ACP supports higher HbA1c targets for pharmacotherapy in adults with T2D

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The ACP believes that informed shared decision-making is critical, and patients should be included in the discussion of HbA1c target levels.
The ACP believes that informed shared decision-making is critical, and patients should be included in the discussion of HbA1c target levels.

The new guidance from the American College of Physicians (ACP) supporting higher glycated hemoglobin (HbA1c) targets for pharmacotherapy in adults with type 2 diabetes (T2D), published in the Annals of Internal Medicine, has been the target of criticism from several diabetes organizations.1 Together, the American Diabetes Association (ADA), the Endocrine Society, the American Association for Clinical Endocrinologists (AACE), and the American Association of Diabetes Educators (AADE) issued a statement strongly disagreeing with the proposed new guidance.2,3 While all the organizations agree on the need to individualize treatment based on patient-specific factors, the 4 diabetes organizations disagree with the ACP's recommendation that clinicians should aim to achieve a hemoglobin A1c (HbA1c) level between 7% and 8%.

Endocrinology Advisor consulted the ACP regarding this issue. The interview was conducted by email exchange and compiled for this article.

Endocrinology Advisor: What is your response to the concern that a higher HbA1c target range (between 7% and 8%) could prevent many people with T2D from receiving the full benefits of long-term glucose control?

ACP: Clinical trials show that achieving an HbA1c between 7% and 8% will best balance long-term benefits with harms such as low blood sugar, other medication-related adverse effects, medication burden, and costs.

The rationale in the guidelines that recommended lower treatment targets (<7% or <6.5%) is that more intensive blood sugar control would reduce microvascular complications over many years of treatment. However, the evidence for reduction is inconsistent, and reductions were seen only in surrogate microvascular measures such as the presence of excess proteins in the urine.4-11

The ACCORD trial, which targeted an HbA1c <6.5% and achieved the lowest target HbA1c level of the included studies (6.4%), was discontinued early because of increased overall death, cardiovascular mortality, and severe low blood sugar events.6

The ADVANCE study also failed to find a statistically significant clinical benefit and had more adverse effects with an achieved median HbA1c of 6.4% vs 7.0%.8 In addition, more intensive treatment to achieve a lower target is more costly and associated with increased patient burden.

Endocrinology Advisor: How would you justify the higher HbA1c range given the increased risk of serious complications such as cardiovascular disease, retinopathy, amputation, and kidney disease, which can occur as the result of higher HbA1c levels?

ACP: Treatment to lower HbA1c ranges than recommended by the ACP did not decrease the risk of the serious complications you describe. In fact, the achieved HbA1c levels for intensive treatment in the 2 trials (UKPDS 33 and 34)10,11 widely cited for showing small benefits among younger individuals with newly diagnosed diabetes were 7% or greater and thus provide additional strong justification for the ACP guidance statements.

We analyzed the evidence supporting current recommendations from various organizations and found that when treating T2D with drugs, intensive blood sugar control targeting an HbA1c of ≤7% did not reduce deaths or macrovascular complications such as heart attack or stroke compared to targets of around 8%.5-6,8,10-11 Clinical trials also showed that achieving lower HbA1c targets did not lead to substantial reductions in clinical microvascular events such as visual impairment, painful neuropathy, or need for renal replacement therapy.4-11 In addition, intensive treatment targeting an HbA1c of <7% resulted in harms, especially low blood sugar.

Endocrinology Advisor: Are there cases where more stringent targets may be more appropriate?

ACP: Most of the guidelines that we evaluated noted that a target in the lower end of the range (7%) applied best to patients with newly diagnosed diabetes and those without substantial diabetes-related complications. The rationale for this is based on the UKPDS 33 trial.11 This trial showed that treatment to a target of about 7% with a sulfonylurea and insulin if needed in adults with newly diagnosed diabetes did not reduce the risk of any diabetes-related end point or all-cause mortality after 10 years but was associated with a small absolute reduction in these outcomes after 17 years of follow-up.4 A sub-study (UKPDS 34) also showed a modest reduction in diabetes-related end points and all-cause mortality with metformin treatment in overweight or obese adults (median  HbA1c achieved was 7.4%).10

Endocrinology Advisor: Would you comment on the concern over the missing consideration of the positive impact of several newer medication classes (sodium-glucose cotransporter-2 [SGLT2] inhibitors, dipeptidyl peptidase-4 [DPP-4] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) that are associated with low risk for hypoglycemia, favorable effects on weight, and improved cardiovascular disease outcomes?

ACP: Our guidance statements were based on studies and corresponding guideline information specifically addressing HbA1c targets. The drugs you mentioned were not used in the studies evaluating intensive vs less-intensive treatment targets and were not included by any of the guideline groups (including the ADA, AACE, and AADE) in their recommendation statements related to HbA1c targets. We previously addressed and compared various drug treatments for T2D in "Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus,”12 though data on several of these newer drugs were not yet available.

Current evidence shows that metformin is still the best first-line medication to treat patients with T2D even though there are many new promising treatments, such as DPP-4 inhibitors and SGLT2 inhibitors, in the market. This might change with time as many trials are underway. At this time, however, the newer medications are expensive and have not shown better efficacy than metformin, especially as first-line therapy. While they may have modest favorable effects on weight and hypoglycemia, they do have other harms, and we currently do not have any long-term safety data. If they are to be prescribed, it will be because physicians and patients believe these drugs provide a possible benefit on cardiovascular outcomes as "add-on medications" in patients with diabetes at high risk for cardiovascular disease, rather than their role in getting HbA1c to lower-than-recommended values.

Endocrinology Advisor: Would you like to add any concluding remarks regarding this debate?

ACP: Although our guidance statement focuses on drug therapy to control blood sugar, a lower treatment target is appropriate if it can be achieved with diet and lifestyle modifications such as exercise, dietary changes, and weight loss.

We firmly believe that informed shared decision-making is critical, and patients should be included in the discussion of HbA1c target levels. The goal should be personalized based on a discussion of benefits and harms of drug therapy, patients' preferences, patients' general health, treatment burden, and costs of care. 

References

  1. Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA; for the Clinical Guidelines Committee of the American College of Physicians. 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 [published online March 6, 2018]. Ann Intern Med. doi: 10.7326/M17-0939
  2. The American Diabetes Association®, the American Association of Clinical Endocrinologists, 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]. Arlington, VA: American Diabetes Association. Published March 9, 2018. Accessed March 17, 2018.
  3. American Diabetes Association® deeply concerned about new guidance from American College of Physicians regarding blood glucose targets for people with type 2 diabetes [press release]. Arlington, VA: American Diabetes Association. Published March 8, 2018. Accessed March 17, 2018.
  4. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589.
  5. Hayward RA, Reaven PD, Wiitala, et al; for the VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372:2197-2206.
  6. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.
  7. The ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364:818-828.
  8. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
  9. Duckworth W, Abraira C, Moritz T, et al; for the VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.
  10. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.
  11. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
  12. Qaseem A, Barry MJ, Humphrey LL, Forciea MA; for the Clinical Guidelines Committee of the American College of Physicians. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166:279-290.
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