Early Insulin, Singular Focus on HbA1c Not Always Best
By Brenda L. Mooney
NASHVILLE — New VA research soon might change the way clinicians treat veterans with type 2 diabetes.
Despite the increased push for early initiation of insulin in patients with type 2 diabetes, a new Nashville VA study suggests that might not always be a good idea. Another recent VA study, conducted by researchers in Michigan, questions whether the benefits of type 2 diabetes treatment are even worth the risks, side effects and inconvenience for some patients.
Among patients with diabetes who were receiving metformin, the addition of insulin compared with a sulfonylurea was associated with an increased risk of nonfatal cardiovascular outcomes and all-cause mortality, according to researchers from the Veterans Health Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, and Vanderbilt University, both in Nashville. Their report was published recently in the Journal of the American Medical Association.1
Lead author Christianne L. Roumie, MD, MPH,explained that “adding insulin is a reasonable option for patients who desire fast or flexible blood sugar control. However, there’s no advantage on cardiovascular disease for adding insulin early. And we feel that most patients could be managed with a sulfonylurea as the second-line therapy.”
Roumie said she and her colleagues embarked on the study because, despite the treatment guidelines recommending adding any of five medication classes, if initial treatment with metformin plus diet and exercise does not adequately reduce hemoglobin A1c, “There is a lack of critical evidence on which of these medications may be the best. Our study looked at the association between metformin with sulfonylurea vs. metformin plus insulin on cardiovascular disease and all-cause mortality.”
Guidelines from the American Diabetes Association and the European Association for the Study of Diabetes recommend that patients with preserved kidney function begin diabetes treatment with metformin and lifestyle changes to achieve a glycated hemoglobin (HbA1c) level of less than or equal to 7%. While a second agent often is required for patients to reach the goal, no consensus has been reached as to which therapy to choose, according to background in the study.
Because a few trials have shown that insulin can offer fast and flexible control of blood glucose level, early initiation of insulin as well as its use as add-on therapy to metformin has been widely promoted, according to the report.
For the Tennessee study, the researchers reviewed data from national Veterans Health Administration, Medicare and National Death Index databases, which included veterans with diabetes initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. The therapies were compared for risk of heart attack, stroke or all-cause mortality.
Roumie pointed out that about 35% of the veteran cohort had a past medical history of cardiovascular disease or stroke, and most had been on metformin about 14 months.
In the study, among 178,341 metformin monotherapy patients, 2,948 added insulin and 39,990 added a sulfonylurea. The authors analyzed a propensity-matched subset of 2,436 patients from the insulin group and 12,180 patients from the sulfonylurea group to find that in 14 months of follow-up heart attack and stroke rates were statistically similar. However, the rate of all-cause death among patients who received insulin was higher.
“Our finding of a modestly increased risk of a composite of cardiovascular events and death in metformin users who add insulin compared with sulfonylurea is consistent with the available clinical trial and observational data. None of these studies found an advantage of insulin compared with oral agents for cardiovascular risk, and several reported increased cardiovascular risk or weight gain and hypoglycemic episodes, which could result in poorer outcomes,” the authors wrote. “Our study suggests that intensification of metformin with insulin among patients who could add a sulfonylurea offers no advantage in regard to risk of cardiovascular events and is associated with some risk.”
Roumie added that the study subjects’ hemoglobin A1c at the time of initiation of the second drug was an average of 8.1%, dropping to an average of about 7% after one year on insulin or a sulfonylurea.
At the same time, she said, researchers found a 30% increased risk for the composite outcome of hospitalization for heart attack, stroke or all-cause mortality among patients taking metformin plus insulin as compared to those on metformin and a sulfonylurea.
“Most of the risk came with an increased risk for all-cause mortality,” she explained.
“These findings require further investigation to understand risks associated with insulin use in these patients and call into question recommendations that insulin is equivalent to sulfonylureas for patients who may be able to receive an oral agent,” study authors emphasize.
Roumie said future VA research will look at why the risk of death is increased among patients using insulin.
“There have been multiple hypotheses, that it is hypoglycemia or variation in blood glucose, and we are setting out to understand the relationship between insulin and hypoglycemia and how that may impact the risk of death,” she said.
