Marlene Busko

September 21, 2017

LISBON, PORTUGAL (updated September 22) — 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) suggests.

Compared with patients in the usual-therapy group who had guideline-recommended blood-pressure, lipid, and glucose targets, those in the intensive-therapy group — who had tighter, near-normal treatment targets for these three metabolic parameters — did not have a significantly lower risk of a composite of myocardial infarction (MI), stroke, all-cause death, or revascularization, in an 8.5-year follow-up.

However, this was partly because the control group was so well controlled to begin with. And patients in the intensive-therapy arm did have a significantly reduced risk of this primary outcome after adjustment for baseline differences (mainly that of current smoking).  

Importantly, rates of stroke, nephropathy, and diabetic retinopathy were lower in the intensive-therapy group, without an increase in severe hypoglycemia, Takashi Kadowaki, MD, from the University of Tokyo, Japan, reported at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting.

"Our 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, he said.

"You make life difficult for yourself," session chair Ulf Smith, MD, Gothenburg University, Sweden, suggested facetiously, "when you have a control group that is so well treated."

The assigned commenter, Per-Henrik Groop, University of Helsinki, Finland, added that the small STENO-2 study suggested that a multipronged approach to control blood glucose, lipids, and blood pressure is warranted for type 2 diabetes, but it had less intense target levels than J-DOIT3.

The take-home message from this newest Japanese study "is that we should aim for near-normal metabolic parameters in our patients when it comes to blood pressure, lipids, and glucose control," he told Medscape Medical News.

As a nephrologist, he was struck by the "dramatic decrease in kidney disease" seen in J-DOIT3, and it was "fantastic" that this was attained without a high proportion of patients reaching hypoglycemia.

"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."

J-DOIT3 Bigger Than STENO-2 Trial

Most guidelines recommend that patients with type 2 diabetes aim for an HbA1c of 7.0%, noted J-DOIT3 coauthor Kohjiro Ueki, MD, University of Tokyo, while outlining the background and design of the study.

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," he said, but there were only 80 patients in each arm and the mean HbA1c level was high, at 7.9%.

Thus J-DOIT3 aimed to assess the effects of intensified vs usual control of glucose, blood pressure, and lipids on macrovascular complications, all-cause mortality, and microvascular complications, in a larger cohort.

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.

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.

Intensive Therapy Significantly Reduced Strokes, Nephropathy

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%).

Baseline, Target and Achieved Metabolic Parameters: Conventional Therapy vs Intensive Therapy

Metabolic parameter Baseline Conventional-therapy group Intensive-therapy group
Target Achieved Target Achieved
HbA1c, % 8.0 <6.9 7.2 <6.2 6.8
Systolic BP, mm Hg 134 <130 129 <120 123
Diastolic BP, mm Hg 80 <80 74 <75 71
LDL, mg/dL 125 <120a 104 <80b 85
HDL, mg/dL 55 >40 >40
Triglycerides, mg/dL 122 <150 <120
BMI 25 <24 <22
a. <100 if patient has CAD
b. <70 if patient has CAD

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; = .094)

However, after adjustment for baseline differences (mainly in smoking), there was a significant reduction in risk of this composite outcome (HR, 0.76; = .042).

With intensive therapy, the secondary outcome of MI, stroke, or death was reduced, but this was still not significant (HR, 0.74;= .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 (= .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 (< .001).

Similarly, fewer patients in the intensive therapy developed or had worsening diabetic retinopathy: 317 patients vs 362 patients, a 14% reduction in risk (= .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.

With regard to types of drug used in J-DOIT 3, 62% of 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.

"Important, Long-Awaited Study"

"This is an important and long-awaited study of the effect of multifactorial treatment on macro- and microvascular disease in a large set of patients," Dr Groop summarized.

"We have been alluding to STENO- 2 for such a long time, and the citation rate is very high" (N Engl J Med 2003;348:383-393 was cited 2241 times, and N Engl J Med 2008;358:580-591 was cited 1460 times) — "because that has been the study that tells us that multifactorial treatment works, but we haven't had a big study, and now we have one."

J-DOIT3 showed that targeting normal or near-normal values for these parameters leads to low risk of both macrovascular and microvascular complications, which is "fantastic," he emphasized.

"Finally, now we have a replication of multifactorial treatment scheme introduced by the STENO-2 trial, in a much larger population," about 16 times larger.

The study has been accepted by Lancet Diabetes & Endocrinology for publication, Dr Kadowaki announced, and the researchers are also conducting a follow-up 5-year study.

How Do These New Data Sit With ACCORD, VADT, and ADVANCE?

Asked by Medscape Medical News how these new J-DOIT 3 data sit when viewed alongside older trials such as ACCORD, VADT, and ADVANCE, which showed an increased risk of severe hypoglycemia and even increased risk of cardiovascular mortality with intensive glycemic control, Dr Groop said: "It is well known that these studies…threw the whole field into confusion and even made the ADA and EASD loosen up the glycemic targets. This was not a good decision in terms of prevention of complications, but at the time, after these studies, it was of course a way to avoid unnecessary CV deaths."

Hypoglycemia is and has been a big problem in the treatment of glycemic control in patients with diabetes, he added, but "now we have new medications that do not cause hypoglycemia by themselves (DPP-4 inhibitors, SGLT2-inhibitors, and GLP-1 agonists), and we can in fact achieve optimal glycemic control without the hazard of severe hypoglycemia."

In J-DOIT3, the use of sulfonylureas and insulin (that are definitely closely associated with a higher risk of hypoglycemia) was lower than in trials such as ACCORD, he added. "Thus, in J-DOIT3 they were able to achieve optimal glycemic control with the associated benefits without any additional risk of hypoglycemia."

In Japan, the use of DPP-4 inhibitors is very common, and the Japanese seem to aim at tighter glycemic control than is usual in the West, he noted.

"If you use medications that are not associated with higher risk of hypoglycemia, then you have a chance to achieve better control without the risk of hypoglycemia."

The study was funded by the Ministry of Health, Labor, and Welfare of Japan as well as multiple pharmaceutical companies.

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

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