For Type 2 Diabetes, Less Intensive HbA1c Goals Promise Less Harm

Need for intensive drug treatment to reduce hemoglobin A1C targets called into question by the American College of Physicians but defended by the leading endocrine-related organizations, placing clinicians in the middle of debate over T2D treatment.

Written by Lynne K Schneider PhD

With Jack Ende, MD, and David W. Lam, MD

Nearly 1 in 10 Americans—more than 29 million persons—have type 2 diabetes mellitus (T2D), which is a leading cause of morbidity and mortality in the US.1 Treatment has been focused on lowering blood glucose levels, specifically hemoglobin A1c, to a specific target level in order to minimize risks for cardiovascular, cerebrovascular, neurologic, ophthalmologic, and renal complications (among others).

A growing body of evidence now indicates that reducing blood glucose levels, while beneficial in lowering risk of complications, is also associated with potential harms, additional patient burden, and potentially higher costs for nonpregnant adults.2

This update, “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,” focuses solely on the “benefits and harms of targeting lower versus higher HbA1c levels,” and does not address specific medications or other populations with T2D.

Intensive Treatment for Type 2 Diabetes Should be Replaced with Individualized Care

“The evidence-based analysis determined that the harms associated with intensive treatment with drugs to targets of < 7% could be greater than the benefits,” Jack Ende, MD, President of ACP and the Schaeffer Professor of Medicine at the Perelman School of Medicine at The University of Pennsylvania, in Philadelphia, told EndocrineWeb.

Consequently, the updated American College of Physicians guidance  recommends a HbA1c target of between 7% and 8% to best balance long-term benefits and harms.2 Dr. Ende confirmed that the ACP guidance focuses on the following four recommendations:

  1. Personalized treatment to minimize harms. Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients' preferences, patients' general health and life expectancy, treatment burden, and costs of care.
  2. Target HbA1c to between 7%-8%. Clinicians should aim to achieve an HbA1c level between 7% and 8% in most adults with type 2 diabetes.
  3. Back off on intensive treatment. Clinicians should consider de-intensifying pharmacologic therapy in patients with type 2 diabetes who have achieved HbA1c levels less than 6.5%.
  4. Treat older patients' hyperglycemia. Clinicians should manage patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting HbA1c levels in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure) because the harms outweigh the benefits in this population.

Discussion in Support of the ACP Guidelines

The first guidance statement concurs with the existing guidelines, all of which recommend personalizing treatment. 

The second guidance statement reflects the observation that, collectively, all of the trials upon which these guidelines were based showed that treating to targets of <7% versus around 8% did not reduce mortality or macrovascular morbidity from over 5 to 10 years of treatment but did lead to substantial harms. “Of course, this need not apply to patients who are able to achieve an HbA1c of 6.5% through diet, exercise and lifestyle modifications alone,” observed Dr. Ende. 

According to David W. Lam, MD, Assistant Professor of Medicine in the Division of Endocrinology, Diabetes and Bone Diseases at the Icahn School of Medicine at Mount Sinai (NY), the key takeaway from this updated guideline is the “personalization of care by considering multiple comorbidities of the patient, life expectancy, and ultimately considering the risk/benefit ratio of intensifying glycemic control.

A major change in the paradigm of diabetes treatment comes from guidance statements 3 and 4, more specifically the de-escalation of medical therapy with HbA1c less than 6.5% and the shift from a focus on an HbA1c target to focusing on the avoidance of symptoms from hyperglycemia.”

Dr. Ende commented that de-intensifying pharmacotherapy is not a new strategy -- it is already successfully integrated into the management of asthma and gastrointestinal reflux disorder (GERD). At a minimum, he suggests that clinicians and their patients need to have a discussion about future treatment strategies and goals to determine whether to relax or continue with the existing target.

Finally, Dr. Ende noted that intense therapy is not appropriate for patients whose life expectancy is less than 10 years.  In fact, he noted that the UKDPS study observed benefits of intensive treatment required about 17 years of intensive therapy. 

