Amir Qaseem, MD, PhD, MHA; Timothy J. Wilt, MD, MPH; Devan Kansagara, MD, MCR; Carrie Horwitch, MD, MPH; Michael J. Barry, MD; Mary Ann Forciea, MD; for the Clinical Guidelines Committee of the American College of Physicians *
Note: Guidance statements are “guides” only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians' judgment. All ACP guidance statements are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued.
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations.
Acknowledgment: The CGC thanks members of the ACP Guidelines Public Panel for their review and comments on the paper from a nonclinician public perspective: Cynthia Appley, Jane Eleey, Ray Haeme, James Pantelas, Missy Carson Smith, Janice Tufte, and Lelis Vernon.
Financial Support: Financial support for the development of this guidance statement comes exclusively from the ACP operating budget.
Disclosures: Dr. Barry reports grants and personal fees from Healthwise, a nonprofit, outside the submitted work. Authors not named here have disclosed no conflicts of interest. Authors followed the policy regarding conflicts of interest described at www.annals.org/article.aspx?articleid=745942. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-0939. All financial and intellectual disclosures of interest were declared, and potential conflicts were discussed and managed. Dr. Vijan was recused from voting on the recommendations for an active direct financial conflict. Dr. Manaker was recused from voting on the recommendations for an active indirect financial conflict. A record of disclosures of interest and management of conflicts of interest is kept for each CGC meeting and conference call and can be viewed at www.acponline.org/clinical_information/guidelines/guidelines/conflicts_cgc.htm.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106; e-mail, email@example.com.
Current Author Addresses: Dr. Qaseem: 190 N. Independence Mall West, Philadelphia, PA 19106.
Dr. Wilt: VA Medical Center 111-0, Minneapolis, MN 55417.
Dr. Barry: 50 Staniford Street, 9th Floor, Boston, MA 02114.
Dr. Horwitch: 1100 Ninth Avenue C8-GIM, Seattle, WA 98101.
Dr. Kansagara: 3710 SW US Veterans Hospital Road, Portland, OR 97239.
Dr. Forciea: 3615 Chestnut Street, Philadelphia, PA 19104.
Author Contributions: Conception and design: A. Qaseem, T.J. Wilt, D. Kansagara, M.J. Barry, M.A. Forciea.
Analysis and interpretation of the data: A. Qaseem, T.J. Wilt, D. Kansagara, C. Horwitch, M.J. Barry, M.A. Forciea.
Drafting of the article: A. Qaseem, T.J. Wilt, D. Kansagara, C. Horwitch, M.A. Forciea.
Critical revision of the article for important intellectual content: A. Qaseem, T.J. Wilt, D. Kansagara, M.J. Barry, M.A. Forciea.
Final approval of the article: A. Qaseem, T.J. Wilt, D. Kansagara, C. Horwitch, M.J. Barry, M.A. Forciea.
Statistical expertise: A. Qaseem, T.J. Wilt.
Obtaining of funding: A. Qaseem.
Administrative, technical, or logistic support: A. Qaseem.
Collection and assembly of data: A. Qaseem, T.J. Wilt, D. Kansagara, M.J. Barry.
The American College of Physicians developed this guidance statement to guide clinicians in selecting targets for pharmacologic treatment of type 2 diabetes.
The National Guideline Clearinghouse and the Guidelines International Network library were searched (May 2017) for national guidelines, published in English, that addressed hemoglobin A1c (HbA1c) targets for treating type 2 diabetes in nonpregnant outpatient adults. The authors identified guidelines from the National Institute for Health and Care Excellence and the Institute for Clinical Systems Improvement. In addition, 4 commonly used guidelines were reviewed, from the American Association of Clinical Endocrinologists and American College of Endocrinology, the American Diabetes Association, the Scottish Intercollegiate Guidelines Network, and the U.S. Department of Veterans Affairs and Department of Defense. The AGREE II (Appraisal of Guidelines for Research and Evaluation II) instrument was used to evaluate the guidelines.
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.
Clinicians should aim to achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes.
Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%.
Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA1c 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.
