The role of cardiovascular risk factor reduction in reducing the incidence of cardiovascular diseases has recently taken a front stage in the management of cardiac patients. However, the optimal goals for glycemic control, blood pressure and cholesterol control are still a matter of debate. The Effect of an Intensified on Cardiovascular Outcomes and Mortality in Type 2 Diabetes Study (J-DOIT3) aimed to quantify the cardiovascular risk reduction in patients with intensive risk factor control.¹

The investigators conducted a multicenter, open-label, unblinded randomized trial in Japan enrolling 2542 eligible patients with type 2 diabetes mellitus, hypertension and dyslipidemia to conventional (n = 1271) versus intensive (n = 1269) risk reduction therapy, with two ineligible patients removed. Conventional therapy consisted of a goal hemoglobin A1c (HbA1c) of <6.9%, blood pressure <130/90 mmHg, low-density lipoprotein cholesterol (LDL-C) <120 mg/dl (or 100 mg/dL in patients with coronary artery disease), while intensive therapy targeted a HbA1c <6.2%, blood pressure <120/75 mmHg and LDL-C <80 mg/dL (or <70 mg/dL in coronary artery disease patients). The intensive therapy group achieved targeted goals with regards to glycemic, cholesterol and blood pressure control through aggressive lifestyle modifications with diet and exercise and with escalation to pharmacotherapy if said modifications were insufficient to reach goals. The primary outcome was a composite of all-cause mortality, myocardial infarction, cerebrovascular accident, coronary revascularization, carotid artery revascularization and cerebrovascular revascularization. A low cumulative event rate (roughly 1/6 the expected value) had led study coordinators to addend the original protocol to add coronary and cerebral revascularization to the primary composite endpoint. The secondary outcomes included the composite of myocardial infarction, stroke and all-cause mortality as well as onset or worsening of nephropathy or retinopathy. Patients were followed for a median of 8.5 years and were analyzed on an intention-to treat-basis with minimal crossover.

Baseline characteristics were largely similar between both groups with the exception of smoking status – a higher proportion of patients in the intensive therapy group were current smokers (26%) compared to the conventional group (21%). Intensive therapy was associated with a reduction in primary outcome events (109 events) compared to conventional therapy (133 events) but this did not meet pre-specified criteria for clinical significance (HR 0.81, 95% CI 0.63-1.04; p = 0.094). The main secondary outcome of all-cause mortality, myocardial infarction and stroke was also not significant (HR = 0.74, 95% CI 0.54-1.01, p = 0.055). There was no significant difference in subgroup analyses between the two groups. In a post-hoc analysis, there was a significant reduction in cerebrovascular events in the intensive group compared to the conventional group (HR 0.42, 95% CI 0.24-0.74, p = 0.002). All-cause mortality was similar between both groups with roughly 4% mortality in each treatment group and the most common cause of death was cancer-related in both groups (3% vs. 2%).

These results may stimulate discussion on the necessity for aggressive risk factor modification to prevent cardiovascular and cerebrovascular events given the lower rate of stroke in the post-hoc analysis and the trend toward significance in the main secondary outcome (p = 0.055). The higher rate of current smokers in the intensive group may have led to an increased incidence of primary and secondary endpoints in the intensive therapy cohort and underestimated the true difference in risk between the two groups. Additionally, the primary cause of death in this study was primarily cancer-related (60% of deaths) rather than due to cardiovascular or cerebrovascular complications, which is consistent with overall mortality trends in Japanese diabetic patients but may also underestimate risk reduction in non-Japanese patients, where vascular mortality is more common. It is also worth mentioning that retinopathy (HR 0.86, p < 0.046) and nephropathy (HR 0.68, p < 0.0001) were significantly reduced in the intensive group compared to the conventional group, respectively, consistent with prior studies.²

However, there was not a significant reduction in the primary and secondary endpoints in the primary analysis, and one may argue that conventional risk factor targets are sufficient to reduce the burden of cardiovascular and cerebrovascular disease. This study was perhaps too successful in meeting its target therapy goals in the conventional therapy group, eliminating potential difference in risk even with significant reductions in mean HbA1c (6.97% versus 6.69%), systolic blood pressure (128.2 mmHg versus 124.9 mmHg), and mean LDL-C (97.2 mg/dL versus 85.8 mg/dL) in the conventional group compared to the intensive group, respectively (all p<0.001). Indeed, the incidence of cardiovascular and cerebrovascular endpoints was much lower in the J-DOIT3 study compared to previous studies such as the UK Prospective Diabetes Study (UKPDS) trial and the Japan Diabetes Complications Study (JDCS) trial.^3-5

