Annals of Internal Medicine | 2019
To What Target Hemoglobin A1c Level Would You Treat This Patient With Type 2 Diabetes?
Abstract
About Beyond the Guidelines Beyond the Guidelines is a multimedia feature based on selected clinical conferences at Beth Israel Deaconess Medical Center (BIDMC). Each educational feature focuses on the care of a patient who falls between the cracks in available evidence and for whom the optimal clinical management is unclear. Such situations include those in which a guideline finds evidence insufficient to make a recommendation, a patient does not fit criteria mapped out in recommendations, or different organizations provide conflicting recommendations. Clinical experts provide opinions and comment on how they would approach the patient s care. Videos of the patient and conference, the slide presentation, and a CME/ MOC activity accompany each article. For more information, visit www.annals.org/GrandRounds. Series Editor, Annals: Deborah Cotton, MD, MPH Series Editor, BIDMC: Risa B. Burns, MD, MPH Series Assistant Editors: Eileen E. Reynolds, MD; Gerald W. Smetana, MD; Anjala Tess, MD, Howard Libman, MD This article is based on the Grand Rounds conference held on 13 April 2019 at ACP Internal Medicine Meeting 2019 in Philadelphia. Ms. K is a 60-year-old woman with type 2 diabetes (T2D). Her diabetes was first diagnosed 20 years ago on the basis of a hemoglobin A1c (HbA1c) screening. Since then, she lost 100 pounds (45.4 kg) of body weight from her peak weight of 300 pounds (136.1 kg). She has been reluctant to begin using any injectable medication for diabetes. She has had no micro- or macrovascular complications to date. Her HbA1c level was as high as 9.5% around the time of diagnosis. Values during the past 5 years have ranged from 7.4% to 8.2%, with the most recent being 7.8%. Ms. K understands her HbA1c goal to be less than 7%. The patient s medical history includes obesity, elevated cholesterol levels, hypertension, reactive airways, and uterine fibroids. She works as a hospital unit coordinator. She is an avid walker. Her medications are aspirin, amlodipine, atorvastatin, canagliflozin, glipizide, hydrochlorothiazide, metformin, trandolapril, vitamin C, calcium carbonate, and vitamin D. On physical examination, her weight is 226 pounds (102.5 kg) and her body mass index is 36.5 kg/m2. Her blood pressure is 122/80 mm Hg. She has mild lower-extremity edema. The remainder of her physical examination is normal. Ms. K s Story My paternal grandmother became blind and lost a leg due to diabetes. I had an aunt on my mother s side who had kidney problems; she was on dialysis 3 times a week. I was first diagnosed in the late 1990s at an annual checkup. I didn t have any of the classic symptoms of the excessive thirst, the excessive urinationnone of it. And I think for a long time, that made me think that I didn t have diabetes. The first thing was I don t want to take the needle. I was like, okay, what options do I have? How bad do I have it? I had a wicked sweet tooth. I love to eat. I love to bake. I love to eat what I bake. I am not going to eat a half a cup of rice, okay? I had no knowledge that there were oral medications that could be effective for diabetes, so that was like, Oh, wow, this is great. I can do this. The HbA1c is a number that is a measurement of the average of the highs and lows of the glucose levels in my body. I can t remember the highest I ve ever been, probably in the 8s. I think my most recent HbA1c was 7.7% or 7.6%. The goal is to be under 7%, so that I don t have to hear my doctor tell me that it should be, you know, below 7%. I m not sure where my fear of needles comes from. For me to take the needle, it was like, maybe you didn t try hard enough, or maybe you should have done this or should have done that. I would have felt like I had failed. I don t want to look at it from the perspective of, well I have gotten away with it for this long, so where is the proof that if I reach 7% that everything in my life is going to be better? I am hoping not to have a similar end as some of my family members on either side of my family in terms of amputations or dialysis. See the Patient Video to view the patient telling her story. Context, Evidence, and Guidelines Rates of T2D in the United States continue to be high, in large part because of the obesity epidemic. Currently, 9.4% of all adultsand 25% of those older than 65 yearshave diabetes (1). Diabetes is the seventh leading cause of death and the leading cause of end-stage renal disease and blindness in the United States. Measurement of HbA1c concentration provides an estimate of the mean blood glucose level during the previous 2 to 3 months. Controversy exists regarding the optimal HbA1c target to reduce diabetic micro- and macrovascular complications while minimizing the morbidity of treatment. In this context, in 2018 the American College of Physicians (ACP) published a guidance statement on HbA1c targets for glycemic control