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Intensive Control Again Shows Greater Benefits

Intensive control of blood pressure, glucose, and lipids benefits patients with type 2 diabetes, the long-awaited, large Japan Diabetes Optimal Integrated Treatment Study for 3 Major Risk Factors of Cardiovascular Diseases (J-DOIT3).

The current study again shows that intensive control of blood glucose levels and other health markers benefits people with type 2 diabetes more than standard care.

Those with near-normal treatment targets across blood sugar, blood pressure and lipids had lower rates of stroke, nephropathy and retinopathy. They also experienced less severe hypoglycemia. However, those with tighter control did not have a significantly lower risk of myocardial infarction (MI), stroke, revascularization or all-cause death, which researchers attributed to the control group having such good diabetes management to begin with. The Japanese DOIT3 trial tells clinicians that metabolic control – optimal lipid, blood pressure, and glycemic control – is important, and the better the targets you can achieve, the less microvascular and macrovascular complications you have.

The results show that strict glycemic control can be achieved without increasing severe hypoglycemia and suggest a benefit of a stricter blood-pressure target” than 130/80 mm Hg for primary prevention of stroke.

During 8.5 years of follow-up, there were 133 primary-outcome events (deaths, MIs, stroke or revascularization) in the standard care group, and 109 in the intensive therapy group. While the reduction was nonsignificant, adjustment for variables such as smoking showed there was a significantly reduced risk of these outcomes among the intensive therapy group.

The American Diabetes Association (ADA) and EASD recently changed its blood-pressure targets for patients with type 2 diabetes from 130/80 mm Hg to 140/90 mm Hg and 140/85 mm Hg, respectively, but the Japanese Diabetes Society (JDS) still recommends a target of 130/80 mm Hg due to the high risk of stroke in Japan.  STENO-2 demonstrated that a multifactorial intervention for glucose, blood pressure, and lipids had beneficial effects on microvascular and macrovascular complications and mortality, but there were only 80 patients in each arm and the mean HbA1C level was high at 7.9%.

From 2006 through 2016, the researchers enrolled 2540 patients at 81 diabetes clinics in Japan who had type 2 diabetes, were 45 to 69 years old, and had HbA1C >6.9% plus hypertension and/or dyslipidemia. The patients were randomized to receive conventional vs intensified therapy to reach standard vs tighter glycemic, lipid, and blood-pressure targets. Patients in the conventional-therapy group received Japanese-guideline-recommended lifestyle counseling (about diet, exercise, and smoking cessation) and an accelerometer and a blood-pressure manometer. The patients had a mean age of 59, 38% were women, and 11% had a history of cardiovascular disease. They had relatively well-controlled glucose, blood pressure, and lipids at baseline and had had diabetes for a median of 8.5 years. Patients in both groups had similar baseline characteristics except that patients in the intensive-therapy group were more likely to be current smokers (26% vs 21%) and less likely to be former smokers (29% vs 33%).

Patients in the intensive-therapy group received more frequent education from nutritionists and diabetes educators and a recordable accelerometer, blood glucose meter, blood-pressure manometer, and smoking-cessation aids, if needed. Medications in the intensive-therapy arm were increased in a stepwise manner.

During follow-up, there were 133 primary-outcome events (40 deaths, 11 MIs, 37 strokes, and 45 revascularizations [coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or cerebral revascularization]) in the conventional-therapy group, and 109 primary-outcome events (45 deaths, five MIs, 15 strokes, and 44 revascularizations) in the intensive-therapy group.

With intensified therapy, there was a nonsignificant reduction in the primary outcome of MI, stroke, death, or revascularization (HR, 0.81; P = .094). With intensive therapy, the secondary outcome of MI, stroke, or death was reduced, but this was still not significant (HR, 0.74;P = .055). However, there was “a very clear” 58% reduction in cerebrovascular events (mostly strokes) in the intensive-therapy group compared with the conventional-therapy group (P = .002).

In the conventional-therapy group, there were 37 strokes and three cerebrovascular revascularizations, and in the intensive-therapy group there were 15 strokes and two cerebrovascular revascularizations. Significantly fewer patients in the intensive-therapy group developed nephropathy during follow-up: 181 patients vs 257 patients, a 32% reduction in risk (P < .001).  Similarly, fewer patients in the intensive therapy developed or had worsening diabetic retinopathy: 317 patient’s vs 362 patients, a 14% reduction in risk (P = .046). There were seven patients in the intensive-therapy group and four patients in the usual-therapy group who developed severe hypoglycemia, but the annual incidence of severe hypoglycemia was the same (<0.1%) in both groups.

Patients in the intensive-control arm were taking metformin compared with 56.5% in the usual-therapy group by the final study visit; for dipeptidyl peptidase-4 (DPP-4) inhibitors, these figures were 51.2% and 54.2%, respectively; for sulfonlyureas, 43.7% and 48.5%; and for alpha-glucosidase inhibitors 29.9% and 25.5%. Just 14.1% of the intensive-treatment arm were taking insulin, as were 9.8% of the usual-care arm. Glucagonlike peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors were used by less than 5% of patients in all arms.

Practice Pearls:

  • There was “a very clear” 58% reduction in cerebrovascular events (mostly strokes) in the intensive-therapy group compared with the conventional-therapy group.
  • Significantly fewer patients in the intensive-therapy group developed nephropathy.
  • With intensified therapy, there was a nonsignificant reduction in the primary outcome of MI, stroke, death, or revascularization


European Association for the Study of Diabetes 2017 Annual Meeting. September 15, 2017, Lisbon, Portugal. Statement