As the authors of the study pointed out, the risk reduction for cerebrovascular disease may be explained by the small difference in blood pressure due to the longer period of follow-up (mean follow-up 8.5 years) compared to prior studies like the landmark Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (mean follow-up 4.7 years).⁶ And although ACCORD used stricter cutoffs for management of diabetes when assessing cardiovascular outcomes (HbA1c goals less than 6%), there was an increased risk of all-cause and cardiovascular mortality, weight gain and hypoglycemia. Additionally, although this reduction in cerebrovascular disease risk is consistent with the results of the Insulin Resistance after Intervention (IRIS) trial,⁷ which showed that aggressive glycemic control plays a role in reducing cerebrovascular events in non-diabetics, this trial focused on the study of a single agent for vascular risk reduction rather than comparing HbA1c targets as a goal for optimizing blood sugar control, reducing its generalizability. The Systolic Pressure Interventional Trial (SPRINT) showed lower rates of cardiovascular events with systolic blood pressure treated to less than 120 mmHg at the cost of increased adverse events in the intensively treated group.⁸ Clearly, intensive risk reduction itself carries a risk of adverse events such as hypoglycemia (also seen in this study), which could lead to cardiovascular morbidity, as well as a higher risk of cardiovascular mortality independently, the same adverse event the intensive risk reduction is aiming to prevent.

The current 2017 American College of Cardiology/American Heart Association hypertension guidelines currently target a blood pressure of <130/80 mmHg (3) with or without diabetes - the same as current Japanese Diabetes Society (JDS) 2016 guidelines for blood pressure management of diabetics.^9,10 The American Association of Clinical Endocrinologists and American College of Endocrinology suggest a target HbA1c of ≤6.5% in low-risk patients in their 2015 guidelines,¹¹ compared to a JDS target of <6.0 when aiming for normoglycemia and <7.0 when aiming to prevent complications. The American guidelines are generally congruent with JDS guidelines and both groups are likely aiming for blood pressure and blood sugar targets that reduce cardiovascular morbidity and mortality in a large majority of patients internationally.

Controlling multiple cardiovascular risk factors does have a benefit in cardiovascular outcomes and mortality, as this trial also showed.^12,13 The negative findings of the J-DIOT3 study are likely due to the relatively small difference between the conventional treatment group and the intensive treatment group, but there did appear to be benefit in reducing risk of stroke, nephropathy and retinopathy, along with a higher risk of adverse events like hypoglycemia. Further studies with outcomes data will hopefully help select patients that would benefit from intensive risk reduction while minimizing risk of adverse events.

References

1. Ueki K, Sasako T, Okazaki Y, et al. Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial. Lancet Diabetes Endocrinol 2017;5:951-64.
2. Gaede P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia 2016;59:2298-307.
3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.
4. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.
5. Sone H, Tanaka S, Iimuro S, et al. Long-term lifestyle intervention lowers the incidence of stroke in Japanese patients with type 2 diabetes: a nationwide multicenter randomised controlled trial (the Japan Diabetes Complications Study). Diabetologia 2010;53:419-28.
6. Ismail-Beigi F, Craven T, Banerji M, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 2010;376:419-30.
7. Kernan W, Viscoli C, Furie K, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321-31.
8. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.
9. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2018;71:e127-248.
10. Haneda M, Nnoda M, Origasa H, et al. Japanese clinical practice guideline for diabetes 2016. J Diabetes Investig 2018. [Epub ahead of print]
11. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American association of clinical endocrinologists and american college of endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocr Pract 2015;21:1-87.
12. Wong N, Zhao Y, Patel R, et al. Cardiovascular risk factor targets and cardiovascular disease event risk in diabetes: a pooling project of the Atherosclerosis Risk in Communities Study, Multi-Ethnic Study of Atherosclerosis, and Jackson Heart Study. Diabetes Care 2016;39:668-76.
13. Bittner V, Bertolet M, Barraza Felix R, et al. Comprehensive cardiovascular risk factor control improves survival: the BARI 2D trial. J Am Coll Cardiol 2015;66:765-73.

Keywords: Metabolic Syndrome, Diabetes Mellitus, Diabetes Mellitus, Type 2, American Heart Association, Blood Glucose, Blood Pressure, Blood Pressure Determination, Carotid Arteries, Cardiovascular Diseases, Cause of Death, Cerebrovascular Disorders, Cerebral Revascularization, Cholesterol, LDL, Cohort Studies, Coronary Artery Disease, Diabetes Complications, Diet, Dyslipidemias, Follow-Up Studies, Glycated Hemoglobin A, Hypertension, Hypoglycemia, Insulin Resistance, Intention to Treat Analysis, Life Style, Myocardial Infarction, Neoplasms, Risk Factors, Risk Reduction Behavior, Smoking, Stroke

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