Intensive Glucose Control Lowers Microvascular Risks

Liam Davenport

April 11, 2017

Intensive glucose lowering in patients with type 2 diabetes significantly reduces the risk for microvascular kidney and eye complications over the longer term, according to the results of an individual-participant-data meta-analysis. The findings underscore the role for glucose lowering in preventing adverse outcomes.

The study, which was published online in Lancet Diabetes & Endocrinology on March 29, involved data on more than 27,000 patients from four studies that compared more and less intensive glucose control.

Intensive glucose control was associated with a 20% lower risk for kidney events and a 13% lower risk for eye events. There was no significant effect on the risk for nerve-related microvascular events.

Lead researcher Sophia Zoungas, MD, from the George Institute for Global Health, University of Sydney, New South Wales, Australia, told Medscape Medical News that the findings reinforce the need to follow best practice in managing type 2 diabetes.

"There was some concern that, with individualization of glucose targets, people were maybe being a little bit too lenient in some individuals with the targets and that, for want of a better word, people were taking their foot off the pedal," she said.

"These data just reinforce the importance of glucose control for the prevention of microvascular complications," alongside blood-pressure lowering, lipid management, and diet and exercise.

However, Dr Zoungas emphasized that the findings are not able to say which approach to lowering glucose is best, as that depends on the individual patient's target glucose levels and would require comparative-effectiveness trials looking at one drug vs another.

In aiming for target glucose levels, Dr Zoungas explained that this should be weighed against the risk for hypoglycemia. "If there's someone on agents that don't intrinsically increase the risk of hypoglycemia, that we should aim for near-normalizing HbA1c, so 6.5%," she said.

"Where that's not achievable, because the patient needs more complex interventions, such as sulfonylureas or insulin, we may need to be more modest with the target and balance the risk of hypoglycemia."

She added: "Even bringing someone down from an HbA1c of 9.0% to 8.0% would still give us the benefits of what we're seeing [in] the meta-analysis."

"Any improvement is going to be better than none, but if you can get right down to near-normal levels, without agents that cause hypoglycemia, that's obviously going to be the best outcome," she explained.

To compare the impact of intensive vs less intensive glucose control on the risk for microvascular events, the researchers conducted an individual-participant-data meta-analysis of randomized controlled trials comparing the two treatment strategies.

The researchers included trials if they focused on patients with type 2 diabetes and had at least 1000 patient-years of follow-up in each treatment group, as well as at least 2 years of follow-up on randomized treatment.

The primary outcomes were composites of kidney, eye, and nerve events. Kidney events were end-stage kidney disease, renal death, and an estimated glomerular filtration rate less than 30 mL/min per 1.73 m2, and eye events were the need for retinal photocoagulation therapy or vitrectomy, the development of proliferative retinopathy, and diabetic retinopathy progression. Nerve events were the loss of vibratory sensation, ankle reflexes, and light touch.

Four randomized controlled trials met the inclusion criteria:

•  Action to Control Cardiovascular Risk in Diabetes (ACCORD).

•  Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE).

•  UK Prospective Diabetes Study (UKPDS).

•  Veterans Administration Diabetes Trial (VADT).

Together, the trials randomly assigned 27,049 patients with type 2 diabetes to more intensive or less intensive glucose control and followed them up for a median of 5.0 years. The mean age of the participants ranged from 53.3 years to 65.8 years, and the median duration of diabetes was 0 to 10 years. The mean baseline HbA1c ranged from 7.0% to 9.4%.

More intensive glucose control resulted in a pooled absolute difference in mean HbA1c compared with less intensive control of -0.90%, with a mean HbA1c of 6.80% vs 7.74% at the end of follow-up.

More intensive control also resulted in a difference in mean fasting plasma glucose between the two groups of -1.69 mmol/L.

During follow-up, there were 1626 primary kidney events, 795 primary eye events, and 7598 primary nerve events.

More intensive glucose control was associated with a significant reduction in the relative risk for the composite primary kidney outcome vs less intensive control, at a hazard ratio of 0.80 (P < 0.0001). This was largely driven by reductions in the development of every nephropathy.

In addition, more intensive control was associated with a significant reduction in the risk for the composite primary eye outcome, at a hazard ratio of 0.87 (P = 0.042), which was driven largely by reductions in the progression of retinopathy.

There was, however, no significant reduction in the risk for the composite primary nerve outcome, at a hazard ratio of 0.98 (P = 0.68).

Dr Zoungas believes that the lack of significant effect on nerve outcomes may be due to "the way they are measured," adding that "we need to have more standardized ways to be able to assess those particular outcomes."

The team concludes that "glucose lowering remains important for the prevention of long-term microvascular complications in adults with type 2 diabetes."

In an accompanying comment, William G Herrington, MD, PhD, and David Preiss, MD, PhD, from the Nuffield Department of Population Health, University of Oxford, the United Kingdom, describe the microvascular benefits seen with tight glycemic control in the meta-analysis as "important, but modest."

They add: "However, extension of the meta-analysis to the posttrial period is required for a complete assessment of risks vs benefits of this treatment strategy.

"Moreover, this meta-analysis highlights the need to consider potential pathophysiological mechanisms other than glycemic control per se, because residual microvascular risk remains high, despite intensive glycemic control."

They also note that there have been conflicting findings for benefits of intensive glucose control on macrovascular complications.

Consequently, without an individual-participant meta-analysis of all the data from the included trials, "the full absolute benefits of intensive glycemic control on microvascular and macrovascular complications — both overall and among subgroups—will remain uncertain."

Dr Zoungas reports personal fees from Amgen, AstraZeneca/Bristol-Myers Squibb, Janssen Cilag, Merck Sharp & Dohme, Novartis, Sanofi, Servier, and Takeda and institutional contract work from AstraZeneca/ Bristol-Myers Squibb outside the submitted work. Disclosures for the coauthors are listed in the paper. The editorialists have reported no relevant financial relationships.

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Lancet Diabetes Endocrinol 2017. Published online March 29, 2017. Article, Editorial



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