23 (1.16–1.31) with triglycerides and decreased by 0.86 (0.82–0.91) with high-density lipoprotein cholesterol. Retinopathy was associated with triglycerides and high-density lipoprotein cholesterol in matched analysis but not significantly after additional adjustment. Conclusions— Diabetic kidney disease is associated worldwide with higher levels of plasma triglycerides and lower levels of high-density lipoprotein cholesterol among patients with good control of low-density lipoprotein cholesterol. Retinopathy was less robustly associated with these lipids. These results strengthen the rationale for studying dyslipidemia treatment to prevent diabetic microvascular disease.

Dipeptidyl peptidase-4 inhibitors and the risk of heart failure: a systematic review and meta-analysis

BACKGROUND Given recent discrepant results from randomized controlled trials (RCTs), we examined the totality of RCT evidence assessing the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and heart failure. METHODS MEDLINE, Embase and ClinicalTrials.gov were searched without language restrictions to August 2016 for RCTs comparing DPP-4 inhibitors to placebo or no therapy for a period of 24 weeks or more. We included all heart failure outcomes when listed either as a serious adverse event or adverse event. Pooled analyses used random-effects. RESULTS We identified 100 RCTs (n = 79 867) - 3 large cardiovascular-safety RCTs (SAVOR-TIMI 53[saxagliptin]/n = 16 492, EXAMINE[alogliptin]/n = 5380, and TECOS[sitagliptin]/n = 14 735), and 97 smaller RCTs with a primary outcome that was usually change in glycated hemoglobin. Virtually all RCTs were high-quality, multicentre, placebo-controlled trials. A total of 96% (1192/1244) of heart failure events were prespecified, blindly adjudicated and required hospital admission. Pooled results suggested a 13% increase in heart failure (relative risk [RR] 1.13, 95% confidence interval [CI] 1.01-1.26, I2 = 0%; 32 RCTs, n = 54 640, 1244 events). When including only the 3 large RCTs, the increase was similar, but not significant (RR 1.14, 95% CI 0.97-1.32; 3 RCTs, n = 36 543, 1169 adjudicated events; number needed to harm 246) owing to heterogeneity (I2 = 42%), which lead to wider CIs, because SAVOR-TIMI 53 showed increased heart failure (RR 1.26, 95% CI 1.06-1.49) and TECOS showed no effect (RR 1.00, 95% CI 0.83-1.19). INTERPRETATION Despite pooled data from 79 867 patients, whether DPP-4 inhibitors increase heart failure overall or exhibit within-class differences remains unresolved. Our results highlight the importance of ongoing trials that are comparing DPP-4 inhibitors to placebo, although no large cardiovascular-safety RCTs are comparing different DPP-4 inhibitors to each other; consequently, these will address the overall but not class-difference question.

Specialist-led diabetes registries and predictors of poor glycemic control in type 2 diabetes: Insights into the functionally refractory patient from the LMC Diabetes Registry database

The aim of the present study was to explore features associated with glycemic control in type 2 diabetes (T2D) patients undergoing care by specialist clinics.

Specialist-Led Diabetes Registries and Prevalence of Poor Glycemic Control in Type 2 Diabetes: The Diabetes Registry Outcomes Project for A1C Reduction (DROP A1C).

OBJECTIVE To highlight the utility of a large patient registry to identify functionally refractory patients (persistent HbA1c ≥75 mmol/mol [9.0%]) with type 2 diabetes, identify their barriers to glycemic control, and implement barrier-specific care path strategies to improve glycemic control. RESEARCH DESIGN AND METHODS A working group developed a structured tool to optimize the collection of information on barriers to glycemic control and designed structured care paths to address each barrier. Participants were identified from a large Canadian registry and were assigned to a certified diabetes educator (CDE) as their case manager for a 12-month period to coordinate assessment of their barriers and to implement appropriate care path strategies. The primary outcome measure was the mean change in HbA1c from baseline at 12 months. RESULTS Overall, 3,662 refractory patients were initially identified of whom 1,379 were eligible for inclusion and 155 enrolled. The most common barrier categories participants identified were psychological/support (93%), socioeconomic (87%), and accessibility (82%), with high concordance (75–94%) between participant and CDE. No specific barriers were predictive of hyperglycemia. After implementation of barrier-specific care paths, the mean reduction in HbA1c at 12 months was 17 mmol/mol (1.5%; P < 0.01 vs. baseline) versus only 5 mmol/mol (0.5%) in the source cohort (n = 966) who continued with standard care. The incidence of severe hypoglycemia did not change significantly during the study. CONCLUSIONS In registry-identified hyperglycemic patients with type 2 diabetes, the use of barrier-specific care paths significantly improved glycemic control in otherwise refractory patients with persistently elevated HbA1c. Further studies using this strategy in other practice settings are warranted.

