A Personalized Approach for A1C Goals

Transcription

1 This Clinical Resource gives subscribers additional insight related to the Recommendations published in April 2018 ~ Resource # A Personalized Approach for A1C Goals Introduction Recommendations for A1C targets in patients with type 2 diabetes differ somewhat between guidelines. However, the American Diabetes Association (ADA), Canadian Diabetes Association (CDA), American Association of Clinical Endocrinologists (AACE), Department of Veterans Affairs, and American College of Physicians (ACP) all recommend a personalized approach to A1C goals. The benefit of intensive glucose lowering for reducing microvascular complications (e.g., retinopathy, neuropathy, nephropathy) is well established. However, studies do not seem to show the same reduction in macrovascular complications (i.e., cardiovascular outcomes). Recommendations reflect these findings and suggest individualizing A1C goals based on patient factors such as life expectancy, risk of hypoglycemia, etc. This document reviews the evidence and recommendations for a personalized approach for glycemic control. Evidence Microvascular disease. The Diabetes Control and Complications Trial (DCCT) showed that good glycemic control (i.e., A1C <7%) reduced the risk of microvascular disease (e.g., nephropathy, neuropathy, retinopathy) in patients with type 1 diabetes. Later, in the United Kingdom Prospective Diabetes Study (UKPDS), good glycemic control was shown to also reduce the risk of microvascular complications in patients with type 2 diabetes. 1 Patients 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 the intensive control was not maintained. 1 Additional analysis of the data from these studies suggests that lowering A1C from 7% to 6% will further reduce the risk of microvascular complications; however, the absolute risk reduction is much lower as you approach AIC of 6%. 1,2 The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial has also shown a significant reduction in the risk of nephropathy, with A1C levels of 6.4% compared to 7%. 3 And an analysis of the 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 of <6%; 6.4% vs 7.5% achieved). 1,4 The risk of microvascular complications increases in patients with type 1 diabetes as A1C levels increase, with an even greater acceleration of risk when A1C levels exceed 9%. It s assumed that this risk is likely similar in patients with type 2 diabetes, but evidence is lacking. 2 Macrovascular disease. Data from the randomized, controlled trials ADVANCE, ACCORD, and Veterans Affairs Diabetes Trial (VADT) have not shown a significant benefit of reducing A1C to less than 7% for 3.5 to 5.6 years 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. No clear explanation for the increased mortality was identified. 5 The long-term follow-up of the ADVANCE study patients showed no difference between the groups in cardiovascular outcomes. 1 End-stage renal disease rates were found to be lower in the intensively treated group. 1 A 10-year follow-up of VADT patients showed a reduction in the risk of cardiovascular events in the intensively treated group, but no benefit in either cardiovascular or overall mortality. 1 In all three of these trials, severe hypoglycemia was significantly more likely in intensively treated groups. 1 The ADVANCE, ACCORD, and VADT studies all enrolled older subjects, with existing or at highrisk for cardiovascular complications, with around Copyright 2018 by Therapeutic Research Center

