Who gets the cardioprotective agents? Are newer agents affordable? And, how low should A1c go?
New and effective drugs are available to combat the growing type 2 diabetes epidemic. However, new drugs are giving rise to new questions for which there are no easy answers.
For example, should lower-risk patients get drugs with proven cardiovascular (CV) benefits, or should these agents be reserved for those with established CV disease? Does the efficacy of the new treatments justify their cost? How aggressively should glycemic goals be pursued – and how ambitious should those goals be in the first place?
Patient Care recently spoke with William H. Herman, MD, MPH, the Stefan S. Fajans/GlaxoSmithKline Professor of Diabetes and Director of the Michigan Diabetes Research and Training Center, University of Michigan, Ann Arbor, to discuss the latest controversies with new diabetes drugs, clinical trials, and guidelines.
“We have a lot of different medications now available, and we have data on for whom they seem to be most effective,” says Herman, who spoke on these unresolved questions at the ACP Internal Medicine Meeting 2018 in New Orleans, Louisiana. “I think the main issue is to personalize treatment according to each individual patient's needs, both with respect to target levels of glycemia and to the choice of agents.”
Key Question 1: Which drugs should we give?
Key Question 1: Should drugs with proven CV benefits be given to lower-risk patients?
While trials of DPP-4 inhibitors are not suggestive of an impact on CV outcomes, more recent trials with the GLP-1 agonists and SGLT-2 inhibitors have shown a reduction in composite CV outcomes compared to standard of care therapy. Accordingly, the American Diabetes Association (ADA) has for the first time recommended1 that when patients with type 2 diabetes mellitus (T2DM) and an established CV disease require additional therapy beyond metformin, an agent proven to reduce major CV events and mortality should be added.
So where does that leave individuals without established CV disease? “The observational studies have been all over the place,” says Herman. Two large observational studies did recently suggest that SGLT-2 inhibitors substantially reduce the rate of all-cause death in all patients with T2DM – not just those at increased CV risk. However, one recent assessment2 of those trials found that they were subject to time-related biases that may exaggerate the benefits of the drugs.
That means there is still a lack of evidence, said Herman, that SGLT-2 inhibitors would be especially helpful in comparison to other antihyperglycemic agents for patients without established atherosclerotic CV disease.
In light of that, Herman recommended proceeding according to the ADA guidelines, which state in part that second-line antihyperglycemic therapy for patients without CV disease should be tailored to the individual patient based on hypoglycemia risk, impact of the drug on weight, side effects, patient preferences, and cost, which brings us to the 2nd key question.
Key Question 2: Can we pay?
Key Question 2: Can we afford the new therapies?
With significant efficacy often comes a substantial price tag. Patients can struggle with the cost of newer therapies, and formulary restrictions are clearly a barrier that can demand a lot of time on the part of the provider, notes Herman.
The current ADA guidelines1 make it a bit easier to address the affordability issue by outlining cost information for a number of treatments. In particular, they include a table showing the median US monthly cost of noninsulin glucose-lowering agents when given at the maximum approved daily dose, along with a table showing the median cost of insulin products.
Time might ameliorate some of the cost issue, says Herman, when today’s branded drugs go off patent and competition from generics may drive down prices.
In the meantime, cost effectiveness studies would be helpful, particularly head-to-head comparisons of drugs. Expect to see some insights from the ongoing GRADE3 study, which is testing 4 different treatments added to metformin with respect to CV disease risk factors, adverse effects, cost-effectiveness, and more.
The drugs under study in GRADE include a DPP-4 inhibitor, a GLP-1 receptor agonist, a sulfonylurea, and basal insulin – but no SGLT-2 specific drugs. “The big gap in that study is it doesn't have an SGLT-2 inhibitor, because it started just before they came to the market,” explains Herman.
Key Question 3: How low to go?
Key Question 3: How stringent should glycemic goals be?
The American College of Physicians (ACP) just caused a stir by releasing guidelines4 on A1c targets that do not appear to march in lockstep with recommendations from the ADA.
Traditionally, the ADA has said an A1c of <7% is a reasonable goal for many non-pregnant adult patients with T2DM. They suggest less stringent goals (eg, <8%) for patients with limited life expectancy, extensive comorbidities, or other conditions that might make the 7% goal too challenging.
The ACP now recommends that clinicians shoot for a goal A1c of 7% to 8% for most patients, and even suggests avoiding targeting A1c goals in some situations, such as advanced age (eg, aged 80 years or older) and end-stage kidney disease. Moreover, they suggest clinicians might consider “deintensifying” pharmacologic treatment in patients who achieve an A1c <6.5%.
“It's read as relaxing the hemoglobin A1c glycemic targets for people with type 2 diabetes,” Herman explains. “That's really caused a lot of controversy, particularly in the endocrine community, which has pushed for more stringent hemoglobin A1c goals.”
But are the 2 statements really that different? Herman says the ACP guidelines lean toward highlighting the risks and the people in whom aggressive glucose control might not be warranted, whereas the ADA guidelines highlight the cohorts of individuals where early intensive glycemic control can produce major benefits.
“Both the ADA and the ACP agree that treatments need to be tailored,” says Herman. “My interpretation is, for people who can achieve lower HbA1c levels with minimal therapy, minimal side effects, and particularly early in the natural history of type 2 diabetes, there are benefits to that.”
1. American Diabetes Association. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes – 2018. Diabetes Care. 2018;41:S73-S85.
2. Suissa S. Lower risk of death with SGLT2 inhibitors in observational studies: Real or bias? Diabetes Care. 2018;41:6-10.
3. NIDDK. A comparative effectiveness study of major glycemia-lowering medications for treatment of type 2 diabetes (GRADE). Available from: https://clinicaltrials.gov/ct2/show/NCT01794143. NLM identifier: NCT01794143. Accessed May 7, 2018.
4. Qaseem A, Wilt TJ, Kansagara D, et al. Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: A guidance statement update from the American College of Physicians. Ann Intern Med. 2018;168:569-576.