Pharmacologic Glycemic Management of Type 2 Diabetes in Adults

• Healthy behaviour interventions should be initiated in people newly diagnosed with type 2 diabetes. • In people with type 2 diabetes with A1C <1.5% above the person’s individualized target, antihyperglycemic pharmacotherapy should be added if glycemic targets are not achieved within 3 months of initiating healthy behaviour interventions. • In people with type 2 diabetes with A1C ≥1.5% above target, antihyperglycemic agents should be initiated concomitantly with healthy behaviour interventions, and consideration could be given to initiating combination therapy with 2 agents. • Insulin should be initiated immediately in individuals with metabolic decompensation and/or symptomatic hyperglycemia. • In the absence of metabolic decompensation, metformin should be the initial agent of choice in people with newly diagnosed type 2 diabetes, unless contraindicated. • Dose adjustments and/or additional agents should be instituted to achieve target A1C within 3 to 6 months. Choice of second-line antihyperglycemic agents should be made based on individual patient characteristics, patient preferences, any contraindications to the drug, glucose-lowering efficacy, risk of hypoglycemia, affordability/access, effect on body weight and other factors. • In people with clinical cardiovascular (CV) disease in whom A1C targets are not achieved with existing pharmacotherapy, an antihyperglycemic agent with demonstrated CV outcome benefit should be added to antihyperglycemic therapy to reduce CV risk. • In people without clinical CV disease in whom A1C target is not achieved with current therapy, if affordability and access are not barriers, people with type 2 diabetes and their providers who are concerned about hypoglycemia and weight gain may prefer an incretin agent (DPP-4 inhibitor or GLP-1 receptor agonist) and/or an SGLT2 inhibitor to other agents as they improve glycemic control with a low risk of hypoglycemia and weight gain. • In people receiving an antihyperglycemic regimen containing insulin, in whom glycemic targets are not achieved, the addition of a GLP-1 receptor agonist, DPP-4 inhibitor or SGLT2 inhibitor may be considered before adding or intensifying prandial insulin therapy to improve glycemic control with less weight gain and comparable or lower hypoglycemia risk.

The Canadian Hypoglycemia Assessment Tool Program: Insights Into Rates and Implications of Hypoglycemia From an Observational Study

OBJECTIVE The true prevalence of hypoglycemia in insulin-treated patients with diabetes and its impact on patients, employers and healthcare providers is poorly appreciated owing to a paucity of real-world data. The global Hypoglycemia Assessment Tool (HAT) study addressed this issue, and here we report data from the Canadian cohort of patients. METHODS This noninterventional, 6-month retrospective and 4-week prospective study enrolled patients aged ≥18 years receiving insulin treatment for >12 months from community endocrinology practices. Data were collected using self-assessment questionnaires and patient diaries. The primary endpoint was the proportion of patients experiencing ≥1 hypoglycemic event during the 4-week prospective observational period. RESULTS Four hundred ninety-eight patients with type 1 diabetes (n=183) and type 2 diabetes (n=315) were enrolled. The prevalence of hypoglycemia was similar in the retrospective (type 1 diabetes, 92.3%; type 2 diabetes, 63.5%) and prospective (type 1 diabetes, 95.2%; type 2 diabetes, 64.2%) periods. Prospective rates of any, nocturnal and severe hypoglycemia per patient-year (95% confidence interval) were 69.3 (66.4; 72.2), 14.2 (12.9; 15.6) and 1.8 [1.4; 2.4]. Higher rates were reported retrospectively, reaching significance for nocturnal hypoglycemia per patient-year (30.0 [28.1; 32.0] vs. 14.2 [12.9; 15.6]; p<0.001). Hypoglycemia led to increased healthcare utilization and absenteeism and was associated with potentially harmful self-care behaviours (e.g., reduced or skipped insulin doses) and increased blood glucose self-monitoring. CONCLUSIONS Prevalence and incidence of hypoglycemia were high among insulin-treated patients with diabetes in Canada, and some patients took harmful or costly actions when they experienced hypoglycemia. Identifying the insulin-treated patients who are at greatest risk may help to reduce the incidence of hypoglycemia.

A practical approach and algorithm for intensifying beyond basal insulin in type 2 diabetes

Despite the availability of long‐term data demonstrating the benefits of timely and aggressive intensification of antihyperglycaemic regimens among individuals with type 2 diabetes, intensification beyond basal insulin continues to be suboptimal and a global challenge. This review summarizes the evidence surrounding the various options of advancing glucose‐lowering management beyond basal insulin and provides a practical algorithm to assist in optimizing patient care and enhancing glycaemic target achievements.

Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): The DERIVE Study

Dapagliflozin is a selective inhibitor of sodium glucose co‐transporter 2 (SGLT2). This study assessed the efficacy and safety of dapagliflozin 10 mg vs placebo in patients with type 2 diabetes (T2D) and moderate renal impairment (estimated glomerular filtration rate [eGFR], 45–59 mL/min/1.73 m2; chronic kidney disease [CKD] stage 3A).

Semaglutide: Review and Place in Therapy for Adults With Type 2 Diabetes

Guidelines increasingly highlight the importance of multifactorial management in type 2 diabetes, in contrast to the more traditional focus on glycemic control. Semaglutide, a recently approved glucagon-like peptide-1 receptor agonist, is indicated in Canada for adults with type 2 diabetes to improve glycemic control as monotherapy with diet and exercise when metformin is inappropriate or as an add-on to either metformin alone or metformin plus a sulfonylurea or basal insulin. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial program for semaglutide comprises 6 pivotal global phase 3a trials (SUSTAIN 1 through 6) and 2 Japanese phase 3a trials. Phase 3b trials include SUSTAIN 7, and SUSTAIN 8 and 9 (both ongoing). Results from the completed trials support the superiority of semaglutide for reduction of glycated hemoglobin levels and weight loss vs. placebo as well as active comparators, including sitagliptin, exenatide extended-release, dulaglutide and insulin glargine. SUSTAIN 6 trial data confirmed cardiovascular safety and demonstrated significant reductions in major cardiovascular events with semaglutide vs. placebo, an outcome that confirmed the noninferiority of semaglutide. The robust and sustained effects of semaglutide on glycated hemoglobin levels and weight loss vs. comparators, as well as its safety and possible cardiovascular benefit, address an unmet need in the treatment of type 2 diabetes. This article overviews data from across the semaglutide clinical trial program, including efficacy and safety results and findings from post hoc analyses. The potential place of semaglutide in clinical practice is discussed.