A Personalized Approach for A1C Goals

Transcription

1 PL Detail-Document # This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER July 2012 A Personalized Approach for A1C Goals Introduction The American Diabetes Association (ADA) standards of care recommend a personalized approach to A1C goals. The benefit of intensive glucose lowering for reducing microvascular complications is established. However, newer studies haven t shown a significant reduction in cardiovascular outcomes. The ADA recommendations reflect these findings and suggest individualizing A1C goals based on patient factors such as duration of diabetes, comorbidities, history of hypoglycemia, etc. This document reviews the evidence that supports a more personalized approach for glycemic control. Evidence Microvascular disease. Good glycemic control was first shown to reduce the risk of microvascular disease (e.g., nephropathy, neuropathy, retinopathy) in the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes. Later, in the United Kingdom Prospective Diabetes Study (UKPDS), good glycemic control was shown to reduce the risk of microvascular complications in patients with type 2 diabetes. 1 Subjects in both of these studies had short duration of disease. The benefit of early intensive glycemic control on microvascular complications persisted over time, even when intensive control was not maintained. 1 More recently, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial showed a significant reduction in the risk of nephropathy with A1C levels of 6.4% compared to 7%. 2 An analysis of data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial suggested that the onset and progression of microvascular complications are slowed with intensive glycemic control (i.e., A1C target <6%; 6.4% vs 7.5% achieved). 1,3 Macrovascular disease. Data from randomized, controlled trials like ADVANCE, ACCORD (Action to Control Cardiovascular Risk in Diabetes), and VADT (Veterans Affairs Diabetes Trial) have generally not shown a benefit of reducing A1C to less than 7% on cardiovascular outcomes in patients with type 2 diabetes. In the ACCORD study, despite the fact that the group who received intensive therapy to target A1C less than 6% for 3.7 years had a reduction in nonfatal heart attacks at five years, there was an increase in mortality compared with the group that received standard therapy. 4 Note that these studies enrolled older subjects, at high cardiovascular risk, with around a ten-year history of diabetes. 1,2,5,6 The UKPDS and DCCT trials also did not show improved cardiovascular outcomes during the periods of the trials. However, long-term follow-up data from both studies suggest that A1C targets below or around 7% in the years soon after diagnosis of diabetes is associated with long-term reduction in the risk of cardiovascular disease. As with microvascular complications, benefits are seen even if intensive glycemic control is not maintained. The A1C values increased over time to around 8%, and some patients were followed for up to 30 years. 7,8 Both UKPDS and DCCT enrolled healthier and younger subjects than ADVANCE, ACCORD, or VADT. The Latest Recommendations Per the ADA, the general A1C target for nonpregnant adults with type 1 or type 2 diabetes continues to be less than 7% (estimated average glucose [eag] less than 154 mg/dl). 1,9 Likewise, the Canadian Diabetes Association (CDA), recommends an A1C of 7% or lower for most adult patients with type 1 or type 2 diabetes. 10 But based on the findings of both newer and older studies, certain patients may benefit from lower or higher A1C goals. 1 Higher A1C goals (e.g., 7.5% to 8%, or slightly higher). Less stringent goals might be appropriate for patients with a recent history of

