ACCORD analyses find a few faint glimmers of hope Reply

New analyses of the ACCORD trial, presented at the ADA meeting and published online in the Lancet and the New England Journal of Medicine, find a few, very faint glimmers of hope amid the generally dismal results of the trial.

In the Lancet paper, Faramarz Ismail-Beigi and fellow ACCORD investigators  report on the prespecified analysis of the microvascular composite outcomes of the intensive versus standard glucose control randomized comparison (which was stopped early in 2008 due to excessive mortality in the intensive control arm). In the current analysis, the researchers found no difference between the groups in the prespecified composite endpoints: dialysis or renal transplantation, high serum creatinine (>291·7 μmol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome).

On the other hand, providing a few bits of straw for some, intensive glucose treatment postponed the onset of albuminuria and some measures of eye complications and neuropathy, as well as several secondary outcomes.

The authors write: “We recorded no significant effect of intensive glycaemia therapy on the two prespecified composite microvascular outcomes—advanced renal or eye complications, or these two outcomes or peripheral neuropathy…The 22% relative and 0·27% per year absolute increase in all-cause mortality recorded with intensive glycaemia therapy in ACCORD prompted the discontinuation of intensive glycaemia control and transition of patients to standard glycaemia therapy. Additionally, intensive therapy led to increased body-mass index and a three-fold increase in frequency of severe hypoglycaemia. Furthermore, no overall cardiovascular disease benefit had accrued.”

They conclude: “The observed benefits associated with intensive glycaemia management should be weighed against higher total and cardiovascular-related mortality, weight gain, and severe hypoglycaemia in patients at high risk of cardiovascular disease. Hence, caution should be exercised in pursuit of a strategy of intensive glycaemic control for prevention of microvascular complications in patients with established type 2 diabetes and characteristics similar to those in the ACCORD trial. An HbA1c target of 6·0% or less with present strategies seems imprudent. Long-term assessment of benefits versus risks should be done through follow-up of the ACCORD participants.”

In an accompanying Comment, Ronald Klein wrote  that “the study was too short and the power too low to observe a protective effect for the severe microvascular endpoints.” He concluded that the trial should not “cause clinicians to doubt the importance of glycaemic control in preventing microvascular complications of diabetes. Long-term follow-up of the UKPDS and the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications studies showed that intensive glycaemic control reduced both microvascular and macrovascular complications of diabetes. It might be that the regimen used in ACCORD was perhaps more aggressive than is prudent in patients with type 2 diabetes at high risk for cardiovascular disease. However, with the expected doubling or tripling in the number of people worldwide who will develop type 2 diabetes over the next 20–30 years, it is important that ACCORD’s findings not be misinterpreted as a justification for a return to poor glycaemic control that was common before UKPDS reported.”

In a comment for CardioBrief, Sanjay Kaul said that “clinicians will not given up on the perceived benefits of tight glycemic control (nor should they, in my opinion). However, the ACCORD results do not support any benefit of intensive glycemic control, on “hard” microvascular outcomes. Any treatment benefit in surrogate or intermediate endpoints has to be interpreted within the limitation of a positive result for a secondary endpoint within the setting of a failed primary endpoint – a slippery slope in my assessment!”

ACCORD and Retinopathy

In the second paper, published in the New England Journal of Medicine, the ACCORD Study Group and the ACCORD Eye Study Group report the results of all three ACCORD trials (intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control) on the progression of diabetic retinopathy in a subset of 2,856 ACCORD participants.

At 4 years, the investigators found that intensive glycemic control and intensive combination treatment of dyslipidemia significantly slowed the progression of retinopathy. Intensive blood pressure control had not effect on retinopathy.