2 (Clinical Resource #340403: Page 2 of 4) a ten-year history of diabetes unlike those enrolled in UKPDS. 1,3,6,7 Even though the ADVANCE, ACCORD, and VADT studies did not show a significant benefit of intensive glycemic control on cardiovascular outcomes in high-risk 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. 3,6,7 The UKPDS and DCCT trials also did not show improved cardiovascular outcomes during the trial periods. However, long-term follow-up data from both studies suggest that A1C targets below or around 7% in the years soon after a patient s 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. 8,9 Both UKPDS and DCCT enrolled healthier and younger subjects than ADVANCE, ACCORD, and VADT. The Latest Recommendations The ADA and CDA both recommend a general A1C target for nonpregnant adults with type 1 or type 2 diabetes of less than 7% ( 7 per CDA) (estimated average glucose [eag] less than 154 mg/dl [8.6 mmol/l]) [Evidence level A- 1]. 1,10,11 However, their recommendations also recognize that many patients may benefit from lower or higher A1C goals. 1,11 The American Association of Clinical Endocrinologists (AACE) recommend an optimal target A1C of 6.5% or less in patients with type 2 diabetes who can meet it in a safe and affordable way. 12 However, the American College of Physicians (ACP) differs with a recommendation for a target A1C of between 7% and 8% for most patients with type 2 diabetes. 15 Higher A1C goals (e.g., 7.5% to 8%, or slightly higher). These less intensive goals might be appropriate for patients with a recent history of severe hypoglycemia, limited life expectancy (<5 years), older age, advanced microvascular or macrovascular complications, extensive comorbid complications, and/or those with longstanding diabetes in whom a target A1C of less than 7% is difficult to achieve. 2,4,10 One of the criticisms of the intensive glycemic control trials is that therapy changes were made very fast and aggressively. 3,6 Some experts suggest that a more optimal 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. This may help more patients reach the general A1C goal of less than 7% more easily. It is the general consensus that it s not necessary to back off on therapy if patients are doing well. Lower A1C goals (e.g., <6.5%). As mentioned, results of the ADVANCE study suggest that targeting an A1C closer to 6.5% reduces the risk of microvascular complications even further. Data from the ACCORD study suggest that the onset and progression of microvascular complications (i.e., retinopathy, albuminuria) are slowed with A1C target values of less than 6%. 4,6 The risk reduction for microvascular complications becomes smaller as A1C approaches 6%. Plus, lower goals are associated with a much higher risk of hypoglycemia, making this target inappropriate for all patients. 1,4,6 The ideal target A1C for most pregnant women is <6.5%, as this has been associated with the lowest risk of congenital anomalies. 1 Other patients who may benefit from a lower A1C goal of below 6.5% are those who can reach this goal without significant hypoglycemia or other adverse effects (e.g., polypharmacy, excessive costs, etc). Younger, healthier patients who may be suited to lower goals include those with: 1,2,4,10,12 A shorter duration of diabetes Type 2 diabetes managed with lifestyle or metformin alone Long life expectancy (because microvascular complications develop over an extended period of time) No significant cardiovascular disease For these patients, it may be appropriate to make therapy changes to further lower A1C even when A1C is in the low 7% range. 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. Copyright 2018 by Therapeutic Research Center

3 (Clinical Resource #340403: Page 3 of 4) Conclusion Most 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]. 1,11 Older patients with a longer duration of disease and comorbidities may sometimes be better off with a less aggressive goal than the general recommendations of 7% [Evidence level B]. 3,4,6,13,14 Other patients, who can tolerate lower goals, might benefit from A1C values of less than 6.5% for reduction of microvascular complications [Evidence level C]. 1,3,4,11 The determination of the A1C goal should be made with patients. There must be a balance between the patient s absolute risk for microvascular complications vs risk of hypoglycemia and other adverse reactions, as well as the risks inherent with polypharmacy and overall treatment burden. 2 Be vigilant in helping patients prevent hypoglycemia. A1C should not be lowered aggressively if this cannot be achieved safely. Severe or frequent hypoglycemia is an indication to change a patient s treatment regimen, which may include setting higher A1C goals. 1 Remember that A1C goals will change over time and need to be regularly assessed. 12 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. 1,10,11 Continue to encourage all patients with diabetes to make healthy lifestyle changes, such as stopping smoking, eating healthy, and exercising. For additional strategies and resources to optimize diabetes management, see our toolbox, Improving Diabetes Outcomes. Users of this resource 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. Levels of Evidence In accordance with our goal of providing Evidence- Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish. Level Definition Study Quality A B C Good-quality patient-oriented evidence.* Inconsistent or limited-quality patient-oriented evidence.* 1. High-quality RCT 2. SR/Meta-analysis of RCTs with consistent findings 3. All-or-none study 1. Lower-quality RCT 2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings 3. Cohort study 4. Case control study Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening. *Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life). RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69: Project Leader in preparation of this clinical resource (340403): Annette Murray, BScPharm References 1. American Diabetes Association. 6. Glycemic targets: standard of medical care in diabetes Diabetes Care 2018;41(Suppl 1):s Conlin PR, Colburn J, Aron D, et al. Synopsis of the 2017 U.S. Department of Veterans Affairs/U.S. Department of Defense clinical practice guideline: management of type 2 diabetes mellitus. Ann Intern Med 2017;167: 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: Copyright 2018 by Therapeutic Research Center

