Section overview: Hyperglycemia in ACS

ACC/AHA UA/NSTEMI and STEMI guidelines: Post-discharge management of patients with diabetes Secondary prevention guidelines include recommendations for specific interventions directed at patients with diabetes (class of recommendation and LOE): Initiate lifestyle and pharmacotherapy to achieve near-normal A1C of <7%. (I B) Begin vigorous modification of other risk factors (eg, physical activity, weight management, blood pressure [BP] control, and cholesterol management according to guidelines recommendation). (I B) Coordinate diabetic care with the patient’s primary care physician (PCP) or endocrinologist. (I C) Abbreviations: ACC = American College of Cardiology NSTEMI = non-ST-elevation myocardial infarction UA = unstable angina

DIGAMI 2 post-hoc analysis: Glucose-lowering drugs and long-term outcome Mellbin et al followed 1181 DIGAMI 2 participants who were discharged from hospital following AMI treatment. The median follow-up was 2.1 years. At each follow-up visit, information was obtained on ongoing glucose-lowering therapy. There was no difference in mortality among insulin, metformin, and sulfonylureas. However, there was an increased risk for nonfatal MI or stroke with insulin.

Observational studies of insulin and clinical outcomes The Euro Heart Survey on Diabetes and the Heart in a multi-center registry conducted in 25 European countries. The present report concerns the cohort (n = 1281) with diabetes (established diagnosis or on glucose-lowering drugs) and coronary artery disease (CAD). In patients treated with insulin only (n = 378) compared with those treated with oral agents only (n = 675), there was a higher risk of all-cause mortality (HR 2.23, 95% CI 1.24-4.03) and a nonsignificant trend for higher risk of CV events (HR 1.27, 95% CI 0.85-1.87). However, these findings were not confirmed in a second, larger observational study. Engel-Nitz et al conducted a retrospective medical records study of 342,692 enrollees in a US managed care plan. The OR for a CV event in those receiving insulin (n = 14,167) compared with those receiving oral agents (n = 328,077) was 0.66 (95% CI 0.61-0.71).

Insulin and clinical outcomes: Limitations of available data Limitations of the 3 trials discussed in the previous slides include their retrospective design, the lack of randomization of study drugs, and the lack of adjustment for underlying disease severity (ie, was insulin reserved for sicker patients?). Thus, these trials can be considered hypothesis-generating only.

ACCORD, ADVANCE: Addressing 3 key questions The Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trials are designed to provide insight into a common set of questions relating to reduction of CV disease events in high-risk patients with T2DM. Both trials are randomized and controlled. Each also has a factorial design. Abbreviations: HDL-C = high-density lipoprotein cholesterol LDL-C = low-density lipoprotein cholesterol TG = triglyceride

ACCORD: Study design ACCORD was designed to test 3 different medical strategies: Intensive (A1C <6%) vs standard (A1C 7%-7.9%) glycemic control. Study investigators could use all currently available glucose-lowering drugs using algorithms developed for the trial. Intensive (systolic BP [SBP] <120 mm Hg) vs standard (SBP <140 mm Hg) BP control. Multifactorial lipid modulation with statin plus fibrate vs LDL-C lowering alone with a statin. Study subjects (N = 10,251) had T2DM and either confirmed CV disease or combinations of risk factors and/or conditions suggesting a high likelihood of CV disease. The primary outcome was time to first occurrence of CV death, MI, or stroke.

ADVANCE: Study design ADVANCE was designed to test 2 different strategies: Intensive (A1C 6.5% or lower) vs standard (guidelines-based) glycemic control. The intensive arm was based on a modified-release formulation of the sulfonylurea gliclazide. Those participants in the other arm continued with their usual glucose-lowering regimens except gliclazide. Perindopril 4 mg plus indapamide 1.25 mg vs placebo. Other antihypertensive medications, with the exception of angiotensin-converting enzyme inhibitors (ACEIs) and thiazide diuretics, were permitted. Study subjects (N = 11,140) had T2DM, were 55 years of age or older, and had either a history of CV disease or at least 1 other CV risk factor. The macrovascular primary outcome was a composite of CV death, MI, and stroke. The microvascular primary outcome was a composite of new/worsening nephropathy (development of macroalbuminuria, doubling of serum creatinine to a level of at least 2.26 mg/dL, need for renal replacement, or death due to renal disease) or retinopathy (development of proliferative retinopathy, macular edema, or diabetes-related blindness, or retinal photocoagulation therapy).