Sorting Diabetes Guidelines on Treat-to-Target for Hb A1

To better guide clinicians in personalizing targets for pharmacologic treatment of T2D, the Clinical Guidelines Committee of the American College of Physicians (ACP) reviewed how the following six existing guidelines addressed HbA1c targets in patients with type 2 diabetes:2

Each of these guidelines includes a recommendation to personalize HbA1c target levels based on specific patient characteristics – such as comorbid conditions and risk for hypoglycemia – albeit in different ways and with different target goals.

All six professional recommendations suggest increasing the HbA1c targets in patients with comorbid conditions and reduced life expectancy.3-8  For example, AACE/ACE recommends a target of 6.5% (if it can be safely achieved) whereas ADA and SIGN recommend a HbA1c target of 7% for the general population.6,7 The NICE guidelines recommend a target of either 6.5% or 7%, depending upon the treatment regimen.3 Both ICSI and VA/DoD recommend ranges of HbA1c targets, with ICSI recommending targets of <7% to <8% based on patient factors, and VA/DoD recommending 3 different tiers of target ranges.4,8

Reviewing the Evidence Behind the Guidelines

The ACP examined evidence from the five large, long-term, randomized controlled trials (each of which used a treat-to-target strategy) that were considered by the various professional organizations to develop their guidelines,9-13 in developing this current Guidance Statement Update.2

Specifically, results from the ACCORD (Action to Control Cardiovascular Risk in Diabetes),9 ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation),10 the 2 UKPDS (United Kingdom Prospective Diabetes Study),11,12 and VADT (Veterans Affairs Diabetes Trial)13 trials demonstrated that treatment with drugs to targets of <7% versus 8% did not necessarily reduce mortality or morbidity, including macrovascular complications (such as cardiovascular or cerebrovascular events) or microvascular (renal failure, doubling of serum creatinine, visual impairment, retinal photocoagulation, and neuropathy)  complications.

However, these complications were associated with increased risk of substantial harms, including higher rates of all-cause mortality, increases in cardiovascular-related death, severe hypoglycemia, increased weight gain, increased fluid retention, and more frequent hospitalizations.9-13

Assessment of Clinical Adjustments to Care for T2D

“Guidelines serve to provide a framework for clinical care,” Dr. Lam. Noting that PCPs are likely to treat more patients with T2D then endocrinologists, Dr. Lam told EndocrineWeb, their interpretation of these guidelines has the “potential to have even more of a clinical impact.”  He hopes that these guidelines will inspire clinicians to have more in-depth conversations with their patients about how diabetes is impacting their lives, and to initiate discussions with their patients regarding goals of therapy to ensure they are all on the same page with regard to treatment.”

When asked what barriers patients might face in accepting these new guidelines, Dr. Lam said, “some patients may have difficulty understanding the change in targets. As such, for clinicians choosing to implement the new guidelines, it is important to explain [to patients] the reasoning behind making changes to their current treatment goals.”

Similarly, Dr. Ende said that while he has already integrated these guidance statements into practice, particularly with his elderly patients and those on multiple medications, not all patients are open to relaxing their HbA1c targets – they may be reluctant and excited at the same time.

Professional Organization Take Issue with ACP's Proposed Changes to HbA1c Goals

The Endocrine Society, American Association of Clinical Endocrinologists, American Diabetes Association, and the American Association of Diabetes Educators have issued a harsh rebuke to the ACP guidance, which proposed that it may be more beneficial to relax current goals for nonpregnant adults with type 2 diabetes.13 ,14

"While there are several topics listed in the American College of Physicians’ statement on which we agree, there are several significant areas that do not align with ADA’s  2018 Standards of Medical Care in Diabetes,"13 according to the ADA press release.