4 (Clinical Resource #340403: Page 4 of 4) 7. 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: Nathan DM, Cleary RA, Backlund JY, et al. 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: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35: Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, Imran SA, Rabasa- Lhoret R, Ross S. Targets for glycemic control. Can J Diabetes 2013;37:S Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2018 executive summary. Endoc Pract 2018;24: Dluhy RG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med 2008;358: Petrillo LA, Gan S, Jing B. Hypoglycemia in hospice patients with type 2 diabetes in a national sample of nursing homes [research letter]. JAMA Intern Med doi: /jamainternmed Qaseem A, Wilt TJ, Kansagara D, 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 doi: /M Cite this document as follows: Clinical Resource, A Personalized Approach for A1C Goals. Pharmacist s Letter/Prescriber s Letter. April Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2018 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com

5 This Professional Resource gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER October 2016 ~ Resource # Management of New-Onset Type 2 Diabetes There are lots of medications available and many ways to start therapy. The guidelines use a variety of A1C cutoffs for treatment recommendations, such as when to initiate insulin or consider dual therapy. 1-3 Ultimately, medication selection should be based on the patient s clinical presentation, blood glucose levels or A1C, and patient specific factors (e.g., concomitant conditions, renal function, etc). Consider using these strategies to initiate therapy for any patient with new-onset type 2 diabetes, even those presenting with a very high blood glucose level (e.g., >350 mg/dl [~20 mmol/l]). First Step: Patient Assessment Assess patient stability and need for urgent treatment. o For unstable patients, see the section below: How Should UNSTABLE Patients With High Blood Glucose Be Managed? Check an A1C to get a more accurate picture of the overall blood glucose levels. o Don t wait on these results to start therapy, if not readily available. If necessary, distinguish between type 1 and type 2 diabetes: o It may not be clear at the time of diagnosis if a patient has type 1 or type 2 diabetes. 1 o The assumption that type 2 diabetes only occurs in adults and type 1 only occurs in children is no longer accurate. Accurate classification is important to determine the most appropriate therapy. 1 o Evaluate a C-peptide or serum insulin level to help distinguish type 1 from type 2 diabetes. If necessary, check autoimmune markers as type 1 diabetes is defined by the following markers: 1 Islet cell autoantibodies Insulin autoantibodies (e.g., GAD [GAD65], tyrosine phosphatases [e.g., 1A-2, 1A-2β], and ZnT8) Address lifestyle choices for everyone: 1-3 o Facilitate diabetes and healthy eating patient education. o Encourage physical activity (e.g., 150 minutes per week), smoking cessation, and weight management, if necessary. Initiating Medication in STABLE Patients With Type 2 Diabetes: Feel comfortable starting with a single oral medication, even in patients with significantly elevated sugars (e.g., 350 mg/dl [~20 mmol/l]). 4 See our chart, Diabetes Medications and Cardiovascular Impact, for an overview of available cardiovascular data. See our chart, Drugs for Type 2 Diabetes (U.S. subscribers) and our algorithm, Stepwise Treatment of Type 2 Diabetes (Canadian subscribers), for the benefits and risks associated with available medications. First Choice: 1-3 o Metformin 500 mg once daily, unless contraindicated (e.g., acute metabolic acidosis, creatinine clearance <30 ml/min). o Increase by 500 mg per day every few days to a goal dose of 2 g per day. o See our algorithm, Improving Tolerability to Metformin, for slower dosing titrations and other strategies to address gastrointestinal effects. Second Choice: (if metformin is contraindicated or not tolerated) consider any one of the following depending on concomitant conditions. 1-3 Copyright 2016 by Therapeutic Research Center

