ACP Glycemic Treatment Target Guidance: An Author Makes the Case

An Interview With Timothy J. Wilt, MD, MPH

Jay H. Shubrook, DO; Timothy J. Wilt, MD, MPH


May 21, 2018

Editor's Note
What does this article tell you that you may not already know?
  • ACP released a guidance statement in March 2018 presenting evidence indicating that the optimal balance of clinical benefits and harms occurs with HbA1c levels between 7% and 8%.

  • No treat-to-target trial has found that achieving an HbA1c level below 7% reduced mortality or macrovascular outcomes. Reductions in “microvascular events” were small, inconsistent, and typically surrogate events, not clinical outcomes.

  • ACP recommends that physicians focus on minimizing symptoms related to hyperglycemia rather than achieving a specific HbA1c target in patients who have a relatively short life expectancy.

Jay H. Shubrook, DO: Hi. I am Jay Shubrook, DO, family physician; diabetologist; and professor at Touro University, Vallejo, California. Today we are continuing our series, Everyday Diabetes: Practical Management for Primary Care.

I am delighted to have with me Timothy Wilt, MD, MPH, a core investigator and staff physician at the Veterans Affairs Center for Chronic Disease Outcomes Research in Minneapolis, and a professor of medicine at the University of Minnesota School of Medicine. Dr Wilt, welcome aboard.

Timothy J. Wilt, MD, MPH: Thanks so much for talking with me today and for your interest in our guidance statements.

Shubrook: I think we have a really great topic today. We are going to talk about diabetes, particularly HbA1c pharmacology guidelines. There has been a recent guidance statement from the American College of Physicians (ACP) on treatment targets for patients with diabetes.[1] Dr Wilt, can you tell me about your role in this update and the specifics of this guideline statement?

Wilt: The ACP issued an updated clinical practice guidance statement on the pharmacologic management of nonpregnant adults with type 2 diabetes. We reviewed the evidence from other clinical practice guidelines related to treatment targets, and issued several guidance statements based on our findings. There were commonalities among all the guideline groups, but areas in which ACP differed and where we found some optimal balance were benefits and harms.

Shubrook: I think that is really important. Each medical group's guidelines are somewhat different, and each has its own recommendations. What are the key statements in ACP's guidance for HbA1c targets?

Wilt: Let me first describe some of our guidance statements from this report; then we can talk about how we arrived at our recommendations and why our guidance statements may differ slightly from those of other groups.

First, I want to emphasize that the cornerstone of diabetes treatment involves lifestyle management. All patients should be encouraged to have a healthy lifestyle that includes exercise, healthy diet, weight loss, smoking cessation, and blood pressure (BP) and cholesterol control. The focus of our recommendations in this guidance statement is on pharmacologic management, but we would support [nonpharmacologic] management for patients who can achieve a lower or normal HbA1c level through lifestyle modifications.

For pharmacologic management, all of the guideline groups suggest individualizing a patient's HbA1c targets on the basis of his or her other medical conditions. By reviewing data from five large, randomized controlled trials, which were also assessed by all of the other clinical guideline groups, we found that the optimal balance of clinical benefits and harms occurs [with HbA1c levels] between 7% and 8%. In addition, we found convincing evidence that there are no benefits, but considerable harms, to patients receiving pharmacologic therapy who achieve HbA1c levels below 6.5%. For individuals with HbA1c levels persistently below 6.5%, we recommend physicians consider deintensifying or deimplementing medications.

We also suggest that physicians focus on minimizing symptoms related to hyperglycemia rather than achieving a specific HbA1c target in patients who have a relatively short life expectancy related to advanced age or serious comorbidities. The rationale behind this recommendation is that all five studies demonstrate a fairly small clinical benefit to achieving a specific HbA1c target—one that takes many years to attain (sometimes 10 or 20 years), while at the same time subjecting patients to the harms, cost, and burden of medications.

[Studies enrolled a wide range of individuals with diabetes, including those who were middle-aged and with newly diagnosed diabetes. Results were similar regardless of patient age, diabetes duration, or coexisting vascular disease. Studies followed patients for 10-30 years. Future studies focused on young patients with newly diagnosed diabetes might show a benefit in the very long-term, but these individuals would have to balance any very long-term clinical benefits with ongoing medication and monitoring harms, burden, and costs. ACP agrees that a HbA1c target at the lower range (approximately 7%) is reasonable for younger, healthy individuals if it can be achieved in the absence of medication side effects and unacceptable burden and costs of care to patients.]

Shubrook: Thank you for your comprehensive review; it really helped me to understand the key aspects of the guidance statements. You mentioned the large, randomized controlled trials that contributed to the ACP guidance statements, which have been the baseline for diabetes guidance—ACCORD (Action to Control Cardiovascular Risk in Diabetes),[2,3] ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation),[4] VADT (Veterans Affairs Diabetes Trial),[5,6] and UKPDS (UK Prospective Diabetes Studies) 33 [7]and 34.[8]

One of the challenges I have heard relates to the inclusion of some of the newer diabetes medications. Do these newer medications factor into or influence the ACP guidance statements?

