FLAT-SUGAR: Benefit of Reducing Glycemic Variability in Diabetes?

Lisa Nainggolan

June 17, 2015BOSTON — Initial results from a small feasibility study have shown that use of a short-acting glucagonlike peptide (GLP-1) agonist given with meals reduces glycemic variability compared with use of bolus insulin — while maintaining similar HbA_1c levels — in a type 2 diabetes population at high risk of cardiovascular events.
The results of the Fluctuation Reduction With Insulin and GLP-1 Added Together (FLAT-SUGAR) study provide evidence to support a larger, longer outcomes-based trial examining this strategy, Irl B Hirsch, MD, of University of Washington, Seattle, told the Presidents’ Oral Session at the recent American Diabetes Association (ADA) 2015 Scientific Sessions.
But one audience member asked whether the differences demonstrated in FLAT-SUGAR, “which are pretty modest in [glycemic] variability and biomarkers, are really sufficient for a large outcomes study.”
Dr Hirsch told Medscape Medical News: “It’s a fair question; the real answer is we don’t know,” and this will depend on what outcome is selected for the primary end point in a larger trial — a microvascular end point, such as albuminuria, or a larger cardiovascular end point, he noted.
Coinvestigator Jeffrey L Probstfield, MD, from the University of Washington, who is the lead author of a paper just published in Diabetes Care detailing the design of FLAT-SUGAR (Diabetes Care. 2015; DOI:10.2337/dc14-2689), told the meeting: “We learned so much from this trial, the most important thing being how to do this in a multicenter fashion. I’m convinced we can show larger variations in future trials.”
Rationale Behind Reducing Glucose Variability
Dr Hirsch explained the rationale behind the FLAT-SUGAR trial to Medscape Medical News: “HbA_1c is our only gold-standard biomarker; it goes back 30+ years, and it’s important, but what we’ve learned over time is that it does not appear to [correlate with] the entire risk of diabetes complications. It may provide only a relatively small amount of the risk for complications and, if that is the case, what are some of the other risks?”
Some evidence that HbA_1c may not represent the whole story comes from the ACCORD trial, say the FLAT-SUGAR investigators, in which intensive reduction of HbA_1c (to <6.5%) actually increased mortality in a population of type 2 diabetic patients at high risk for cardiovascular events.
HbA_1c levels may therefore not directly reflect the frequency or severity of either hypoglycemic events or hyperglycemic increments after meals, both of which may cause physiologic changes that contribute to long-term risks, they add.
“There’s enough supportive data to suggest that the ‘up and down’ of glucose, which causes reactive oxygen species to accumulate and causes activation of inflammation, is associated with diabetes-related complications,” Dr Hirsch said.
“So perhaps the [glycemic] variability is one of the other things on top of the HbA_1c that is responsible for complications?”
And in patients with long-standing type 2 diabetes, management of postprandial hyperglycemia with preprandial injections of rapid-acting insulin added to basal insulin “is challenging and often ineffective,” he and his coauthors say in their design paper.
Newer treatments for type 2 diabetes, particularly the shorter-acting GLP-1 agonists such as exenatide (Byetta, AstraZeneca) and lixisenatide (Lyxumia, Sanofi), “are of particular interest because of their ability to blunt postprandial glycemic increments (mainly by slowing gastric emptying) while also potentiating endogenous insulin secretion and suppressing inappropriate elevations of glucagon.”
And improved devices for continuous glucose monitoring (CGM) allow for more complete assessment of 24-hour glycemic patterns.
Initial FLAT-SUGAR Results
At the meeting, Dr Hirsch reported initial findings from FLAT-SUGAR. The 102 participants were insulin-requiring type 2 diabetes patients who were similar to ACCORD participants, with a mean age of 62 years, a mean duration of diabetes of 16 years, and a mean body mass index of 34 kg/m². Mean HbA_1c was 7.9%.
Of the patients, 32% had a prior cardiovascular event, 18% had microalbuminuria, and 3% had macroalbuminuria.
The patients all received metformin and basal insulin treatment using once- or twice-daily insulin glargine, plus a bolus rapid-acting insulin analog at mealtimes.
They were then randomized to either continue to use bolus insulin at mealtimes — aspart, glulisine, or lispro (BBI group n = 50) — or to use the GLP-1 agonist exenatide instead of bolus insulin, with mealtime dosing of exenatide, up to a maximum of 20 μg/day (n = 52).
In general, twice-daily or three-times-daily dosing was used with both mealtime regimens depending on meal patterns.
The investigators made titration decisions for basal insulin and bolus insulin and for exenatide at clinic visits and as needed with supplementary telephone contact or electronic communications.
The goal of titration was HbA_1c within a range of 6.7 to 7.3%.
CGM and metabolic markers of cardiovascular risk were assessed at baseline and at 13 and 26 weeks. The primary outcome was change in glycemic variation, as assessed by the coefficient of variation in CGM.
Glycemic Variability and Weight Differ, but Other Outcomes Don’t
At 26 weeks, the coefficient of variation in CGM was significantly different between the two groups (-2.4 for GLP-1 group vs +0.4 for BBI group; P = .047 on t-test) while HbA_1c levels were similar (7.1% vs 7.2%).
There was no clear difference in hypoglycemia episodes between the two groups, but those taking the GLP-1 agonist did lose a significant amount of weight compared with the other group (-4.7 kg, vs +0.8 kg in the BBI group; P < .001), for an overall 5.45 kg, or 12 lb, a “profound” weight difference between the groups, according to Dr Hirsch.
There was also a significant reduction in some biomarkers in the GLP-1 agonist group (alanine transaminase [P = .0002] and serum amyloid [ P = .0225]) compared with the BBI group.
However, for several other biomarkers — interleukin-6 and high-sensitivity C-reactive protein (CRP) — or for albuminuria and urinary isoprostanes, there was no difference between the two groups.
FLAT-SUGAR demonstrates “the successful and safe completion of a complex, demanding trial and the attractiveness of a GLP-1 agonist–based strategy for reducing glucose variability while maintaining nearly equivalent HBA_1c values,” Dr Hirsch said.
Asked by Medscape Medical News whether any pharmaceutical company is interested in funding larger trial of this approach, Dr Hirsch said, “There’s a lot of interest in this topic, whether it’s funded by industry or the [National Institutes of Health] NIH.”
Dr Hirsch is on the advisory boards for Abbott Diabetes Care, Roche Diagnostics, and Valeritas and receives research support from Sanofi and Novo Nordisk. Dr Probstfield is a consultant to Sanofi. Disclosures for the coauthors are listed in the abstract.
American Diabetes Association 2015 Scientific Sessions; June 9, 2015; Boston, Massachusetts. Abstract 385-OR

Medscape Medical News © 2015  WebMD, LLC