Mean AGREE II scores for items in each domain across the 6 reviewers.
Each question was rated on a Likert scale with a minimum of 1 point and a maximum of 7 points. The scores were averaged for each of the 6 reviewers. Error bars represent calculated standard deviation. AACE/ACE = American Association of Clinical Endocrinologists and American College of Endocrinology; ADA = American Diabetes Association; AGREE II = Appraisal of Guidelines for Research and Evaluation II; GDG = guideline development group; ICSI = Institute for Clinical Systems Improvement; NICE = National Institute for Health and Care Excellence; SIGN = Scottish Intercollegiate Guidelines Network; VA/DoD = U.S. Department of Veterans Affairs and Department of Defense.
Appendix Table 1. Scaled AGREE II Domain Scores for Each Guideline and Overall Assessment
Appendix Table 2. Study, Patient, and Outcome Characteristics of Major Type 2 Diabetes Trials Included in the Assessed Guidelines
Appendix Table 2. Continued
Summary of the American College of Physicians guidance statement on HbA1c targets for glycemic control with pharmacologic therapy in nonpregnant adults with type 2 diabetes mellitus.
To arrive at these guidance statements, the authors reviewed guidelines from the National Institute for Health and Care Excellence, the Institute for Clinical Systems Improvement, the American Association of Clinical Endocrinologists and American College of Endocrinology, the American Diabetes Association, the Scottish Intercollegiate Guidelines Network, and the U.S. Department of Veterans Affairs and Department of Defense. HbA1c = hemoglobin A1c.
Glucose targets should be individualized and take into account life expectancy, disease duration, presence or absence of micro- and macrovascular complications, CVD [cardiovascular disease] risk factors, comorbid conditions, and risk for hypoglycemia, as well as the patient's psychological status (Grade A; BEL [best evidence level] 1). In general, the goal of therapy should be an A1C level ≤6.5% for most nonpregnant adults, if it can be achieved safely … (Grade D; BEL 4). …
In adults with recent onset of T2D [type 2 diabetes] and no clinically significant CVD, glycemic control aimed at normal (or near-normal) glycemia should be considered, with the aim of preventing the development of micro- and macrovascular complications over a lifetime, if it can be achieved without substantial hypoglycemia or other unacceptable adverse consequences (Grade A; BEL 1). … A less stringent glucose goal should be considered (A1C 7 to 8%) in patients with history of severe hypoglycemia, limited life expectancy, advanced renal disease or macrovascular complications, extensive comorbid conditions, or long-standing DM [diabetes mellitus] in which the A1C goal has been difficult to attain despite intensive efforts, so long as the patient remains free of polydipsia, polyuria, polyphagia, and other hyperglycemia-associated symptoms (Grade A; BEL 1). (9)
A reasonable A1C goal for many nonpregnant adults is <7% (53 mmol/mol). ([Grade] A)
Providers might reasonably suggest more stringent A1C goals (such as <6.5% [48 mmol/mol]) for selected individual patients if this can be achieved without significant hypoglycemia or other adverse effects of treatment (i.e., polypharmacy). Appropriate patients might include those with short duration of diabetes, type 2 diabetes treated with lifestyle or metformin only, long life expectancy, or no significant cardiovascular disease. ([Grade] C)
Less stringent A1C goals (such as <8% [64 mmol/mol]) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in whom the goal is difficult to achieve despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. ([Grade] B). (10)
A clinician should personalize goals with patients diagnosed with T2DM [type 2 diabetes mellitus] to achieve glycemic control with a hemoglobin A1c < 7% to < 8% depending on individual patient factors [strong recommendation, high-quality evidence]. (8)
Involve adults with type 2 diabetes in decisions about their individual HbA1c target. Encourage them to achieve the target and maintain it unless any resulting adverse effects (including hypoglycaemia), or their efforts to achieve their target, impair their quality of life. …
For adults with type 2 diabetes managed either by lifestyle and diet, or by lifestyle and diet combined with a single drug not associated with hypoglycaemia, support the person to aim for an HbA1c level of 48 mmol/mol (6.5%). For adults on a drug associated with hypoglycaemia, support the person to aim for an HbA1c level of 53 mmol/mol (7.0%). …
In adults with type 2 diabetes, if HbA1c levels are not adequately controlled by a single drug and rise to 58 mmol/mol (7.5%) or higher:
• reinforce advice about diet, lifestyle and adherence to drug treatment and
• support the person to aim for an HbA1c level of 53 mmol/mol (7.0%) and
