NEW HBA1c LIMIT FOR DIABETICS

In new guidance, the American College of Physicians (ACP) recommends a target HbA_1c of 7% to 8% for most nonpregnant adults with type 2 diabetes.

"ACP's analysis of the evidence behind existing guidelines found that treatment with drugs to targets of 7% or less, compared with targets of about 8%, did not reduce deaths or macrovascular complications, such as heart attack or stroke, but did result in substantial harms,” said Jack Ende, MD, ACP president, in a statement.

"For most people with type 2 diabetes, achieving an HbA_1c between 7% and 8% will best balance long-term benefits with harms such as low blood sugar, medication burden, and costs,” he added.

But experts from the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) contacted by Medscape Medical News take issue with these higher glycemic control targets, which they argue don't consider, for example, the cardiovascular disease (CVD) benefits of newer therapies which often lower HbA_1c levels.

The new ACP guidance could therefore cause confusion for internists and primary care physicians, who may not know whether to follow the new guidance or stick with the advice from the ADA and AACE.  

But Timothy J Wilt, MD, MPH, who coauthored the ACP statement, noted, "Importantly, HbA_1c target recommendations from other guideline groups also did not include information about these newer drugs which have been mainly studied in higher risk [those with, or at high risk of, CVD] individuals."

"ACP's guidance statement reviewed evidence and guideline recommendations related to HbA_1c treatment targets and did not specifically address newer diabetes drugs that may have benefits and harms beyond the specific HbA1c target or lowering effect," he added.  

The new ACP guidance was published online March 5 in the Annals of Internal Medicine.

One issue all the societies agree on is that type 2 diabetes treatment should be individualized, but William T Cefalu, MD, chief scientific, medical and mission officer, ADA, said all clinicians caring for people with diabetes should rely on the same patient factors, "and so HbA_1c targets should not vary between types of clinicians or clinical settings."

Yehuda Handelsman, MD, Metabolic Institute of America, Tarzana, California, chair of the diabetes scientific committee and 2012 & 2015 comprehensive diabetes guidelines, AACE, was more vocal in his criticism of the ACP's stance, noting that their “new guidance will surely add confusion."

ADA and AACE guidelines are "quite similar as both endorse personalized treatment, focusing on lower HbA_1c goals and recommending newer medications with lower risk of hypoglycemia," he said.

"Hopefully most primary care clinicians will continue to follow the current leading guidelines" — those from the ADA and AACE.

But Wilt responded: "ACP's guidance statement is based on evidence of benefits and harms. We encourage other guideline groups to review our statement, the evidence included, and adopt our statements to enhance consistency and improve the care we provide our patients with type 2 diabetes."

"ACP believes that, given the evidence, most primary care physicians will implement ACP's recommendations and that many patients with type 2 diabetes will be pleased to learn that less intensive care leads to better health outcomes," he stressed.

Guidance Development Process

ACP aimed to develop a guidance statement for HbA_1c targets for adults with type 2 diabetes based on a review of existing guidelines in May 2017.

The authors identified six guidelines from AACE/American College of Endocrinology (ACE); ADA; Scottish Intercollegiate Guidelines Network (SIGN); US Department of Veterans Affairs and Department of Defense (VA/DoD); UK National Institute for Health and Care Excellence (NICE); and Institute for Clinical Systems Improvement (ICSI).

These guidelines analyzed evidence from five large, long-term randomized trials of a "treat-to-target" strategy in type 2 diabetes: Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), United Kingdom Prospective Diabetes Study (UKPDS) trials 33 and 34, and Veterans Affairs Diabetes Trial (VADT).

Recent cardiovascular outcomes studies evaluating newer diabetes drugs such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists were not designed to evaluate treat-to-target strategies, the authors note, so they were not included in the evaluation.

Four Guidance Statements

The ACP guidance includes four statements.

Statement 1: "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."  

"This guidance is consistent with ADA's 2018 Standards of Medical Care,"  Cefalu told Medscape Medical News. "We have long recommended that treatment goals be individualized based on factors ... such as age, life expectancy, duration of disease, resources and support systems, and comorbid conditions."

"This is important, and we are in agreement," Handelsman concurred.

Statement 2: "Clinicians should aim to achieve an HbA_1c level between 7% and 8% in most patients with type 2 diabetes."

This differs from ADA and AACE recommendations. It is most closely aligned with the ICSI guideline, which "highlights that efforts to achieve HbA_1c levels below 7% may increase risk for death, weight gain, hypoglycemia, and other adverse effects in many patients," the ACP authors write. "We share these concerns." Moreover, none of the three trials achieving an HbA_1c level below 7% showed a reduction in all-cause or cardiovascular mortality, they add.  

ADA's response

"The ADA recommends that a reasonable HbA_1c goal for 'many' nonpregnant adults is less than 7% based on evidence available to date," Cefalu said.

It is unlikely that "most patients" with type 2 diabetes have severe hypoglycemia, limited life expectancy, advanced micro- and/or macrovascular complications, extensive comorbid conditions, or long-standing diabetes, so "a reasonable goal remains less than 7%," based on the UKPDS.

Patients in ACCORD, ADVANCE, and VADT (cited in the ACP guidance) were older and sicker than in the UKPDS. The UKPDS, which included patients with newly diagnosed type 2 diabetes with an average age of 54 years, showed the benefits of an HbA_1c less than 7% and a continual reduction in risk for microvascular complications.

"The ADA believes all people diagnosed with type 2 diabetes ... should have the opportunity to reduce their risk of serious diabetes complications through appropriate blood glucose targets," Cefalu stressed.