2 severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid complications, and those with longstanding diabetes in whom a target A1C of less than 7% is difficult to achieve. 1,3,9 One of the criticisms of the newer intensive glycemic control trials is that therapy changes were made very fast and aggressively. 2,5 Some experts suggest that a good approach to therapy in patients similar to subjects in these newer trials (e.g., older, cardiovascular risk factors, longstanding diabetes) is to make treatment changes slowly and in small increments. Some of these patients may not be able to reach the general goal of less than 7%. In these cases it may not be necessary to make drug therapy changes even when A1C is in the high 7% range. 1 However, others will be able to make the general goal of less than 7%. Clinicians say it s not necessary to back off on therapy if patients are doing well. Even though the ADVANCE, ACCORD, and VADT studies did not show a benefit of intensive glycemic control on cardiovascular events in highrisk patients, it s important to note that the range of A1C values in these studies is one where the reduction in cardiovascular risk isn t expected to be drastic. 1,2,5,6 As such, the ADA recommendations stress that the results of these studies should not be interpreted to underestimate the importance of reducing A1C values in poorly controlled patients (e.g., A1C >9%). 1 Lower A1C goals (e.g., 6% to 6.5%). As mentioned, results of the ADVANCE study suggest that targeting an A1C closer to 6% reduces the risk of albuminuria and data from the ACCORD study suggest that the onset and progression of microvascular complications (i.e., retinopathy, neuropathy, albuminuria) is slowed with A1C target values of less than 6%. 3,5 However, the risk reduction for microvascular complications becomes smaller as A1C approaches 6%. And there is no proof that these lower goals prevent significant vision loss or development of nephropathy. 3 Plus, lower goals are associated with a higher risk of hypoglycemia. The risk of hypoglycemia can at least double or triple. 1,3,5 So targeting A1C of around 6% is not appropriate for all patients, including those with a recent history of significant hypoglycemia. 1,3 Patients who might benefit from an A1C approaching a normal value of 6% include those (PL Detail-Document #280708: Page 2 of 3) with a shorter duration of diabetes, a long life expectancy, and no significant cardiovascular disease. 1,3,9 In these patients it may be appropriate to make therapy changes to further lower A1C even when A1C is in the low 7% range. The CDA suggests that a target A1C of 6.5% or lower may be considered in some patients with type 2 diabetes to further reduce the risk of nephropathy. Of course this should be balanced against the risk of hypoglycemia and possible increased risk of mortality in patients at high cardiovascular risk. 10 Although there s no bottom number for lowering A1C, it s generally accepted to not push the A1C much below 6%. This is because there s not much evidence that lowering A1C to the normal range improves outcomes. Conclusion Treatment recommendations suggest personalizing A1C targets for patients based on duration of diabetes, age, life expectancy, comorbid conditions, history of cardiovascular disease, and predisposition to hypoglycemia [Evidence level C; consensus]. 1 Older patients with a longer duration of disease and comorbidities may sometimes be better off with a less aggressive goal than the general recommendations. 2,3,5,11 Other patients who can tolerate lower goals might benefit from A1C values closer to 6% for reduction of microvascular complications. 1-3,10 Interventions proven to reduce cardiovascular risk, like reaching blood pressure and lipid goals, and low-dose daily aspirin in patients with heart disease, are important for diabetes patients. 1,9,10 Remember that although diabetes does increase the risk of coronary heart disease, it is no longer considered to be a cardiovascular risk equivalent in all patients. 12 Continue to encourage all patients with diabetes to make healthy lifestyle changes, like stopping smoking, eating healthy, and exercising. Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

3 (PL Detail-Document #280708: Page 3 of 3) Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65: Project Leader in preparation of this PL Detail- Document: Stacy A. Hester, R.Ph., BCPS, Assistant Editor References 1. American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2012;35(Suppl 1):S The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358: Ismail-Beigi F, Moghissi E, Tiktin M, et al. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med 2011;154: The ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364: 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: Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360: Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359: DCCT/EDIC Study Research Group. Intensive diabetes treatment and cardiovascular diseases in patients with type 1 diabetes. N Engl J Med 2005;353: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care 2012;35: Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008;32:S1-S Dluhy RG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med 2008;358: PL Detail-Document, Cardiovascular Risk in Patients with Diabetes. Pharmacist s Letter/Prescriber s Letter. May Cite this document as follows: PL Detail-Document, A Personalized Approach for A1C Goals. Pharmacist s Letter/Prescriber s Letter. July Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA ~ TEL (209) ~ FAX (209) Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to or