• intensify drug treatment. …
Consider relaxing the target HbA1c level … on a case-by-case basis, with particular consideration for people who are older or frail, for adults with type 2 diabetes:
• who are unlikely to achieve longer-term risk-reduction benefits, for example, people with a reduced life expectancy
• for whom tight blood glucose control poses a high risk of the consequences of hypoglycaemia, for example, people who are at risk of falling, people who have impaired awareness of hypoglycaemia, and people who drive or operate machinery as part of their job
• for whom intensive management would not be appropriate, for example, people with significant comorbidities. (7)
An HbA1c target of 7.0% (53 mmol/mol) among people with type 2 diabetes is reasonable to reduce risk of microvascular disease and macrovascular disease. A target of 6.5% (48 mmol/mol) may be appropriate at diagnosis. Targets should be set for individuals in order to balance benefits with harms, in particular hypoglycemia and weight gain (Grade A). (11)
We recommend setting an HbA1c target range based on absolute risk reduction of significant microvascular complications, life expectancy, patient preferences and social determinants of health. [Strong recommendation]
We recommend developing an individualized glycemic management plan, based on the provider's appraisal of the risk-benefit ratio and patient preferences. [Strong recommendation]
We recommend assessing patient characteristics such as race, ethnicity, chronic kidney disease, and non-glycemic factors (e.g., laboratory methodology and assay variability) when interpreting HbA1c, fructosamine and other glycemic biomarker results. [Strong recommendation]
We recommend an individualized target range for HbA1c taking into account individual preferences, presence or absence of microvascular complications, and presence or severity of comorbid conditions. [Strong recommendation]
We suggest a target HbA1c range of 6.0-7.0% for patients with a life expectancy greater than 10-15 years and absent or mild microvascular complications, if it can be safely achieved. [Weak recommendation]
We recommend that in patients with type 2 diabetes, a range of HbA1c 7.0-8.5% is appropriate for most individuals with established microvascular or macrovascular disease, comorbid conditions, or 5-10 years life expectancy, if it can be safely achieved. [Strong recommendation]
We suggest a target HbA1c range of 8.0-9.0% for patients with type 2 diabetes with life expectancy <5 years, significant comorbid conditions, advanced complications of diabetes, or difficulties in self-management attributable to e.g., mental status, disability or other factors such as food insecurity and insufficient social support. [Weak recommendation]
We suggest that providers be aware that HbA1c variability is a risk factor for microvascular and macrovascular outcomes. [Weak recommendation] (12)
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Derek T O’Keeffe, Spyridoula Maraka
National University of Ireland Galway, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System
March 13, 2018
Finding the Sweet Spot in Diabetes Management
To the Editor The recent ACP guidelines (1) examined the evidence behind the diabetes recommendations of other organisations (2-5). They concluded that drug treatment to HbA1c <8% produced the same clinically significant endpoints (e.g. heart attacks, vision impairment) as treatment to <7%, but with a reduced risk of hypoglyemic harm, medication burden and associated costs.This highlights a more complex issue in medicine with regards to how a disease is defined and treated. Physiology has taught us about the exquisite mechanism of homeostasis, whereby parameters (e.g. sodium) have a normal range and deviations cause morbidity and even mortality at extremes. Therefore, rising glucose levels above the reference range is non-physiological and ultimately harmful to the body. The practical question however, is at which point you diagnose the disease and what the treatment target range should be. As clinicians we are constantly trying to balance risk versus benefit in the best interests of our patients.To date HbA1c<7% has been the general diabetes treatment target, as that is where evidence of early harm starts to occur (e.g. microalbumineria). However, these controversial ACP guidelines do not put as much weight on early microvascular damage but instead highlight the familiar U-shaped harm curve associatied with diabetes treatment where clinicians titrate medications for the optimum “sweet spot” between hypo/hyper-glycaemia. This is similar to hypertension management where overtreatment can cause iatrogenic harm versus undertreatment which can cause pathological outcomes.Certain diabetes medications (e.g. sulfonylureas) can certainly cause hypoglycaemia