"Individualization of targets is the key factor, and by lumping 'most' people with type 2 diabetes into a 7–8% target range, ACP's new guidance may cause potential harm to those who may safely benefit from lower evidence-based targets."

AACE's response

"This is absolutely wrong and regressive," Handelsman asserted. "We were quite (terribly) surprised by such gross neglect of data and the evidence."

"It is sad that ... the ACP, has stepped back in time, ignoring all the scientific and pharmaceutical development of the past 10–15 years, displaying a lack of understanding of the available data and resort to this plausible statement, calling their position 'evidence-based guidance' to support their conclusions."

"There is no evidence to support higher goals in the management of the majority of patients with diabetes, while there is overabundance of evidence to show that lower HbA_1c is better."

"The top diabetes experts, nationally and internationally, through the leading medical societies in diabetes — ADA, AACE, EASD, International Diabetes Federation [IDF], and others — all agree that the HbA_1c goal for most patients should be ≤ 6.5% (AACE, IDF) or < 7% (ADA, EASD). Clearly the evidence supports these goals, while the ACP's position is not supported."

ACP Defends Its Position

But Wilt argues: "There is no high quality evidence that achieving an HbA_1c of < 7% improves clinical outcomes, and it leads to harms, medication burden, and costs."

Any benefits, for example, reductions in microvascular complications in the UKPDS and other studies "were small in absolute numbers, required many years to accrue, were not consistently found, and typically were limited to 'laboratory or physiologic' measures, such as protein in the urine, rather than clinical outcomes, such as painful neuropathy, impaired vision, or kidney failure," he added.

"Evidence does not support an HbA_1c of < 6.5%, but rather demonstrates that this leads to no benefit and substantial harms and costs," Wilt said.

"ACP's guidance statement ... demonstrates that a target range of 7–8% for most patients provides an optimal balance of clinical benefits and harms," he reiterated.

Statement 3: "Clinicians should consider de-intensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA_1c levels less than 6.5%."

"Results from studies included in all the guidelines demonstrate that health outcomes are not improved by treating to HbA_1c levels below 6.5%,” Ende said.

ADA's response

"This guidance is different from the ADA's 2018 Standards of Care," noted Cefalu.  

"However, we do recommend de-intensification or simplification of complex regimens to reduce the risk of hypoglycemia in older adults, if this can be achieved within the individualized HbA_1c target. Any de-intensification should be based on these factors, such as the presence of hypoglycemia, and not on a number."

"In 2018, the ADA recommended that patients with existing cardiovascular disease not meeting HbA_1c targets on metformin alone receive a medication proven to reduce risk of CVD death and/or events," he noted.

"It's possible that this add-on therapy may reduce HbA_1c levels to below 6.5% — the ACP guidance would suggest that the add-on therapy be removed, thus increasing the risk of morbidity and mortality."

Higher targets for people with existing CVD may mean that treatment intensification with these potentially life-saving medications isn't considered, Cefalu observed.

AACE's response

"How not smart ... to reduce pharma therapy in patients who are at goal. Once the medication stops, that patient will lose [glycemic] control," Handelsman opined.

"Contemporary management of diabetes is simple, effective, and safe," he said. A common option is to prescribe a once-weekly GLP-1 receptor agonist with a fixed-dose combination of slow-release metformin and an SGLT-2 inhibitor. Such a combination has the potential to reduce HbA_1c by at least 2.5–3% without hypoglycemia and promotes weight loss and blood pressure reduction.

"This type of combination treatment, together with lifestyle, can offer good control (HbA_1c < 7%, even < 6.5%) safely to patients even with high baseline HbA_1c of up to 10%, which represents nearly 80% of all patients with type 2 diabetes."

Other new therapies, like longer-acting and hence more stable insulin, reduce hypoglycemia (compared with older insulins), and drugs from the SGLT-2 inhibitor and GLP-1 receptor agonist families reduce morbidity and mortality in patients with diabetes who have established CVD.

Wilt stressed that the ACP's guidance "did not specifically address newer diabetes drugs that may have benefits and harms beyond the specific HbA _1c  target or lowering effect."

Statement 4: "Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA_1c level 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."

ADA's response

"This guidance is consistent with ADA's end-of-life recommendations; however, the ADA disagrees that this applies broadly to anyone over age 80, anyone living in a nursing home, or anyone with chronic conditions, and who has a limited life expectancy," said Cefalu.

Each specific case should be individually evaluated, as a person in a nursing home or with a chronic condition may have years to live and would likely prefer to live without diabetes complications, he stressed.

"It's important to note that the average life expectancy for an 80-year-old man is more than 8 years, and it's nearly 10 years for a woman the same age. And that's an average — for some individuals, it's even longer."

AACE's response

"For the very sick, those with cancers, short lifespan, etc, rather than using HbA_1c, focusing on just glucose makes more sense," agreed Handelsman.

Keeping glucose between, for example, 100–250 mg/dL (or possibly 80–300 mg/dL) would assure no hypoglycemia nor symptoms of hyperglycemia such as polydipsia or polyuria.   

Handelsman has received research grants, consultant fees, and speaker honoraria from Aegerion, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gan & Lee, Gilead, Grifols, Hamni Pharmaceutical, Intarcia, Janssen, Lexicon, Lilly, Merck, Mylan, Merck-Pfizer, Novo Nordisk, Regeneron, and Sanofi. Ce falu had no financial disclosures as an ADA employee.

Ann Intern Med. Published online March 5, 2018. Article