ACCORD: Treatment effects on glucose control At 1 year, median A1C levels were 6.4% and 7.5% in the intensive- and standard-therapy groups, respectively. The difference between the two groups was maintained for the duration of the study. The rate of hypoglycemic episodes requiring medical assistance was 3.1% per year and 1.0% per year, respectively.

ACCORD: Treatment effect on primary outcome The primary outcome occurred in 6.9% and 7.2% of patients in the intensive and standard groups, respectively; HR 0.90 (95% CI 0.78-1.04), P = 0.16.

ACCORD: Treatment effect on all-cause mortality The all-cause mortality rate was 5.0% and 4.0% in the intensive and standard groups, respectively; HR 1.22 (1.01-1.46), P = 0.04. CV death followed a similar trend: 2.6% and 1.8%, respectively; HR 1.35 (1.04-1.76), P = 0.02 (data not shown). However, nonfatal MI was lower in the intensive group: 3.6% vs 4.6%; HR 0.76 (0.62-0.92), P = 0.004 (data not shown). Nonfatal stroke and congestive HF did not differ significantly between the groups (data not shown).

ADVANCE: Treatment effect on glucose control After a median of 5 years, mean A1C values were 6.5% and 7.3% in the intensive and standard treatment groups, respectively. Severe hypoglycemia occurred in 2.7% and 1.5%, respectively.

ADVANCE: Treatment effect on primary macrovascular outcome The macrovascular primary outcome occurred in 10.0% and 10.6% of the intensive and standard groups, respectively; HR 0.94 (0.84-1.06), P = 0.32. The combined primary outcome occurred in 18.1% and 20.0% of patients, respectively; HR 0.90 (0.82-0.98), P = 0.01 (data not shown). The microvascular primary outcome occurred in 9.4% and 10.9% of patients, respectively; HR 0.86 (0.77-0.97), P = 0.01 (data not shown).

ADVANCE: Treatment effect on all-cause mortality The all-cause mortality rate was 8.9% and 9.6% in the intensive and standard groups, respectively, a nonsignificant difference; HR 0.93 (0.83-1.06). Secondary CV outcomes also did not differ significantly between the groups, including CV death, nonfatal MI, nonfatal stroke, and HF (data not shown).

VADT: Effect of intensive therapy on A1C The Veterans Affairs Diabetes Trial (VADT) was designed to compare the effects of intensive vs standard glucose control on CV events in patients with T2DM. Subjects (n = 1791) with poorly controlled T2DM were randomized to receive either intensive or standard glucose control. Subjects with a BMI of 27 kg/m(2) or greater were placed on metformin and rosiglitazone; subjects with a BMI <27 kg/m(2) were started on glimepiride and rosiglitazone. Subjects in the intensive group were started on maximal dose; those in the standard group were started on one-half of the maximal dose. Insulin was given to subjects on a case-by-case basis. Mean age and time since T2DM diagnosis at baseline were 60.4 years and 11.5 years, respectively. Median follow-up was 5.6 years; longest was 7.5 years. Mean A1C value at baseline was 9.4% for both groups. At study end, median A1C values in the intensive and standard groups were 6.9% and 8.4%, respectively.

VADT: Effect of intensive therapy on time to major CV event The primary outcome was the time to first occurrence of a major CV event, a composite of myocardial infarction, stroke, CV death, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. This outcome occurred in 235 patients in the intensive group and in 264 patients in the standard group, which did not attain statistical significance.

ACCORD, ADVANCE, VADT: Long-term glycemic control in high-risk T2DM In confirmation of other studies, the ADVANCE results show that intensive glucose control adds incremental benefit over standard glucose control with regard to reduction in microvascular events. However, intensive glucose control does not significantly lower CV events in high-risk patients with T2DM. In an accompanying editorial, Robert G. Dluhy, MD, and Graham T. McMahon, MD, MMSc, write, “Clinicians caring for patients with diabetes should continue to focus on smoking cessation, dietary and exercise counseling, blood-pressure control, and providing aspirin and a statin to a greater extent than achieved even in the ADVANCE and ACCORD studies.”(1) Consensus is lacking on optimal long-term glucose targets, although in patients with diabetes who are at high-risk for CV events it would be prudent to set a goal A1C of approximately 7%. Consensus is also lacking on strategies for achieving and maintaining glucose targets. 1. Dluhy RG, McMahon GT. N Engl J Med. 2008;358:2630-33.

Post-discharge, long-term glycemic control: Summary While there is strong evidence that lowering glucose reduces risk of microvascular events, there is no consensus regarding its effect on macrovascular events, particularly following AMI. Pending results of ongoing clinical trials, decisions regarding glycemic targets for long-term control and the optimal regimens for achieving those targets will have to be based on clinical judgment.