ORLANDO – according to a draft consensus report on the management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM).
Dr. John Buse
The report, a project of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), is currently under review and will be presented in final form Oct. 5 at the EASD annual meeting in Berlin.
The current draft calls, generally, for the initial use of metformin followed by the addition of antihyperglycemic medications based on patient comorbidities and concerns “as we await answers to the many questions that remain,” John Buse, MD, PhD, cochair of the consensus statement writing group, said during a summary of the draft recommendations at the annual scientific sessions of the ADA.
The first step, however, is to assess key patient characteristics; these can include comorbidities, clinical characteristics, issues such as motivation and depression, and cultural and socio-economic context, Deborah J. Wexler, MD, 1 of 10 writing group members, said during the same presentation.
Patients with ASCVD or heart failure
Given new evidence from trials such as EMPA-REG and LEADER showing outcomes benefits with the use of specific antihyperglycemic medications in patients with established atherosclerotic cardiovascular disease (ASCVD), an important early step in the proposed approach is to consider the presence or absence of ASCVD and heart failure, said Dr. Wexler of Massachusetts General Hospital, Boston.
“The presence of cardiovascular disease is a compelling indication for the selection of certain glucose-lowering drugs,” she said.
The draft consensus recommendation in this regard – a new recommendation since the last consensus report in 2015 – differentiates between T2DM patients in whom ASCVD predominates and those in whom heart failure predominates.
“What’s new since 2015 is that we recommend that these comorbidities be considered first and foremost because they do influence the choice of a particular glucose-lowering medication, and the recommendation is that, among patients with type 2 diabetes with established ASCVD, sodium-glucose cotransporter 2 [SGLT2] inhibitors or glucagonlike peptide 1 [GLP-1] receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” she said.
However, it is important to note that ASCVD is defined differently across trials, and patients considered in the development of these recommendations are those with much higher cardiovascular risk than the average patient with T2DM, she added.
“It’s also important to keep in mind that each cardiovascular outcomes trial, while large, is but a single experiment ... and we don’t have the benefit of replication,” she said, noting that it is not always clear whether differences in trial findings within a drug class are related to trial design or true differences in individual medications.
“So we try to read into them and interpret these data, but it’s just important to consider that ... and when evidence suggests a hierarchy, we noted that,” she said.
That said, if ASCVD predominates, the recommendation is for treatment with either a GLP-1 receptor agonist with proven cardiovascular benefit (favoring liraglutide over semaglutide and over long-acting exenatide) or an SGLT2 inhibitor with proven cardiovascular benefit if estimated glomerular filtration (eGFR) is adequate (favoring empagliflozin over canagliflozin).
These recommendations are based on the LEADER trial finding of significant improvement in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with liraglutide vs. placebo (hazard ratio, 0.87; number needed to treat [NNT], 52 over 3.8 years) and on the EMPA-REG trial finding of significant improvement in the same primary outcome with empagliflozin vs. placebo (HR, 0.86; NNT, 62 over 3.1 years).
Keep in mind that there is no evidence of cardiovascular benefit from these treatments in patients at lower risk and also that the “expensive and complicated” combination of an SGLT2 inhibitor and a GLP-1 receptor agonist has not been tested in cardiovascular outcomes trials and there is no evidence of additional benefit from a cardiovascular perspective with this combination, Dr. Wexler said.
If heart failure predominates, the recommendations call for consideration of an SGLT2 inhibitor as part of the treatment strategy because patients with T2DM are at increased risk for heart failure with reduced or preserved ejection fraction and because significant, consistent reduction in hospitalizations for heart failure were seen in SGLT2 inhibitor trials, writing group member Peter Rossing, MD, explained during the session; he noted, however, that the trials were not designed to adjudicate heart failure and that most patients did not have clinical heart failure at baseline.
In those in whom SGLT2 inhibitors are contraindicated – because of impaired renal function, for example – a GLP-1 receptor agonist with proven cardiovascular benefit is recommended.
“Then we suggest that if you are still not at [hemoglobin A1c] target, you should avoid thiazolidinediones [TZD] because of the risk of fluid overload, and you could then consider, if needed, combining an SGLT2-inhibitor and a GLP-1 receptor agonist ... or you could use a [dipeptidyl peptidase–4 (DPP-4) inhibitor] if you are not on an GLP-1 receptor agonist. And we point out that saxagliptin has unfavorable data on heart failure,” Dr. Rossing of Steno Diabetes Center, Copenhagen, said, noting that basal insulin or sulfonylurea are other alternative options.
In EMPA-REG, hospitalization for heart failure was reduced by 35% with empagliflozin vs. placebo (HR, 0.65; NNT, 71 over 3 years), and similar findings were seen in the CANVAS trial. In LEADER, a nonsignificant 13% reduction was seen in hospitalization for heart failure with liraglutide vs. placebo (HR, 0.87). However, this was a secondary outcome; ongoing studies are addressing heart failure as a primary outcome, Dr. Rossing said.
The report also includes a recommendation that, for patients with chronic kidney disease and high cardiovascular risk, GLP-1 receptor agonists and SGLT2 inhibitors can be used but with dose reductions for some medications – several of which have demonstrated renal benefit and cardiovascular benefits in those populations and can be considered as part of treatment.