6 (Professional Resource #321004: Page 2 of 4) o Glucagon-like peptide-1 (GLP-1) receptor agonist Give preference to liraglutide due to outcomes data. o Sodium-glucose co-transporter 2 (SGLT2) inhibitor or flozin Give preference to empagliflozin due to outcomes data. o Dipeptidyl peptidase-4 (DPP-4) inhibitor or gliptin Give preference to sitagliptin due to outcomes data. o Thiazolidinedione (TZD) Give preference to pioglitazone due to outcomes data. Avoid in patients with heart failure. Third Choice (if the above options aren t tolerated or cannot be used) consider one of the following: 1-3 o Sulfonylurea Use these with caution due to risk of weight gain and hypoglycemia. o Meglitinide (repaglinide, nateglinide [U.S. only]) Use these with caution due to risk of weight gain and hypoglycemia. o Alpha glucosidase inhibitor Use these with caution due to frequent dosing, gastrointestinal adverse effects, and modest impact on A1C. o Insulin See section below, When Should Insulin Be Considered? Monitor Blood Glucose o Instruct patients on monitoring blood glucose levels. See our chart, Comparison of Blood Glucose Meters (U.S. subscribers); (Canadian subscribers). o Share our patient education handout, Understanding Your Blood Sugar Numbers (U.S. subscribers) (Canadian subscribers). o Initial monitoring may be more frequent to help patients develop a comfort level with how medicine and diet impact blood glucose control. Recommend testing once daily for patients on oral medications, and any time they feel hypoglycemic (e.g., shaking, sweating). 10 Monitoring may be more frequent in patients receiving insulin. 10 See our commentary, Self- Monitoring of Blood Glucose in Patients with Type 2 Diabetes. o Arrange close follow-up to adjust medication doses based on blood glucose levels. When to Add a Second Medication: o If goal blood glucose readings are not achieved after titrating initial therapy within about three months, consider adding another medication. o Base medication selection on concomitant conditions. See details in the Second Choice section above. When Should More Than One Medication Be Started at Diagnosis? Guidelines recommend considering dual therapy for A1C >9% (>8.5% per Canadian guidelines). 1-3 However, there are no data to show that initial combination therapy improves outcomes compared to sequential therapy in otherwise asymptomatic patients. 5 Before using dual therapy for initial treatment, consider the following: o No data exist to show initial combination therapy improves adherence. 5 o Initial dual therapy may increase risk of hypoglycemia and potentially reduce patient buy-in on the importance of blood glucose control. o With dual therapy an accurate assessment of individual medication effectiveness and tolerability is difficult. 5 o In addition to increased costs, dual therapy can make it difficult to determine the specific cause if adverse effects occur. 5 Copyright 2016 by Therapeutic Research Center