One main criticism the ADA raised about the ACP’s guidance is that “it does not consider the positive legacy effects of intensive blood glucose control confirmed in multiple clinical trials, and therefore, are not reflective of the long-term benefits of lower A1c targets.”13 

The ADA argued, "There is clear, convincing evidence of a long-term reduction in diabetes complications with A1cs at and below 7 percent. ADA is also concerned by the missing consideration of the positive impact of several newer medication classes (ie, SGLT2 inhibitors and GLP-1 receptor agonists) that are associated with low risk for hypoglycemia have favorable effects on weight and improved cardiovascular disease outcomes."6,13

"While the ACP's guidance is only one additional percentage point, this equates to a difference of nearly 30 points when blood glucose is measured in mg/dl. This difference in the lower and higher A1cs in the range ACP suggests also has been shown to have clear differences in microvascular complications," 14  according to a joint press statement.

In the end, patient-centered care will determine the best approach to care; something about which both professional organizations could agree.

As if to break the tie, Dr. Ende said, “Ultimately, we have to take the lead from our patients.”  

Authors not named here have disclosed no conflicts of interest. However,  A record of disclosures of interest and management of conflicts of interest is kept for each ACP committee meeting and conference call.

Sources

  1. Centers for Disease Control and Prevention (CDC). National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Atlanta: U.S. Department of Health and Human Services; 2014.
  2. Qaseem A, Wilt TJ, Kansagara D, et al; for the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. Ahead of print. 2018.  Available at: http://annals.org/aim/fullarticle/2674121/hemoglobin-1c-targets-glycemic-control-pharmacologic-therapy-nonpregnant-adults-type. Accessed March 2, 2018.
  3. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. Available at www.nice.org.uk/guidance/ng28/resources/type-2-diabetes-in-adults-management-pdf-1837338615493.  Accessed March 5, 2018.
  4. Redmon B, Caccamo D, Flavin P, et al; Institute for Clinical Systems Improvement (ICSI). Diagnosis and Management of Type 2 Diabetes Mellitus in Adults. 16th ed. Bloomington, MN: Institute for Clinical Systems Improvement; July 2014.
  5. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology—clinical practice guidelines for developing a diabetes mellitus comprehensive care plan—2015. Endocr Pract. 2015;21(Suppl 1):1-87.
  6. American Diabetes Association. Standards of medical care in diabetes—2017. Diabetes Care. 2017;40(Suppl 1): S48-56.Scottish Intercollegiate Guidelines Network. Management of Diabetes: A National Clinical Guideline. SIGN Publication no. 116. Edinburgh, Scotland: Scottish Intercollegiate Guidelines Network; 2013. Available at www.sign.ac.uk/guidelines/fulltext/55/index.htm. Accessed  March 5, 2018.
  7. The Management of Type 2 Diabetes Mellitus in Primary Care Work Group. VA/DoD clinical practice guideline for the management of type 2 diabetes mellitus in primary care. Version 5.0. April 2017. Available at www.healthquality.va.gov/guidelines/CD/diabetes/VADoDDMCPGFinal508.pdf  Accessed on March 3, 2018.
  8. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-59.
  9. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-72.
  10. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65.
  11. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53.
  12. Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, et al; VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372:2197-2206.
  13. American Diabetes Association. Press release. American Diabetes Association Deeply Concerned About New Guidance from American College of Physicians Regarding Blood Glucose Targets for People with Type 2 Diabetes. March 8, 2018. Available at: http://www.diabetes.org/newsroom/press-releases/2018/ada-acp-guidance-response.html. Accessed March 8, 2018.
  14. The American Association of Clinical Endocrinologists, the American Diabetes Association®, the American Association of Diabetes Educators and the Endocrine Society Strongly Disagree with the American College of Physicians’ Guidance for Higher Blood Glucose Targets for People with Type 2 Diabetes. Press release. March 9,  2018. Available at: http://media.aace.com/press-release/american-association-clinical-endocrinologists-american-diabetes-association-american-. Accessed March 9, 2018.

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