if clinicans are over zealous to achieve a tight target in some patients. However, in addition to metformin, we now have medications such as GLP1-agonists and SGLT2-inhibitors which can achieve reductions in HbA1c without hypoglycemia and favourable CVD outcomes, though with increased medication cost. Therefore, each patient requires an individualised approach to achieve the lowest possible HbA1c with the least amount of hypoglycaemia and medication burden. This is the art of medicine, taking the scientific evidence and balancing it with the unique person who has come to you for help. Indeed, the one thing all of the guidelines agree on is that we should strive for patient centred care and personalise our treatments to each specific presentation.References:1. Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA. 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. Annals of Internal Medicine. 2018.2. American Diabetes Association. Standards of medical care in diabetes—2017.Diabetes Care2017;40:S48-563. Handelsman Y, Bloomgarden ZT Grunberger G, Umpierrez G, Zimmerman RS ,Bailey TS 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 Pract2015;21:1-874. Scottish Intercollegiate Guidelines Network. Management of Diabetes: A National Clinical Guideline. SIGN Publication no. 116. Edinburgh, Scotland: Scottish Intercollegiate Guidelines Network; 2013.5. 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.Conflict of Interest: None
Deep Dutta, Satinath Mukhopadhyay
IPGMER & SSKM Hospital, Calcutta India
March 12, 2018
Deciphering glycemic targets in diabetes: A south Asian perspective
Dear EditorWe read with interest the recent guidance statement from American College of Physicians suggesting a more lenient glycemic target of 7-8% among patients with diabetes (1). The authors do present a valid point on lack of adequate strong scientific data suggesting significant improvement in microvascular and macrovascular complications by achieving HbA1c targets of <6.5% as compared to 7-8%. It is well known that a more stringent HbA1c target is associated with higher risks of hypoglycemia and cardiovascular events as has been documented in ACCORD and VADT trials, where the mean of patients was more than 55 years, having multiple co-morbidities with a significant diabetes duration.In India, the phenotype of diabetes is drastically different from the west. With a population of 1.3 billion, 9-10% diabetes prevalence, 10-15% prediabetes prevalence, highest global rates of prediabetes progression to diabetes (18% per annum), diabetes onset nearly 2 decades earlier than the west, all points to a more aggressive type-2 diabetes (T2DM) phenotype (2). It is not unusual to see patients with T2DM in their 20s and 30s in India. For such individuals, with recent onset T2DM without any co-morbidities and with half a century of life expectance ahead (based on current national averages), It would perhaps be better to strive for a more stringent glycemic control and HbA1c targets of <6.5%. In this scenario, the statement of “Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%” would not be appropriate in young patients with diabetes without co-morbidities who do not have hypoglycemia. Medications with low risk of hypoglycemia like metformin, DPP4 inhibitors and/or SGLT2i can safely achieve HbA1c targets <6.5%. We must realize that glycemic control and risk of end organ damage is a continuum. There is enough data to suggest occurrence of microvascular and macrovascular complications even in the prediabetes state (3-5). The very fact that glycemic targets in pregnancy continue to be HbA1c<6% highlights that lower the HbA1c, the better, the key being not to cause iatrogenic hypoglycemia and glycemic variability. Hence individualization remains the key with regards to glycemic targets in diabetes.Reference:1) Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA. 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. Ann Intern Med. 2018 Mar 6. doi: 10.7326/M17-0939.2) Dutta D, Mukhopadhyay S. Intervening at prediabetes stage is critical to controlling the diabetes epidemic among Asian Indians. Indian J Med Res. 2016;143:401-4. 3) Dutta D, Choudhuri S, Mondal SA, Mukherjee S, Chowdhury S. Urinary albumin : creatinine ratio predicts prediabetes progression to diabetes and reversal to normoglycemia: role of associated insulin resistance, inflammatory cytokines and low vitamin D. J Diabetes. 2014 Jul;6(4):316-22.4) Sörensen BM, Houben AJ, Berendschot TT, Schouten JS, Kroon AA, van der Kallen CJ, Henry RM, Koster A, Sep SJ, Dagnelie PC, Schaper NC, Schram MT, Stehouwer CD. Prediabetes and Type 2 Diabetes Are Associated With Generalized Microvascular Dysfunction: The Maastricht Study. Circulation. 2016 Nov 1;134(18):1339-1352. 5) Wilson ML. Prediabetes: Beyond the Borderline. Nurs Clin North Am. 2017;52:665-677.
