Hemoglobin A1c Goals in Patients with Type 2 Diabetes Mellitus and Established Cardiovascular Disease

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Authors: Kristin Watson, PharmD, BCPS-AQ Cardiology, Jeannie L. Poon, PharmD, BCPS, and Stormi Gale, PharmD, BCPS

Over the last decade, there have been considerable changes in the treatment of type 2 diabetes mellitus (DM). This includes the approval of new medications and changes in diagnostic criteria and treatment goals. The hemoglobin A1c (HbA1c) remains a mainstay target when selecting and titrating therapies. Previously, a HbA1c goal of < 7% was recommended for most non-pregnant adults with allowance for a less stringent goal of < 6% in select patients.¹ The “ideal” HbA1c has been evaluated in several clinical trials, and we’ll discuss the data surrounding stricter HbA1c goals and targets in patients with cardiovascular disease (CVD). Current guideline recommendations for HbA1c goals for those with type 2 DM, including those with CVD, are presented in Table 1.

Table. Guideline/position statement recommendations for glucose control^2-4

Organization(s)	Recommendations
American Association of Clinical Endocrinologists/American College of Endocrinologists – 2017	HbA1c < 6.5%: optimal if it can be achieved safely and affordably and patient has low hypoglycemic risk and does not have serious concurrent illness   HbA1c > 6.5% (up to 8%): if history of severe hypoglycemia, limited life expectancy, advanced renal disease or macrovascular complications, extensive comorbid conditions or long-standing type 2 DM with difficult to control A1c as long as patient is free of hyperglycemic symptoms
American Diabetes Association – 2018	HbA1c < 7%: non-pregnant adults   HbA1c < 6.5% (if can be achieved without significant hypoglycemic or adverse effects of therapy): may be considered in those with short duration of diabetes, type 2 diabetes treated with lifestyle or metformin only, prolonged life expectancy or no significant CVD   HbA1c < 8%: may be appropriate if history of severe hypoglycemia, short life expectancy, advanced micro- or macrovascular disease, extensive co-morbid conditions, or long-standing diabetes that is difficult to control
American Diabetes Association, American College of Cardiology Foundation and American Heart Association – 2009	HbA1c < 7 %: non-pregnant adults   HbA1c goal lower than < 7% (without hypoglycemia or adverse effects of therapy): select individuals to reduce risk of microvascular complications; including those with short duration of diabetes, prolonged life expectancy and no significant CVD   Less stringent HbA1c goal < 7%: may be considered for those with severe hypoglycemia, short life expectancy, advanced micro- or macrovascular disease, extensive co-morbid conditions, or long-standing diabetes that is difficult to control

CVD, cardiovascular disease ; DM, diabetes mellitus; HbA1c, hemoglobin A1c

 

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial compared the risk of vascular events between intensive (HbA1c < 6.5%) versus standard glucose control (HbA1c defined by local guidelines). Additional details for these trials can be found in Table 2. At the end of the 5-year follow-up period, the mean HbA1c was 6.53% ± 0.91 in the intensive treatment arm and 7.30% ± 1.26 in the standard control group. The composite primary endpoint (death from cardiovascular (CV) causes, nonfatal myocardial infarction (MI), nonfatal stroke, new or worsening nephropathy or retinopathy) occurred in 18.1% of those in the intensive care group and 20% in the standard of care group (hazard ratio (HR) 0.90; 95% confidence interval (CI), 0.82 to 0.98; p=0.01). This reduction was driven by a difference in microvascular events; there was no difference in the rate of any macrovascular events. A subgroup analysis of patients with a history of a macrovascular event demonstrated no difference in the primary endpoint (23.3% in the intensive control group and 24.4% in the standard group (relative risk reduction (RRR) 4.0; 95% CI, -10 to 16). This trial demonstrated that more intensive glucose control (HbA1c < 6.5%) can reduce the risk of microvascular events, primarily due to a reduction in nephropathy, but not macrovascular events.⁴

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, 10,251 patients were randomized to either an intensive HbA1c goal of < 6% or a HbA1c between 7.0 and 7.9%. At one year and throughout the follow-up period, the median HbA1c was 6.4% (interquartile range (IQR), 6.1 to 7.0) and 7.5% (IQR, 7.0 to 8.1) in the intensive and standard care groups, respectively. The risk of the primary endpoint (composite of nonfatal MI, nonfatal stroke or CV death) was similar between groups (2.11% per year in the intensive treatment group versus 2.29% per year (HR 0.90; 95% CI, 0.78 to 1.04, p=0.16). The risk of all-cause death (1.41% per year versus 1.14% per year, p=0.04) and CV death (0.79% per year versus 0.56%, p=0.02) were higher in the intensive treatment group. Furthermore, the risk of nonfatal MI (1.11% per year versus 1.45% per year, p=0.004) was lower in the intensive treatment group.⁵