The other study, from the VA Ann Arbor, MI, Healthcare System, the University of Michigan Health System and University College in London, questioned the value of any diabetes medications at all for some patients. In a report published recently in JAMA Internal Medicine, the researchers suggested that, especially for patients older than 50 with type 2 diabetes, side effects such as weight gain or the burden of frequent insulin shots might outweigh the drug’s benefits.2
While current guidelines for type 2 diabetes recommend intensifying treatment until the patient’s hemoglobin A1c drops to a certain level, the researchers posited that the overall benefit from treatment may have as much or more to do with safety, side effects and inconvenience than blood sugar.
“For people with type 2 diabetes, the goal of managing blood sugar levels is to prevent associated diabetes complications, such as kidney, eye and heart disease, but it is essential to balance complication risks and treatment burdens when deciding how aggressively to treat blood sugars,” explained lead author Sandeep Vijan MD, MS, a research scientist at the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and a professor at the University of Michigan Medical School.
“If you’re a patient with fairly low complication risks but are experiencing symptoms from low blood sugar, gaining weight or find frequent insulin shots to be disruptive to your daily life, then the drugs are doing more harm than good. Prescribing medicine isn’t just about reducing risks of complications, but also about helping patients improve their quality of life,” Vijan added.
He pointed out that, for many patients, little additional benefit accrues after moderate levels of glucose control are achieved, yet treatment costs, risks and hassles continue to increase.
The study found that, assuming a low treatment burden (0.001, or 0.4 lost days per year), treatment that lowered HbA1c level by 1% provided benefits ranging from 0.77 to 0.91 quality-adjusted life years (QALYs) for simulated patients who received a diagnosis at age 45 years to 0.08 to 0.10 QALYs for those who received a diagnosis at age 75 years.
“An increase in treatment burden (0.01, or 3.7 days lost per year) resulted in HbA1c level lowering being associated with more harm than benefit in those aged 75 years,” the authors report. “Across all ages, patients who viewed treatment as more burdensome (0.025-0.05 disutility) experienced a net loss in QALYs from treatments to lower HbA1c level.”
The study, which excluded the 15% to 20% of type 2 diabetes patients with very high blood sugar levels who require intensive treatment, found that the benefits of treatment decline with age and, by 75, the harms of most treatments are likely to outweigh any benefits.
“Improving glycemic control can provide substantial benefits, especially for younger patients; however, for most patients older than 50 years with an HbA1c level less than 9% receiving metformin therapy, additional glycemic treatment usually offers at most modest benefits,” according to the researchers.
The authors recommended that, instead of focusing only on glucose goals, a better approach for clinicians is to individualize treatment based on patients’ estimated risk of diabetes complications — taking into account their ages and degree of blood glucose elevation — as well as the side effects and amount of safety data of the medication being considered.
“Current quality measures do not allow doctors and patients to make good decisions for each patient because they emphasize reaching targets instead of thinking of the risks and benefits of starting new medications based on individual circumstances and preferences,” added senior author Rodney Hayward, MD, senior research scientist at the Center for Clinical Management Research at the Ann Arbor VA and a University of Michigan Medical School professor.
This wasn’t the first study to challenge “treat-to-target” guidelines, which are widely used in medicine. Hypertension guidelines were significantly changed last year after research concluded the risks outweighed benefits of drugs intended to achieve specific blood pressure goals in some patients. Similar recommendations also have been implemented for lipid lowering therapy, the study pointed out.
1 Roumie CL, Greevy RA, Grijalva CG, Hung AM, Liu X, Murff HJ, Elasy TA, Griffin MR. Association between intensification of metformin treatment with insulin vs. sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA. 2014 Jun 11;311(22):2288-96. doi: 10.1001/jama.2014.4312. PubMed PMID: 24915260.
2 Vijan S, Sussman JB, Yudkin JS, Hayward RA. Effect of Patients’ Risks and Preferences on Health Gains With Plasma Glucose Level Lowering in Type 2 Diabetes Mellitus. JAMA Intern Med. 2014 Jun 30. doi: 10.1001/jamainternmed.2014.2894. [Epub ahead of print] PubMed PMID: 24979148.
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