7 (Professional Resource #321004: Page 3 of 4) Regimens for Initiating Dual Therapy at Diagnosis Include metformin: o Use metformin as one of the medications unless not tolerated or contraindicated. 1-3 o If metformin can t be used, follow the preferences outlined below for selecting both medications. First Choice: 1-3 o See the Second Choice section above in Initiating Medication in STABLE Patients with Type 2 Diabetes Second Choice: 1-3 o See the Third Choice section above in Initiating Medication in STABLE Patients with Type 2 Diabetes Monitor Blood Glucose o See section above, Monitor Blood Glucose. When Should Insulin Be Considered? Insulin is the gold standard for managing patients with type 1 diabetes. Insulin may be appropriate (even if only used short-term until oral meds and dietary changes kick in) as initial therapy with metformin for patients with type 2 diabetes and an A1C >10% in stable patients (OR >9% [ADA] or >8.5% [CDA], in patients with symptomatic or catabolic features [e.g., ketonuria, unintended weight loss]). 1,3 Recommend a starting dose of basal insulin (e.g., detemir, glargine, NPH) of about 0.1 to 0.2 units/kg at bedtime. 1 o Examples: 80 kg x 0.1 units/kg = 8 units OR 80 kg x 0.2 units/kg = 16 units Monitor Blood Glucose o See section above, Monitor Blood Glucose. How Should Insulin Be Titrated? Titrate dose by 10% to 15% once or twice a week, if fasting readings remain elevated. 1 Example: o o 16 units X 0.1 = 1.6 units OR 16 units X 0.15 = 2.4 units. Using an average of the above two values, you would increase the total daily dose by 2 units, to 18 units. Teach extremely motivated patients to self-titrate their own insulin dose daily. Example: o Increase insulin daily by 1 unit, if fasting blood glucose remains elevated. 7 Once a total daily dose of 0.5 units/kg basal insulin is reached, consider adding rapid acting prandial insulin (e.g., aspart, lispro) 0.1 unit/kg with meals before further basal insulin titrations. 6 Monitor Blood Glucose o See section above, Monitor Blood Glucose. How Should UNSTABLE Patients With High Blood Glucose Be Managed? Unstable patients (e.g., mental status changes, acid/base imbalance, electrolyte abnormalities) require acute care. o Administer insulin and follow your facility s hyperglycemia protocol. Patients may present with diabetic ketoacidosis (DKA) or in a hyperosmolar hyperglycemic state (HHS). DKA is the triad of hyperglycemia (>250 mg/dl [~14 mmol/l]), metabolic acidosis (ph <7.3), and urinary and serum ketones. HHS is the triad of severe hyperglycemia (>600 mg/dl [~33 mmol/l]), hyperosmolality (>320 mosm/kg), and dehydration without ketoacidosis. 7 Patients presenting with DKA or HHS require prompt treatment to reduce mortality. Copyright 2016 by Therapeutic Research Center

8 o o o (Professional Resource #321004: Page 4 of 4) Follow your facility protocol for management of DKA or HHS. Replace fluids initially with normal saline (as long as no cardiac compromise), to restore volume and ensure perfusion. 8,9 Additional fluid choice will be based on hemodynamics, hydration status, electrolytes, and urinary output. 8 Administer intravenous (IV) insulin to bring down blood glucose and assist with correcting acidosis. 8,9 o Replace potassium as necessary. 8,9 o Administer sodium bicarbonate to maintain a ph >7. 8,9 Users of this resource 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. Project Leader in preparation of this professional resource: Beth Bryant, Pharm.D., BCPS, Assistant Editor References 1. Cefalu W, Bakris G, Blonde L, et al. American Diabetes Association standards of medical care in diabetes Diabetes Care 2016;39:S Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2016 executive summary. Endocr Pract 2016;22: Canadian Diabetes Association. Pharmacologic management of type 2 diabetes: 2016 interim update (Accessed September 2, 2016). 4. Amblee A, Lious D, Fogelfeld L. Combination of saxaglipitin and metformin is effective as initial therapy in new-onset type 2 diabetes mellitus with severe hyperglycemia. J Clin Endocrinol Metab 2016:101: Cahn A, Cefalu WT. Clinical considerations for use of initial combination therapy in type 2 diabetes. Diabetes Care 2016;39:s Henske JA, Griffith ML, Fowler MJ. Initiating and titrating insulin in patients with type 2 diabetes. Clin Diabetes 2009;27: Canadian Diabetes Association. Appendix 3: examples of insulin initiation and titration regimens in people with type 2 diabetes. ppendix3. (Accessed September 7, 2016). 8. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009;32: Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, Goguen J, Gilbert J. Hyperglycemic emergencies in adults. Can J Diabetes 2013;37:S Mayo Clinic. Blood sugar testing: why, when and how. December 20, conditions/diabetes/in-depth/blood-sugar/art (Accessed September 13, 2016). Cite this document as follows: Professional Resource, Management of New-Onset Type 2 Diabetes. Pharmacist s Letter/Prescriber s Letter. October Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2016 by Therapeutic Research Center Subscribers to the Letter can get professional resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com