ACCORDION: increased risk of cardiovascular death seen in ACCORD persists during long-term follow-up

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Macrovascular Residual Risk Studies

15 March 2016

Results from ACCORDION (long-term follow-up of the ACCORD trial), imply that for high risk individuals with type 2 diabetes, clinicians need to balance the beneficial effects of intensive glycaemic control (for 3.7 years) on diabetic retinopathy versus increased risk for cardiovascular mortality.

The ACCORD Study Group Writing Committee. 9-Year effects of 3.7 years of intensive glycemic control on cardiovascular outcomes. Diabetes Care 2016 [Epub ahead of print]

STUDY SUMMARY

Objective:

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial reported both increased total and cardiovascular mortality and reduced nonfatal myocardial infarction in the intensive glucose-lowering group (mean follow-up of 3.7 years). Whether these effects were still evident after long-term follow-up was investigated in the ACCORD Follow-on (ACCORDION) study.

Study design:

The design of the ACCORD study has been previously discussed (refer to the R3i website). In ACCORDION, surviving subjects were followed-up for cardiovascular and other health related outcomes. No active therapies were provided by the study during the open follow-up period.

Study population:

8,601 type 2 diabetes subjects (mean age 62 years, 39% female, mean duration of diabetes 10.8 years, mean HbA1c 8.3%, 33% with previous cardiovascular disease) were monitored for a median 8.8-year follow-up period from randomisation.

Primary variable:

Composite cardiovascular outcome, defined as nonfatal myocardial infarction (MI), nonfatal stroke, or cardiovascular death

Secondary variable:

All-cause death; primary outcome + all-cause death; primary outcome + any revascularisation, or hospitalisation for heart failure; coronary heart disease (CHD) composite (fatal or nonfatal MI, death occurring unexpectedly or after a cardiovascular procedure or noncardiovascular surgery, or unstable angina); and the individual outcomes (nonfatal MI; stroke; nonfatal stroke; all-cause death; cardiovascular death; and heart failure death or hospitalisation.

Methods:

10% of randomly selected cardiovascular outcomes were adjudicated by a masked, independent committee. All cardiovascular outcomes that occurred after randomisation during the active or follow-up period, regardless of the final adjudication status, were analysed.
The incidence rate and number of subjects at risk for events during follow-up was determined using Kaplan-Meier estimates. Hazard ratios and 95% confidence intervals (CIs) for the long-term effect of the allocation (intensive glycaemic control or not) were calculated using models including independent variables that were pre-specified in ACCORD analyses. The level of statistical significance was p<0.05, without adjustment for multiple testing.

Main results:

The difference in HbA1c from ACCORD (7.4% in the intensive therapy group and 7.8% in the standard therapy group, p<0.001) persisted during ACCORDION (7.8% vs. 8.0%, p=0.005) despite similar glucose-lowering treatment regimens and body weight.

Key outcomes are summarised in Table 1.

Allocation to intensive glucose lowering for a mean of 3.7 years had a neutral long-term effect on the first occurrence of the primary composite outcome, and the two secondary composite outcomes.
The increased risk of cardiovascular death reported during ACCORD (1.49; 95% CI 1.19, 1.87; p<0.0001) was still evident during long-term follow-up, although the magnitude of the risk was less (1.20, 95% CI 1.03-1.40, p=0.02).
There was no significant persistent effect on all-cause death in ACCORDION.

Table 1. Clinical outcomes data in ACCORDION

	Allocated to intensive treatment	Allocated to standard treatment	Hazard ratio (95% CI)	P-value
Primary outcome	896 (17.3%)	930 (18.3%)	0.95 (0.87-1.04)	0.27
All-cause death	980 (19.1%)	978 (19.1%)	1.01 (0.92-1.10)	0.91
Nonfatal MI	444 (8.7%)	492 (9.6%)	0.89 (0.79-1.02)	0.09
Nonfatal stroke	227 (4.4%)	261 (5.1%)	0.87 (0.73-1.04)	0.11
CVD death	364 (7.1%)	305 (6.0%)	1.20 (1.03-1.40)	0.02
Primary + all-cause death	1,407 (27.4%)	1,472 (28.7%)	0.94 (0.88-1.02)	0.12
Primary + revascularisation, HF	1,700 (33.2%)	1,792 (35.0%)	0.94 (0.88-1.00)	0.05
CHD composite	898 (17.5%)	961 (18.8%)	0.92 (0.84-1.01)	0.08