in patients with T2D (2). The statement was based on a systematic review of existing guidelines, as well as the randomized controlled trials that were the primary sources informing those recommendations. For its review, the ACP included guidelines from the National Institute for Health and Care Excellence (NICE) (3), Institute for Clinical Systems Improvement (4), American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) (5), American Diabetes Association (ADA) (6), Scottish Intercollegiate Guidelines Network (7), and U.S. Department of Veterans Affairs and U.S. Department of Defense (8). The principal randomized trials of intensive versus less intensive HbA1c target levels were ACCORD (Action to Control Cardiovascular Risk in Diabetes) (9), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) (10), UKPDS (United Kingdom Prospective Diabetes Study) (10, 11), and VADT (Veterans Affairs Diabetes Trial) (12). Table 1 summarizes the key findings from these studies (911) and includes data from the initial study reports, as discussed in the ACP guideline, and from subsequent extended follow-up reports. The principal results initially reported from 3 of the trials showed no difference in cardiovascular mortality between patients in the intensive therapy group and those who received standard care. In ACCORD, a statistically significant increase in cardiovascular mortality was seen in the intensive HbA1c target group (hazard ratio, 1.35 [95% CI, 1.04 to 1.76]). Likewise, the only statistically significant difference in all-cause mortality among the 4 trials was observed among patients in the intensive therapy group in the ACCORD trial (hazard ratio, 1.22 [CI, 1.01 to 1.46]). All but 1 of the trials (VADT) reported significant reductions in microvascular outcomes among patients assigned to intensive HbA1c goals (Table 1). Table 1. Principal Results of 4 Major Studies of the Benefit of Lower HbA1c Targets in T2D* Table 2 summarizes the recommended HbA1c target levels for the 6 included guidelines as well as the ACP statement. Recommended HbA1c target levels for many or most patients range from 6.5% (AACE/ACE and NICE) to 7% to 8% (ACP). The ADA recommends a target of less than 7% for many patients, and 6.5% if it can be achieved safely without hypoglycemia. Most of the guidelines recommend a higher HbA1c target level for patients with comorbid conditions, a shortened expected lifespan, or a history of severe hypoglycemia. The ACP guideline notes that lower HbA1c target levels confer only a small cardiovascular and mortality benefit through at least 10 years of follow-up and that harms, including hypoglycemia, may outweigh any benefit of the lower target. Each set of guidelines also includes additional scenarios in which a higher HbA1c target is appropriate. Table 2. Guidelines for Target HbA1c Levels in T2D The 2018 ACP guideline forms the primary basis for our discussion here. After reviewing 6 guidelines and the randomized controlled trials on which they are based, the ACP made 4 recommendations (Table 3). Table 3. ACP Recommendations for HbA1c Targets in Nonpregnant Adults With T2D In 2019, the Endocrine Society published guidelines on managing T2D in older adults (13). For patients who require pharmacologic therapy, the Endocrine Society advises using metformin as initial therapy, avoiding sulfonylureas and glinides, and using insulin sparingly. It also recommends individualization of HbA1c goals based on the patient s overall health and risk for hypoglycemia. Clinical Questions To structure a debate between our 2 discussants, we mutually agreed on the following key questions to consider when applying this guideline to clinical practice and to Ms. K in particular: 1. What are the risks and benefits of aiming for tight glucose control in patients with T2D? 2. To what target HbA1c level should we treat patients with T2D, and how should we achieve this goal? 3. When is it appropriate to deintensify HbA1c goals and allow higher blood sugar levels in patients with T2D? Discussion A Diabetologist s Viewpoint (Dr. David M. Nathan) Question 1: What are the risks and benefits of aiming for tight glucose control in patients with T2D? After the discovery of insulin, the most clinically significant advance in the management of diabetes in the 20th century was the identification of methods to reduce its long-term complications. These complications have plagued Ms. K s family members. Epidemiologic and clinical trial data from the DCCT (Diabetes Control and Complications Trial) (14) and UKPDS (11) for type 1 diabetes (T1D) and T2D, respectively, have proven the causal role of glycemia in the pathogenesis of these complications. The benefits of tight or intensive glycemic control on microvascular complications are incontrovertible (Table 1). Both the DCCT and UKPDS have shown a continuum of risk for complications with HbA1c levels between approximately 5.5% and 12% (Figure) (15, 16). Beyond the benefits of tight control for diabetes-specifi