March 15, 2018
I believe the evidence regarding diabetic women of childbearing age and glycemic control is clear and without dispute: HgA1c above 6.5 is associated with adverse pregnancy outcome ( increased miscarriage and increased birth defect rates). I have serious concerns that the new ACP recommendations regarding glycemic control will result in women of childbearing age more frequently presenting with a HgA1C close to 8 and resulting in markedly increased adverse pregnancy outcomes. I encourage the ACP to clarify that in this group of patients their HgA1C should be maintained as close to normal as possible.
Joel Zonszein, Michael Brownlee
Montefiore Medical Center and Albert Einstein College of Medicine
March 19, 2018
Conflict of Interest:
Joel Zonszein declares relationship with Novo nordisk, Merck, Behringer Ingelheim
Several of the recent ACP guidelines (1) are scientifically inaccurate and clinically misleading. While we agree with goals that clinicians should individualize treatment for certain patients with Type 2 diabetes (T2D) and aim to minimize hypoglycemia, —statement 2, recommending changing the HbA1c goal from <7.0 to between 7% and 8% is based on seriously flawed analyses of the available data. Statements 3 and 4 recommending to de-intensify treatment if a patient achieves an HbA1c level <6.5%, and avoid HbA1c targets in the elderly and patients with cardiovascular disease, fails to consider that several newer medication classes with lower risk of hypoglycemia may improve morbidity and mortality in high risk T2D. In the US, the half of individuals with T2D who don’t meet glycemic control goals (2) certainly don’t need de-intensifying treatment.
Guidance Statement 2 is based on flawed analyses of available data. It relies excessively on the original ACCORD study analysis. This recommendation was based on ACCORD, ADVANCE, VADT and UKPDS analysis, which failed account for differences in the patient populations, interventions, and goals. Of their five trials, only the archaic UKPDS was designed for disease prevention, and even when the majority did not sustain HbA1c <7%, microvasculopathy improved and fewer CV complications occurred a decade later. The legacy effect data showing that early intensive blood glucose control has long-term benefits was neglected by the authors. Neither the subsequent ACCORD analysis by Riddle nor the ACCORD-EYE study were included, studies that demonstrated increased mortality in those who failed to achieve lower HbA1c, and slower progression of retinopathy in those with lower HbA1c. We also cannot ignore information gathered from 26 large cardiovascular outcome trials (CVOT), done in >190,000 participants (3).
The authors also failed to consider that several newer medication classes have lower risk of hypoglycemia and improve cardiovascular morbidity and mortality in high risk patients with T2D. Stringent HbA1c is associated with hypoglycemia when hypoglycemic agents are used. Metformin alone or in combination with either sodium–glucose cotransporter-2 inhibitors (SGLT-2i) or glucagon-like peptide-1 (GLP-1)–receptor agonists or pioglitazone is effective in achieving HbA1c <6.5% without meaningful hypoglycemia. Glycemic control and hyperglycemic organ damage is a continuum, and de-intensifying medications is the wrong response to hypoglycemia caused by inappropriate medication classes. We don’t need fewer medications, we need the right medications.
1. Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA. 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. Annals of Internal Medicine. 2018.