  • Intensive glycemia therapy vs standard therapy: 7.3% vs 10.4% (p=0.003)
  • Fenofibrate versus placebo: 6.5% vs 10.2% (p=0.006)
  • Intensive blood-pressure therapy vs standard therapy: 10.4% vs 8.8% (p=0.29)

Here is the Lancet press release:

INTENSIVE THERAPY IMPROVES SOME OUTCOMES FOR PATIENTS WITH ESTABLISHED TYPE 2 DIABETES BUT ALSO INCREASES RISK OF DEATH, WEIGHT GAIN, AND HYPOGLYCAEMIA (from ACCORD study)

An analysis of data from the ACCORD study into intensive therapy of blood glucose (sugar) shows that the benefits of such therapy need to be balanced against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia (low blood sugar). The study is published Online First by The Lancet to coincide with presentation at the American Diabetes Association meeting, and is written by Dr Faramarz Ismail-Beigi, Case Western Reserve University, Cleveland, OH, USA, and colleagues for the ACCORD trial group.

ACCORD was a randomised trial done in 77 clinical sites in North America. People with type 2 diabetes for an average of 10 years, high HbA1c *concentrations (>7·5%), and cardiovascular disease (or ≥2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target HbA1c of <6·0%, normal) or standard (7·0–7·9%) glycaemic therapy.

In this new analysis, the prespecified microvascular composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291·7 μmol/L), or retinal photocoagulation or vitrectomy, all signifying advanced kidney disease and eye disease (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified (less severe) microvascular secondary measures of diabetes-related kidney, eye, and peripheral nerve complications were also assessed.

10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of 22% higher mortality in that group compared with the standard therapy group, and patients were transitioned to standard therapy. At the time of transition of the intensively-treated patients to standard treatment, and at the end of the study, patients from both groups were statistically as likely to reach either composite endpoint. Hence, intensive therapy did not reduce the risk of advanced measures of microvascular outcomes (such as the need for dialysis or eye surgery for diabetes complications). However, intensive glucose treatment delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy, including signs of protein leakage into the urine, deterioration of vision, and evidence of nerve damage.

The authors say: “We recorded no significant effect of intensive glycaemia therapy on the two prespecified composite microvascular outcomes—advanced renal or eye complications, or these two outcomes or peripheral neuropathy…The 22% relative and 0·27% per year absolute increase in all-cause mortality recorded with intensive glycaemia therapy in ACCORD prompted the discontinuation of intensive glycaemia control and transition of patients to standard glycaemia therapy. Additionally, intensive therapy led to increased body-mass index and a three-fold increase in frequency of severe hypoglycaemia. Furthermore, no overall cardiovascular disease benefit had accrued.”

They conclude: “The observed benefits associated with intensive glycaemia management should be weighed against higher total and cardiovascular-related mortality, weight gain, and severe hypoglycaemia in patients at high risk of cardiovascular disease. Hence, caution should be exercised in pursuit of a strategy of intensive glycaemic control for prevention of microvascular complications in patients with established type 2 diabetes and characteristics similar to those in the ACCORD trial. An HbA1c target of 6·0% or less with present strategies seems imprudent. Long-term assessment of benefits versus risks should be done through follow-up of the ACCORD participants.”

In an accompanying Comment, Dr Ronald Klein, Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA says the ACCORD study was too short and did not have enough statistical power to observe a protective effect for the severe microvascular endpoints, which usually evolve over a longer period. He says it took the UK Prospective Diabetes Study (UKPDS) about 10 years to show efficacy of intensive glycaemic control for the same advanced endpoints.

He concludes: “I do not believe that the ACCORD experience will (or should) cause clinicians to doubt the importance of glycaemic control in preventing microvascular complications of diabetes. Long-term follow-up of the UKPDS and the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications studies showed that intensive glycaemic control reduced both microvascular and macrovascular complications of diabetes. It might be that the regimen used in ACCORD was perhaps more aggressive than is prudent in patients with type 2 diabetes at high risk for cardiovascular disease. However, with the expected doubling or tripling in the number of people worldwide who will develop type 2 diabetes over the next 20–30 years, it is important that ACCORD’s findings not be misinterpreted as a justification for a return to poor glycaemic control that was common before UKPDS reported.”

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