4 PL Detail-Document # This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER June 2012 Stepwise Approach to Selecting Treatments for Type 2 Diabetes (ADA) (2012 American Diabetes Association and European Association for the Study of Diabetes) Diagnosis of type 2 diabetes in nonpregnant adults 1,a,b Counsel patients regarding lifestyle modification such as healthy diet, weight loss, exercise At or soon after diagnosis, add metformin c monotherapy ( A1C 1%-1.5%) unless contraindicated If target A1C not achieved after approximately 3 months, consider ADDING a second agent (based on patient and drug characteristics) Sulfonylurea d TZD f DPP-4 inhibitor GLP-1 agonist insulin (usually basal) e ( A1C 1%-1.5%) ( A1C 1%-1.5%) ( A1C 0.5%-1%) ( A1C 1%-1.5%) ( A1C 1.5%-3.5%) 2 (2nd generation) -pioglitazone (Actos) -sitagliptin (Januvia) -exenatide (Byetta) -glyburide (not preferred) -saxagliptin (Onglyza) -exenatide extended-release (Bydureon) -glipizide (Glucotrol) -linagliptin (Tradjenta) -liraglutide (Victoza) -glimepiride (Amaryl) If target A1C not achieved after approximately 3 months, consider ADDING a third agent TZD f or SU d or SU d or SU d or TZD f or DPP-4 inhibitor or DPP-4 inhibitor or TZD f or TZD f or DPP-4 inhibitor or GLP-1 agonist or GLP agonist or insulin (usually basal) e insulin (usually basal) e GLP-1 agonist insulin (usually basal) e insulin (usually basal) e If a 3-drug combination (including basal insulin) does not achieve target A1C after 3 to 6 months, move to more complex insulin regimen (multiple daily doses), with 1 or 2 non-insulin agents. Sulfonylureas and meglitinides are generally avoided in patients who require more complex insulin regimens including prandial insulins. 1 See our PL Chart, Drug Classes for Type 2 Diabetes, for more information about the pros and cons of the drugs used for type 2 diabetes. Abbreviations: DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; SU = sulfonylurea; TZD = thiazolidinedione.

5 (PL Detail-Document #280601: Page 2 of 3) The above algorithm does not include pramlintide (Symlin), alpha-glucosidase inhibitors (acarbose [Precose], miglitol [Glyset]), bile acid sequestrant (colesevelam [Welchol]), or dopamine agonists (bromocriptine [Cycloset]), because of modest efficacy and/or intolerable side effects. However, these may be used in selected patients. Insulin is likely to be more effective than other third-line agents, especially in patients with high A1C (e.g., 9% or greater). In patients with severe hyperglycemia (e.g., A1C 10% or greater), a more rapid progression from a two-drug combination directly to a regimen of multiple daily insulin doses is indicated. a. This algorithm provides a summary of the 2012 position statement of the American Diabetes Association and European Association for the Study of Diabetes created for the treatment of adult, nonpregnant patients with type 2 diabetes. Of note, it is based on evidence, where it exists, but also relies on the opinions of experts. The recommendations should be considered within the context of the needs, preferences, and tolerance of the individual patient. b. While the American Diabetes Association Standards of Medical Care in Diabetes recommends lowering the A1C to less than 7% in most patients, some patients may benefit from less stringent A1C goals. For example, an A1C goal of 7.5% to 8.0% or slightly higher may be acceptable in patients with a history of severe hypoglycemia, those with a limited life expectancy, those with advanced complications such as moderate to severe renal dysfunction, or those with extensive comorbid conditions. Conversely, some patients may benefit from more stringent goals (e.g., A1C 6.0% to 6.5%) such as those with a short duration of disease, long life expectancy, and no significant cardiovascular disease. c. Metformin is contraindicated in patients at risk of lactic acidosis such as those with significant renal dysfunction (e.g., serum creatinine values >1.5 mg/dl [males] and >1.4 mg/dl [females]) or alcoholism. For more information about contraindications for metformin, see our PL Detail- Document, Clinical Use of Metformin in Special Populations - Chronic Renal Insufficiency, Heart Failure, and Hepatic Dysfunction. d. Consider rapid-acting secretagogues or the meglitinides (repaglinide [Prandin], nateglinide [Starlix]) in place of sulfonylurea agents in certain patients. For example, meglitinides may be safer in patients with irregular meal schedules or in those who develop late postprandial hypoglycemia while on sulfonylurea agents. e. Basal insulin: insulin glargine (Lantus), insulin detemir (Levemir), or NPH insulin. f. Rosiglitazone use is restricted. It is only available by mail order from specially certified pharmacies. Health care providers and patients must enroll in the Avandia-Rosiglitazone Medicines Access Program. Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

6 (PL Detail-Document #280601: Page 3 of 3) Project Leader in preparation of this PL Detail- Document: Neeta Bahal O Mara, Pharm.D., Drug Information Consultant References 1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care Published on-line ahead of print, April 19, 2012; doi: /dc Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32: Cite this document as follows: PL Detail-Document, Stepwise Approach to Selecting Treatments for Type 2 Diabetes. Pharmacist s Letter/Prescriber s Letter. June Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA ~ TEL (209) ~ FAX (209) Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to or