2. Ali MK, Bullard KM, Gregg EW. Achievement of goals in U.S. Diabetes Care, 1999-2010. N Engl J Med. 2013 Jul 18;369(3):287-8. doi: 10.1056/NEJMc1306652. PMID: 23863067
3. Cefalu WT, Kaul S, Gerstein HC, Holman RR, Zinman B, Skyler JS, Green JB, Buse JB, Inzucchi SE, Leiter LA, Raz I, Rosenstock J, Riddle MC. Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors' Expert Forum. Diabetes Care. 2018 Jan;41(1):14-31. doi: 10.2337/dci17-0057.
Abraham Edgar Gracia-Ramos
Department of Internal Medicine, Specialities Hospital, National Medical Center "La Raza, Instituto Mexicano del Seguro Social
May 29, 2018
Prevention of complications in type 2 diabetes: Beyond of glycemic control
Dear Editor:Many clinical guidelines from professional organizations recommend the tight glycemic control (HbA1c therapeutic goal <6.5 or 7%) in patients with type 2 diabetes because it is considered essential to prevent chronic complications. However, the recent clinical guideline about this issue published in this journal, suggests a therapeutic goal of HbA1c level between 7% - 8% in most patients with type 2 diabetes (1). The recommendation is derived from the results of the 4 main clinical trials (ACCORD, ADVANCE, UKPDS and VADT trials) that investigated intensive versus less intensive treatment target strategies and in which the benefit of strict control is inconsistent. This proposal has led to many criticisms against this recommendation. However, the individual analysis performed is consistent with combined reviews presented in meta-analysis. For example, in 2 meta-analysis carried out by Victor Montori et al. (2,3), that included the evidence of the last 2 decades, they did not report a significant impact of tight glycemic control on the risk of dyalisis/transplantation/renal death, blindness, or neuropathy, and, with regard to macrovascular complications, the tight glycemic control reduced the risk of nonfatal myocardial infarction (MI) by 15%, although, this reduction was not associated with a concomitant reduction of the risk of cardiovascular death. Despite all this weight of evidence, it is possible that the consensus in favor of tight glycemic control be a consequence of the benefits observed in the microalbuminuria and retinal photocoagulation, but this should be taken with caution, since they are surrogate markers and they do not always correlate with clinical end points (for example, niacin causes increase of HDL cholesterol but does not impact the cardiovascular clinical end points )(4).In conclusion, despite the overwhelming consensus in favor of strict glycemic control, the evidence about the benefit of this strategy is inconsistent, which is why the recommendation of the ACP´s current guideline seems adequate. In addition, the lack of evidence to support strict glycemic control should make us reflect and perhaps we should remove the value of glucose as the central goal of treatment, and also think that the proper management of type 2 diabetes requires the control of several objetives beyond glycemic control for an effective prevention of complications (for example: adequate control of hypertension, correct use of statins according to the cardiovascular risk and so forth).1.Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA. 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. Ann Intern Med 2018;168(8):569-576.2. Montori VM, Fernandez-Balsells M. Glycemic control in type 2 diabetes: time for an evidence-based about face? Ann Intern Med 2009;150(11):803-8.3. Rodriguez-Gutierrez R, Montori VM. Glycemic control for patients with type 2 diabetes mellitus: Our evolving faith in the face of evidence. Circ Cardiovasc Qual Outcomes 2016;9(5):504-12.4. Verdola M, Schaffer A, Suryapranata H, De Luca G. Effects of HDL-modifiers on cardiovascular outcomes: a meta-analysis of randomized trials. Nutr Metab Cardiovasc Dis 2015;25(1):9-23.
