Improved Glycemic Control in Diabetes Cuts CV Risk: CREDIT

Marlene Busko

July 02, 2014

SAN FRANCISCO — Among patients with type 2 diabetes who start taking insulin, those who attain good glycemic control are less likely to have a major adverse cardiac event (MACE) in the medium term than those who fail to achieve this, a new, "real-world" study suggests.

"We've had some [conflicting] messages from some clinical trials like ACCORD and ADVANCE over the past few years, but [the current observational study] is based on real clinical practice and demonstrates a very strong effect" of glycemic control on cardiovascular outcomes, lead author Nick Freemantle, PhD, professor of clinical epidemiology and biostatistics at University College London, United Kingdom, told Medscape Medical News.

The findings come from the Cardiovascular Risk Evaluation in People with Type 2 Diabetes on Insulin Therapy (CREDIT) study and were presented as a poster by Dr. Freemantle at the recent American Diabetes Association (ADA) 2014 Scientific Sessions.

The study looked at nearly 3000 patients who had had diabetes for about 9 years but had hyperglycemia (despite generally receiving oral antidiabetic agents) and who were started on insulin. Patients whose HbA1c levels remained high had worse outcomes.

Specifically, a 1% higher HbA1c increased the risk for MACE during a 4-year follow-up by 25% compared with an otherwise-similar patient with a 1% lower HbA1c.

The results show that "it doesn't appear to matter how you get to [glycemic] control; it's getting to control that matters," Dr. Freemantle said. "The take-home message is 'achieve improved HbA1c…by whatever means.' "

It was also "reassuring" that patients who had a severe or symptomatic hypoglycemia event were not at increased risk for death during follow-up, he added.

Controversy Surrounding Glucose Control and CVD Risk

The findings from clinical randomized trials looking at glucose control and cardiovascular events remain controversial, so noninterventional, observational trials may offer a better insight into real-world patients, Dr. Freemantle explained.

CREDIT, a noninterventional observational trial, was designed to evaluate the relationship between blood glucose control and cardiovascular events in people with type 2 diabetes treated with insulin in clinical practice.

Between 2006 and 2008, it enrolled men and women over age 40 with type 2 diabetes in 313 centers in Canada, Japan, and 10 European countries (Diabetes, Obesity and Metabolism 2012;14:901–909). To be eligible, patients had to have started taking insulin in the previous 1 to 12 months. Physicians were asked to report updated participant data every 6 months

The main outcome was a composite of nonfatal stroke or myocardial infarction (MI) or cardiovascular death.

The patients had a mean age of 61, and about half were women. At baseline, they had a median body mass index (BMI) of 28.6. On average, they had had diabetes for close to a decade, and despite taking up to 3 oral antidiabetic agents, their median HbA1c level was 9.3% (interquartile range, 8.1%–10.7%).

About half of the patients (48.7%) were taking 2 antidiabetic agents, less than a quarter were taking either 1 agent (24.2%) or 3 or more agents (20.1%), and only 7% of patients were not taking any agent.

When starting insulin therapy, their oral therapies were biguanides (eg, metformin) (66.3% of patients), sulfonylureas (76%), glinides (8.1%), thiazolidinediones (21.2%), and alpha-glucosidase inhibitors (11.1%).

The initial insulin therapy for about half of the patients was basal insulin alone (52.0%). The others were prescribed premix insulin alone (23.1%), basal insulin plus mealtime insulin (14.0%), mealtime insulin alone (7.5%), or another type of insulin (3.4%).

The starting dose of insulin was a median of 0.20 U/kg body weight, which was titrated upward as needed.

The patients made "substantial gains" in glucose control, Dr. Freemantle pointed out. The median HbA1c dropped to 7.4 % (interquartile range, 6.7%–8.4%) at 1 year and remained around that level at years 2, 3, and 4.

During the study follow-up, there were 44 nonfatal MIs, 57 nonfatal strokes, and 60 deaths from cardiovascular causes. There were 148 deaths from all causes.

A 1% increase in HbA1c above the mean was associated with a significant 36% increased risk for a first stroke (P < .0001) and a 31% increased risk for CV death (P = .0027); it was also linked with a 5% nonsignificant increased risk for MI.

That the risk for MI was not significantly increased was probably due to chance, since the confidence interval for the hazard ratio was large, Dr. Freemantle noted.

About half of the patients (53.7%) reported 1 or more symptomatic hypoglycemic events, and 6.6% reported 1 or more severe hypoglycemic events, but these did not increase their relative risk for cardiovascular or all-cause death during follow-up.

Study Reinforces Need for Good Glycemic Control

"The results confirm that people with better blood glucose control have better cardiovascular outcomes, adding to the view that maintaining good blood glucose control when using insulin therapy may be of advantage in the medium term," Dr. Freemantle reiterated.

Guided-poster-tour moderator Ishwarlal Jialal, MD, from the Laboratory of Atherosclerosis and Metabolic Research, University of California, Davis, in Sacramento, agreed.

"This study suggests getting glycated hemoglobin down with low-dose insulin in combination with other therapies is safe and might be beneficial by reducing CV events," he told Medscape Medical News.

Although it was not a prospective study with a comparator arm, nevertheless "it reinforces that good glycemic control is important to prevent cardiovascular events," he added.

This study was funded by Sanofi. Dr. Freemantle has received research grants and served as consultant to Eli Lilly, Medtronic, Novo Nordisk, Pfizer, and Sanofi and has served on speakers' bureaus for Novo Nordisk and Sanofi. Disclosures for the coauthors are listed in the abstract. Dr. Jialal has reported no relevant financial relationships.

American Diabetes Association 2014 Scientific Sessions; June 15, 2014. Abstract 419-P

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