The United Kingdom Prospective Diabetes Study (UKPDS) aimed to determine the effects of intensive glucose control on both micro- and macrovascular complications. This study randomized 3869 newly diagnosed patients with type 2 DM to intensive therapy (sulfonylurea or insulin with a goal HbA1c < 6%) or conventional therapy (best achievable HbA1c with diet modifications only); overweight patients received metformin.⁶  Over 10 years, the mean HbA1c was 7.0% in the intensive group versus 7.9% in the conventional group. Despite a reduction in HbA1c, there was no difference in macrovascular events with intensive compared to conventional therapy. There was, however, a reduction in any diabetes-related endpoint with the intensive therapy, including a reduction in microvascular complications. A 10-year follow-up revealed a loss of differences in HbA1c between groups after one year. Interestingly though, there was a persistent benefit in terms of any diabetes-related endpoint (48.1% versus 52.2%; risk ratio (RR) 0.91; 95% CI, 0.83 to 0.99; p=0.04) and microvascular disease (11% versus 14.2%; RR 0.76; 95% CI 0.64 to 0.89; p=0.001) with intensive therapy, as well as a reduction in MI (16.8% versus 19.6%; RR 0.85; 95% CI, 0.74 to 0.97; p=0.01). In the 10-year follow-up of patients taking metformin, there was a lower risk of any diabetes-related endpoint (45.7% versus 53.9%; RR 0.79; 95% CI 0.66 to 0.95; p=0.01), MI (14.8% versus 21.1%, RR 0.67; 95% CI, 0.51 to 0.89; p=0.005), and all cause death (25.9% versus 33.1%; RR 0.73; 95% CI, 0.59 to 0.89; p=0.002) compared to conventional therapy.⁷ The results of this trial differ from that of the ADVANCE trial; despite similar HbA1c levels after the initial trial concluded, both trials demonstrated a persistent reduction of microvascular events with more intensive control as well as an emergent reduction in the risk of MI over time.

The Veterans Affairs Diabetes Trial (VADT) evaluated the effect of intensive glucose control on CV outcomes in those with long-standing diabetes. This trial randomized 1,791 patients to intensive treatment (absolute reduction in the HbA1c by 1.5%) or standard therapy. At six months, the median HbA1c was 8.4% in the standard of care group and 6.9% in the intensive treatment group. There was no difference in the primary outcome (composite of CV events including MI, stroke, CV death, new or worsening heart failure) between groups (HR in the intensive-therapy group, 0.88; 95% CI, 0.74 to 1.05; P=0.14). A lower rate of increased albuminuria was also observed in the intensive treatment arm.⁸

Table 2. Summary of Trials^4,5,8

Trial	Population	Exclusion Criteria	Notable Baseline Characteristics
ADVANCE	11,000 patients aged 55 years or older with type 2 DM diagnosed at the age of 30 or greater	Definitive indication or contraindication to study treatment options (i.e., gliclaizide, perinodril, indapamide, metformin, thiazolidinediones, insulin, acarbose)	Mean age: 66 years Mean HbA1c: 7.5% Mean duration of DM: ~8 years History of macrovascular complications: ~32%
ACCORD	10,251 patients with type 2 DM and aged 40 to 79 years with known CVD or age 55 to 79 with CV risk factors	SCr > 1.5 mg/dl Recent serious hypoglycemia BMI > 45 kg/m2 Unwillingness to monitor their glucose at home or inject insulin	Mean age: 66 years Mean HbA1c: 8.1% Median duration of DM: 10 years Prior CV event: ~35%
VADT	1,791 patients with type 2 DM with an inadequate response to maximum doses of an oral agent or insulin	HbA1c < 7.5% History of CV event during the prior six months Advanced heart failure SCr > 1.6 mg/dl	Mean age: ~60 years Mean HbA1c: 9.4% Mean duration of DM: ~11.5 years Prior CV event: ~40%

BMI, body mass index; CV, cardiovascular; CVD, cardiovascular disease; DM, diabetes mellitus; HbA1c, hemoglobin A1c; SCr, serum creatinine

 

The conflicting data presented in these trials should be carefully considered before determining the optimal HbA1c goal. The ACCORD and ADVANCE trials enrolled patients with similar CVD risk, but there is no clear explanation for the higher risk of death in ACCORD.^4,5 Proposed mechanisms include a more marked and rapid reduction in HbA1c concentrations in the ACCORD trial compared to those in ADVANCE. The use of pharmacological therapies differed between these trials owing to more sulfonylurea use in the ADVANCE trial and more thiazolidinedione and insulin use in ACCORD. Those in the ADVANCE trial also had a shorter duration of diabetes than those enrolled in VADT. Additionally, the baseline HbA1c was much higher in VADT (9.4%) compared to the other trials presented (7.5% for ADVANCE and 8.1% for ACCORD).^4,5,8

In patients with CVD, rapid and aggressive lowering of the HbA1c appears to increase the risk of all-cause and CV death as evident in the ACCORD trial. It also appears that more intensive control is likely to be of benefit for those with newly diagnosed diabetes, especially as it relates to the risk of microvascular complications. There is inconsistent evidence regarding the impact of intensive therapy on macrovascular complications. Therefore, the initial HbA1c goal should be achieved gradually and does not have to be as low as < 7% in those with long-standing diabetes or advanced micro- and macrovascular complications, including CVD.

 

	Kristin Watson, PharmD, BCPS-AQ Cardiology Kristin Watson is an associate professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in the ambulatory heart failure clinic at the Veterans Affairs Medical Center in Baltimore, MD. Follow her on Twitter @cards_pharm_gal
	Stormi Gale, PharmD, BCPS Dr. Gale is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist at the University of Maryland Medical Center in Baltimore, MD. Follower her on Twitter @stormigale.
	Jeannie L. Poon, PharmD, BCPS Dr. Poon is the PGY1 program director and practices as a clinical pharmacy specialist in cardiology at Novant Health Presbyterian Medical Center in Charlotte, NC.

 

References

1. American Diabetes A. Standards of medical care in diabetes–2008. Diabetes Care 2008;31 Suppl 1:S12-54.
2. 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. Endocr Pract 2018;24:91-120.
3. American Diabetes A. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2018. Diabetes Care 2018;41:S55-S64.
4. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Circulation 2009;119:351-7.
5. Action to Control Cardiovascular Risk in Diabetes Study G, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
6. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-53.
7. 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;359:1577-89.
8. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-39.

 

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