Authors’ conclusion:

In high-risk people with type 2 diabetes monitored for 9 years, a mean of 3.7 years of intensive glycaemic control had a neutral effect on death and nonfatal cardiovascular events but increased cardiovascular-related death.

COMMENT

Glycaemic control is an essential component of multifactorial intervention for management of cardiovascular risk in type 2 diabetes, providing a rationale for investigating the effects of intensive versus standard glycaemic management in the ACCORD trial (1). The intensive treatment arm of this trial was, however, prematurely terminated due to increased mortality, leading the authors to advise against this strategy in high-risk patients with type 2 diabetes (2). Whether this effect was sustained over time (i.e. a harmful ‘legacy’ effect of intensive glycaemic treatment), was a key question, which was addressed by long-term follow-up of trial subjects in the ACCORDION study. Despite higher mortality during active treatment in the ACCORD trial, ACCORDION showed a neutral effect on mortality and non-fatal cardiovascular events (see Table 1). While the magnitude of the effect on cardiovascular death was less than that observed in the active treatment trial, this was still a significant finding (49% versus 20% increase in risk).

The reason why intensive glycaemic treatment was associated with this increased risk remains indeterminate. The available evidence does not substantiate the extent of glucose lowering in the intensive treatment arm as the reason, as the excess risk was most evident in individuals with a high HbA1c despite intensive treatment or the addition of other glucose-lowering agents (3,4). Was this a chance finding? Two points of evidence might support this; there was reduction in nonfatal myocardial infarction and other nonfatal cardiovascular outcomes during active treatment, and 2) the all-cause mortality signal evident in the active treatment trial was attenuated during long-term follow-up (see Table 1). In addition, long-term follow-up of other trials in similar patient cohorts does not appear to support a persistent negative effect on cardiovascular mortality (5,6); the United Kingdom Prospective Diabetes Study follow-up evaluation, in newly diagnosed type 2 diabetes patients, also showed a reduction in cardiovascular outcomes (7).

While this question remains inconclusive, the findings illustrate in a broader context the issues to be considered in the management of patients with type 2 diabetes at high cardiovascular risk. For glycaemic management, clinicians need to balance the risk of cardiovascular death observed in both ACCORD and ACCORDION, with the reduction in diabetic retinopathy observed in ACCORD-Eye (8).

References

1. Goff DC Jr, Gerstein HC, Ginsberg HN et al. Prevention of cardiovascular disease in persons with type 2 diabetes mellitus: current knowledge and rationale for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol 2007;99(12A):4i-20i.

2. ACCORD Study Group, Gerstein HC, Miller ME, Genuth S et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364:818-28.

3. Riddle MC, Ambrosius WT, Brillon DJ et al; Action to Control Cardiovascular Risk in Diabetes Investigators. Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010;33:983–90.

4. Miller ME, Williamson JD, Gerstein HC et al. Effects of randomization to intensive glucose control on adverse events, cardiovascular disease and mortality in older versus younger adults in the ACCORD Trial. Diabetes Care 2014;37:634–43.

5. Hayward RA, Reaven PD, Wiitala WL, et al; VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;372:2197–206.

6. Zoungas S, Chalmers J, Neal B, et al; ADVANCE-ON Collaborative Group. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes.NEngl JMed2014;371:1392–406.

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. Chew EY, Ambrosius WT, Davis MD et al; ACCORD Study Group; ACCORD Eye Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233–44.

Key words

type 2 diabetes; ACCORD study; intensive glycaemic control; cardiovascular risk