Wilt: I think the newer medications are really important and of interest to physicians, and I would like to make a couple of points about them. HbA1c targets continue to be the focus of both physicians and patients, and frankly, physician performance is often measured by the achievement of HbA1c targets. None of these newer diabetes medications has been studied in treat-to-target trials, nor have any of the clinical practice guideline groups considered these medications in their treat-to-target recommendations.

Furthermore, the newer diabetes medications were studied in high-risk patients whose baseline HbA1c was typically greater than 8%. This is higher than the range ACP and other organizations recommend as an optimal treatment target. The newer medications may have a role in selected individuals who do not achieve an adequate HbA1c target—somewhere between 7% and 8%—who are willing and able to accept the risk associated with these medications, and who are aware that the absolute benefit will be small, probably around 1%.

I also think it is important for patients and providers to realize that these medications are costly, on average $500-$1000 per month. Whereas clinical practice guidelines often do not consider cost, ACP does factor in the cost of medications, and our patients consider cost in the care we provide them.

Shubrook: Thank you. That is an important thing. Ultimately, one can have the best science in the world—or not—but if a patient cannot afford a prescribed treatment, he or she is not going to take that treatment.

Wilt: Not only that, if a patient cannot afford a pharmacologic treatment, he or she also may not be eating as ideally as he or she could, and may not be engaged in other healthy lifestyles. I think if there were evidence that use of these newer pharmacologic therapies to achieve an HbA1c target was beneficial, the ACP and other guideline groups would have commented on that.

Let me just also comment on the effects of these newer agents. Basically, studies show these drugs lower HbA1c by about 0.5%. The reduction in weight and BP is also really quite small: about 2%-3% for weight, and about 1 or 2 mm Hg for BP. These drugs are not approved for weight loss in doses commonly used to treat diabetes or for BP control.

I want to focus again on the studies that were used by all of the guideline groups that looked at treatment-to-target. As you highlighted, there are five large, long-term randomized trials. None of these trials show that achieving an HbA1c level below 7% reduced mortality or cardiovascular mortality. Furthermore, any benefits in clinical outcomes, such as reduction in heart attacks or strokes, was very small—1% or less—and required at least 15 or 20 years to be seen.[7,8] Moreover, because there are considerable harms associated with these medications, we need to set targets that balance benefits with harms.

Improving clinical outcomes is critical. We want to help patients live longer and prevent heart attacks, strokes, amputations, loss of vision, loss of sensation, and painful neuropathy. We have to set treatment targets that balance the benefits with harms.

Finally, Jay, I just want to bring up one other thing. I think that one of the areas where ACP's statements differ from the other guideline groups is that ACP really focused on clinical outcomes. As I mentioned, these are outcomes that patients can see and feel: length and quality of life and prevention of visual impairment, loss of sensation, painful neuropathy, renal failure, strokes, and heart attacks, et cetera. Improvement in these clinical outcomes did not typically occur with more intensive HbA1c targets, or if they occurred, they were very small and inconsistent.

Other guideline groups tend to emphasize changes in microvascular complications. If one looks closely at these studies, though, one sees that these are really not complications but rather findings on laboratory or physiologic measures performed for study purposes—not the clinical signs or symptoms that patients often really care about. These findings include microscopic albumin in the urine, visual findings on an asymptomatic funduscopic examination (typically for screening purposes), loss of ankle reflexes, or loss of feeling using a monofilament. When found, all of these changes were small, inconsistently seen, and developed over many years.

Shubrook: I really appreciate your thorough response. I have one last question for you. As a primary care physician, there was a time when I had no guidance on how to treat patients who have diabetes. Now I have multiple guidances, which do not all agree in their recommendations. If you could give me one message about how to come to terms with conflicted guidelines, what would you recommend?

Wilt: I would recommend you follow the ACP clinical guidance. Let me be serious. We [ACP] carefully reviewed the evidence related to the differences in guidelines. We think that our guidance statements really help provide high-quality clinical care for our patients. They are flexible, evidence-based, and easier for patients to adhere to and for physicians to implement.

Again, let me just summarize the ACP guidance statements:

  1. Physicians should personalize the diabetes care and treatment targets of their patients.

  2. For most patients, an HbA1cA1c target between 7% and 8% ideally balances benefits and harms.

  3. Physicians can consider deimplementing or reducing the number of or the dose of medications of patients who have HbA1c levels persistently below 6.5%.

  4. Physicians should reassure patients of advanced age, with chronic conditions, or with severe disease that they are unlikely to suffer future diabetes-related issues.

  5. Physicians also should explain they can reduce the cost, complexity, burden, and harms of medication by focusing on minimizing symptoms rather than achieving a specific HbA1c treatment target.

Shubrook: Thank you so much for your time and expertise today.

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