Diabetes News

Helen X. Gao, Emily E. Regier, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each quarter, the Journal of Diabetes includes this News feature, in which Gao, Regier, and Close review the latest developments relevant to researchers and clinicians. The International Diabetes Federation World Diabetes Congress 2015 (IDF 2015) took place from 30 November to 4 December 2015 in Vancouver, Canada, bringing together an international audience of over 8000. Primary results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Follow-up Study (ACCORDION) were presented by Dr Hertzel Gerstein (McMaster University, Hamilton, Canada). ACCORDION followed 8601 ACCORD participants (90% of those eligible and 98% of patients who did not experience a major adverse cardiovascular event [MACE] or die during the trial) through up to seven telephone calls and clinic visits following the end of the randomized treatment period for a median total follow-up time of 8.8 years. The HbA1c difference between the intensive and standard control arms had disappeared by the end of follow-up, with an average HbA1c of approximately 7.7% in both groups by Month 57 after the end of ACCORD. There was no difference between groups in the primary MACE composite outcome (cardiovascular [CV] death, non-fatal myocardial infarction [MI], non-fatal stroke) 14 years after randomization (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.87–1.04; P = 0.27). The increase in mortality that caused ACCORD1 to be stopped early quickly resolved after the end of randomized treatment, with an HR of 1.01 (95% CI 0.92–1.10; P = 0.91) after 14 years. The neutral results held true when patients were stratified by sex, age, race/ethnicity, history of CV disease, baseline HbA1c, blood pressure, and lipids. Results for non-fatal MI and non-fatal stroke were both neutral, whereas the increase in CV death was significant, but attenuated. The HR for MI was 0.89 (95% CI 0.79–1.02; P = 0.09) and the HR for stroke was 0.87 (95% CI 0.73–1.04; P = 0.11). The risk of CV death remained significantly elevated in the intensive group (HR 1.20; 95% CI 1.03–1.40; P = 0.02), but was attenuated over time and the curves were parallel after the end of randomized treatment. Dr Emily Chew (National Eye Institute, Bethesda, MD, USA) presented results from the ACCORDION Eye Study (n = 1268) demonstrating a significant legacy effect of intensive glycemic control on retinopathy progression after 8 years. The original ACCORD Eye Study2 (n = 2856) found that a significantly lower percentage of patients in the intensive group experienced progression of retinopathy compared with the conventional group after 4 years (7.5% vs 10.4%). Outcomes were also better in patients treated with fenofibrate in addition to statins compared with those treated with statins alone. There was no difference between the intensive and conventional blood pressure arms. The aim of ACCORDION was to evaluate whether the beneficial effects of intensive glucose control and fenofibrate persisted after the end of randomized treatment and whether blood pressure had more of an effect with long-term follow-up. The results show that 5.8% of patients in the intensive group experienced progression of retinopathy after 8 years compared with 12.7% in the standard group (HR 0.42; 95% CI 0.28–0.63; P < 0.0001). The effect of fenofibrate disappeared after treatment discontinuation, and no significant blood pressure effect emerged. Given the fairly low retention in the study (58% of eligible patients participated), Dr Chew presented sensitivity analyses bolstering the validity of the results. An analysis restricted to sites with >80% retention also demonstrated a favorable hazard ratio, although the benefit was not significant because of the small numbers. A post hoc analysis using a composite outcome of retinopathy progression or death also demonstrated a significant benefit. Dr Anne Murray (Hennepin County Medical Center, Minneapolis, MN, USA) presented results from the Action to Control Cardiovascular Risk in Diabetes Follow-up Study – Memory in Diabetes Follow-Up Study (ACCORDION MIND) demonstrating no significant legacy effect of intensive control on cognitive decline or total brain volume. The original ACCORD MIND3 study (n = 2977) found no significant difference between groups in change in Digit Symbol Substitution Test (DSST) scores or other cognitive measures. It did find a significantly lower decline in brain volume with intensive glycemic control and standard blood pressure treatment, but it also found significantly higher abnormal white matter volume with intensive control. Participants in ACCORDION MIND (n = 1328) underwent a fourth cognitive assessment and a third brain magnetic resonance imaging scan at 80 months after randomization. The results showed no significant difference in mean change in DSST score (P = 0.32), total brain volume (P = 0.91), or abnormal white matter volume (P = 0.41) between groups at 80 months. Dr Murray suggested that patients' long duration of diabetes, the short and transient difference in HbA1c between groups, healthy survivor bias, and younger age could be possible explanations for the lack of an effect. Dr Rury Holman (University of Oxford, Oxford, UK) presented an update on the Trial to Evaluate Cardiovascular Outcomes with Sitagliptin (TECOS)4 safety data. He reviewed and expanded on the previously published renal findings: (i) the marginally improved mean urine albumin : creatinine ratio (UACR) values seen with sitagliptin compared with placebo (–1.0 mg/g) in the subset of 3669 patients with data available; and (ii) the marginally worsened mean estimated glomerular filtration rate (eGFR) values seen with sitagliptin than with placebo (–1.3 mL/min per 1.73 m2) for the entire population. Dr Holman shared new subanalyses indicating that the minor differences seen in mean eGFR values were similar across all chronic kidney disease (CKD) categories. Coupled with the fact that the changes were fairly weak to begin with, Dr Holman concluded that it is unlikely that sitagliptin has a clinically significant effect on renal function. Dr Holman also revisited the trial's heart failure data to provide further clarity on the question of a dipeptidyl peptidase (DPP)-4 inhibitor class effect; the study's preliminary answer was reassuring with a neutral HR of 1.00. Dr Holman stressed that further analyses of recurrent hospitalization for heart failure were just as encouraging, resulting in an unchanged HR of 1.00 after accounting for first and recurrent hospitalizations, along with no evidence that patients in the sitagliptin arm had a differential outcome for heart failure (e.g. CV and all-cause morality in patients with one or more hospitalizations for heart failure events did not differ). Dr Holman also presented a meta-analysis of the three DPP-4 inhibitor CV outcomes trials (Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus [SAVOR],5 Cardiovascular Outcomes Study of Alogliptin in Patients with Type 2 Diabetes and Acute Coronary Syndrome [EXAMINE],6 and TECOS4), demonstrating no statistically significant difference in the risk of hospitalization for heart failure when the studies were pooled (an overall HR of 1.14; P = 0.178). Dr Sophia Zoungas (University of Sydney, Sydney, NSW, Australia) presented a new analysis from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Post-Trial Observational Study (ADVANCE-ON). The analysis demonstrated that the effect of intensive glycemic control on renal death was not significant, although the point estimate favored the intensive group (HR 0.85; 95% CI 0.45–1.62). It also found that the benefits on end-stage kidney disease were greater for patients with lower systolic blood pressure (<140 mmHg) and less advanced kidney disease (no CKD or CKD Stage 1/2) at baseline. There was no evidence of increased harm with intensive glucose control in patients with any stage of CKD at baseline. The relative risk of severe hypoglycemia was also comparable across CKD stages, although the absolute risk was greater with more advanced disease.

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