Timothy J. Wilt, MD, MPH, Michael Barry, MD, Devan Kansagara, MD, Amir Qaseem MD, PhD
American College of Physicians
June 20, 2018
We agree with Drs. O’Keefe, Maraka, Dutta, and Mukhopadhyay regarding the importance of balancing benefits, harms, cost, and patient-centeredness to achieve appropriate hemoglobin A1c (HbA1c) levels in individual patients. Our guidance statement emphasizes a personalized approach for HbA1c targets (1). While patients with long life expectancies are at greater risk for diabetes complications, intensive pharmacologic treatment targets would also require decades to yield benefits. The life-time balance of benefits to harms, costs, and burden of pharmacologic treatment targets <6.5% in young individuals with newly diagnosed diabetes is not known and research is needed. Encouraging a healthy lifestyle (tobacco cessation and exercise) and dietary modifications to achieve normal glycemic levels is indicated.Dr. Walton recommends pharmacologic treatment to “near normal” HbA1c levels in all women of child bearing age due to potential future adverse pregnancy outcomes with higher HbA1c. We do not disagree that higher HbA1c levels are associated with adverse pregnancy outcomes. However, our guidance statement applies to nonpregnant adults. Studies did not assess future pregnancy outcomes of pharmacologic HbA1c targets in nonpregnant women.All authors state that newer drugs should lead to treatment HbA1c targets of <7% in most patients. We disagree. No treat-to-target studies included these medications and none of the guidelines reviewed in our guidance statement addressed these drugs in their HbA1c target recommendations. These agents have small effects on HbA1c levels and may reduce morbidity and mortality when used as add-on (rather than treat-to-target) therapy in high-risk patients, especially those with diabetes of long duration, established cardiovascular disease, and HbA1c >8%(2-3). Absolute benefits, when present, were small and would likely be smaller in patients with HbA1c levels between 7-8%, limited life expectancy, or at lower cardiovascular risk. While these drugs have lower hypoglycemia risk, they have other harms, add treatment burden, and are costly. We disagree with Zonszein and Brownelee that our guidance statements are “scientifically wrong and clinically misleading”. Improvements in macrovascular complications due to intensive HbA1c targets were limited to the UKPDS studies (achieved HbA1c >7%), small in absolute terms, and required >10 years to accrue. No trials targeting HbA1c levels below 6.5% demonstrated improved clinical outcomes. The ACCORD eye study found small reductions in photographic evidence of retinopathy(4). However, vision loss or interventions for retinopathy were not significantly reduced in this substudy or the main ACCORD follow-up(5). Indeed, across all trials, microvasculopathy improvements due to intensive HbA1c targets (<7%) were small, inconsistent, and based on surrogate measures rather than clinical outcomes. Intensive HbA1c targets and pharmacologic therapies have harms, costs, and burden. The authors advocate for HbA1c targets <6.5% despite trials indicating harms without benefit, including the stopping of ACCORD due to higher mortality in patients with achieved HbA1c of 6.4% vs. 7.5%. Results from large, long-term, treat-to-target studies strongly support our guidance statements: personalize glycemic control for all patients, target a range of 7%-8% for most patients, consider pharmacologic deintensification for patients achieving HbA1c levels <6.5%, and treat to minimize hyperglycemia symptoms and avoid targeting HbA1c levels in adults with life expectancy <10 years. Timothy J. Wilt, MD, MPHMinneapolis VA Medical CenterMichael J. Barry, MDMassachusetts General HospitalDevan Kansagara, MD, MCROregon Health and Science University and VA Medical CenterAmir Qaseem, MD, PhDAmerican College of PhysiciansReferences: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. Ann Intern Med. 2018 Mar 6. doi: 10.7326/M17-0939. 2) Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of Clinical Outcomes and Adverse Events Associated with Glucose-Lowering Drugs in Patients with Type 2 Diabetes. A Meta-analysis. JAMA. 2016:316:313-324. 3) Zheng SL, Roddick AJ, Aghar-Jaffar R, et al. Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes. A Systematic Review and Meta-analysis. JAMA. 2018:319(15):1580-1591. 4) The ACCORD Study Group and ACCORD Eye Study Group. Effects of Medical Therapies on Retinopathy Progression in Type 2 Diabetes. New Engl J Med. 2010;363:233-44.5) Imail-Beigi F, Craven T, Banerji, MA. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomized trial. Lancet. 2010;376:419-30.
Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA, et al. 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. Ann Intern Med. [Epub ahead of print 6 March 2018]168:569–576. doi: 10.7326/M17-0939
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Published: Ann Intern Med. 2018;168(8):569-576.
Published at www.annals.org on 6 March 2018
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism, Guidelines.
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