Background

The effect of intensive glucose lowering therapy on cardiovascular disease (CVD) events, as compared with standard therapy, varies across different clinical trials predominantly due to heterogeneity in study populations and treatments. The Veterans Affairs Diabetes Trial (VADT) previously found Intensive glucose control in patients with poorly controlled type 2 diabetes (T2DM) did not significantly reduce incidence of major CVD events during a median follow-up of 5.6 years (hazard ration [HR]: 0.88, 95% confidence interval [CI], 0.74 to 1.05; P = 0.14).¹ With an extended follow-up of five additional years, VADT researchers re-examined glycemic control and cardiovascular outcomes as well as other major endpoints including total mortality and CVD mortality in T2DM patients after the original blinded intervention had ended.

Methods

The original VADT randomly assigned 1,791 military veterans with T2DM to either intensive or standard glucose control groups. The intensive treatment group received multiple treatment regimens with an HbA_1c target of 1.5% lower than the standard therapy group. After the clinical trial had ended, 92.4% of participants were followed through a national data registry and 77.7% agreed to provide additional data to detect outcomes. The primary outcome was a first major CVD event, and the secondary outcomes were CVD death and all-cause death. Kaplan-Meier curves and Cox regression models were used as the main analyses.

Results

The average age of the cohort was 60.5 years with a mean diabetes duration of 11.5 years. During the intervention phase, the difference in HbA_1c levels between the intensive-therapy group and the standard-therapy group remained around 1.5% points (median 6.9% vs. 8.4%). The difference of HbA_1c narrowed to 0.5% one year after the end of trial and still differed by 0.2-0.3% at three years. Within a median follow-up time of 9.8 years, the hazard ratio of intensive treatment for CVD events was 0.83 (95% CI: 0.70-0.99, p = 0.04) compared to standard treatment. The corresponding absolute risk reduction was 8.6 per 1,000 person-years and the 10-year number needed to treat was 116 in order to prevent one CVD event per year. Intensive glycemic control did not significantly reduce CVD mortality or total mortality. The effect of intensive glucose lowering was homogeneous regardless of baseline CVD risk score, prior CVD events, or absolute HbA_1c level.

Conclusion

Tight glycemic control was found to lower the CVD risk of older T2DM patients with long DM duration by 17% after nearly 10 years of follow-up, yet it did not reduce the chances of CVD-related death and all-cause death.

Commentary/Perspective

With follow-up extended to almost 10 years, VADT researchers found that compared to conventional control, tight glycemic control reduced future CVD risk in T2DM patients by 17%. This finding contrasts from the original outcome of the same study five years ago, in which intensive therapy showed no difference in lowering CVD risks (HR: 0.88, 95% CI, 0.74 to 1.05; P = 0.14).

Several large clinical trials have investigated the relationship between intensively lowering the blood glucose and the occurrence of CVD events in patients with T2DM but obtained quite different conclusions. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study found an increased CVD event rate in the intensive therapy group and was discontinued earlier than designed.² The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the original VADT found no difference of CVD incidence in the intensive treatment group versus the conventional treatment group.^1,3 Only the U.K. Prospective Diabetes Study (UKPDS) found beneficial effect of intensive therapy on CVD but only after longer-term follow-up, hence indicating a glycemic legacy effect.⁴ Clinical heterogeneity of these studies may be responsible for the difference. First of all, UKPDS were mostly younger patients with shorter DM duration and better tolerated side effects like hypoglycemia. It was previously found that those with long duration of diabetes had an increased risk of severe hypoglycemia, which may trigger acute CVD events.^5,6 Secondly, the multi-drug therapy (in ADVANCE and VADT) with a more aggressive HbA_1c target might have increased the chance of adverse events to counter the benefit.

Both the UKPDS (targeting T2DM) and the Diabetes Control and Complications Trial (targeting T1DM) indicated a durable effect of intensive therapies in reducing CVD risk despite a loss of the glycemic difference (metabolic memory).^4,7 Although the current paper with the longer-term follow-up of VADT cannot fully demonstrate the legacy effect, it at least provides us some clue. Perhaps further follow-up will demonstrate benefit in additional endpoints (e.g., CVD mortality) not seen from the current follow-up.

The new findings from VADT provide perspective to current clinical practice as well as research insights. As time goes by, the benefit of tight glycemic control is revealed and may persist for years beyond the conclusion of randomized therapy. Thus, treating T2DM patients early at a young age may play critical role in preventing long-term macrovascular complications. In addition, glucose monitoring and prevention of hypoglycemia should take priority during intensive therapy. For those susceptible to hypoglycemia and other adverse events, treatment should be tailored to be both safe and effective. Given that T2DM patients are often accompanied with other metabolic comorbidities, combined therapy with statins, hypertension medication, or/and antiplatelet medication might be more useful to prevent CVD events while sparing patients from high-dose hypoglycemic treatment and potential related adverse events. From the perspective of future research, the paradoxical conclusion from the above-mentioned studies merits exploration, and elucidation of the key components that dictate risk and benefit may in turn help minimize the potential risk:benefit ratio of intensive therapy.

References

1. 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.
2. The Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
3. The ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.
4. 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.
5. Donnelly LA, Morris AD, Frier BM, et al. Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population based study. Diabet Med 2005;22:449–55.
6. Pladziewicz DS, Nesto RW. Hypoglycemiainduced silent myocardial ischemia. Am J Cardiol 1989;63:1531-2.
7. Nathan DM; DCCT/EDIC Research Group. The diabetes control and complications trial/ epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care 2014;37:9-16.

Keywords: Blood Glucose, Cardiovascular Diseases, Comorbidity, Confidence Intervals, Control Groups, Diabetes Mellitus, Type 2, Drug Combinations, Gliclazide, Follow-Up Studies, Glucose, Hypertension, Hypoglycemia, Hypoglycemic Agents, Indapamide, Metabolic Syndrome, Odds Ratio, Perindopril, Prospective Studies, Registries, Risk, Risk Factors, Vascular Diseases

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