The 69th Scientific Sessions of the American Diabetes Association

No difference in mortality risk between surgical and drug treatments for stable heart disease
In people with type 2 diabetes and stable coronary artery disease there is no advantage of prompt revascularisation over intensive medical therapy with regard to total mortality, results from the BARI 2D (Bypass Angioplasty Revascularisation Investigation in Type 2 Diabetes) study show.

This randomised multi-centre trial evaluated both a cardiovascular treatment approach as well as a diabetes control approach for the treatment of stable coronary artery disease in 2368 people with type 2 diabetes. Participants were randomised to receive either prompt revascularisation with intensive medical therapy, or medical therapy alone, and to undergo either insulin-sensitising or insulin-providing therapy. Primary end points were the rate of death and a composite of death and myocardial infarction or stroke (major cardiovascular events).

When considering the composite endpoint, Trevor Orchard, Professor of Epidemiology, University of Pittsburgh Graduate School of Public Health, and Director of the Lipid Management Centre of BARI 2D, said: “Prompt coronary artery bypass surgery, compared to intensive medical therapy alone, had significantly better outcomes when cardiovascular events were considered in addition to death.” A large part of this benefit consisted of a reduction in non-fatal heart attacks.

Regarding the different strategies for glucose control, both insulin-providing and insulin-sensitising drugs yielded similar results with regard to mortality and cardiovascular events. It is of note that no increase in heart attacks was observed in participants receiving rosiglitazone.

“BARI 2D results further inform the clinical management of type 2 diabetes in patients with stable coronary artery disease and ischaemia, and strengthen the choice of early coronary bypass surgery over medical therapy alone in those who are appropriate candidates for bypass surgery,” said Saul Genuth, Professor of Medicine, Case Western Reserve University and Director of the Diabetes Management Centre of BARI 2D. He continued: “Some of the observations also support the concurrent use of glycaemic management aimed at reducing insulin resistance”.

Safety of rosiglitazone investigated in RECORD study
When used in appropriately selected individuals, rosiglitazone carries no overall increase in cardiovascular (CV) risk with regard to major morbidity or mortality compared with metformin or sulphonylureas or a combination of both, according to results from the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) study. Over 4000 participants were followed up for an average of 5.5 years in this open-label, multi-centre, randomised trial.

Philip Home, chairman of the study’s steering committee and Professor of Diabetes Medicine, Newcastle University, said “the primary outcome question was whether rosiglitazone was equivalent to its comparators in terms of CV hospitalisation and CV death, and RECORD found that to be the case.”

The incidence of the key secondary outcome – a composite of cardiovascular death, stroke and heart attack – was slightly, but not significantly improved with rosiglitazone compared with metformin or sulphonylurea, with a hazard ratio of 0.93 (confidence interval [CI] 0.74–1.15).

Rosiglitazone was associated with a doubled risk of heart failure, but positive findings in other areas, especially CV death and stroke, almost exactly balanced out the total numbers for the primary outcome, thus meeting the criterion of non-inferiority for rosiglitazone (hazard ratio 0.99; CI 0.85–1.16) compared with metformin and sulphonylurea. Rosiglitazone is not recommended in people with a history of heart failure.

Look AHEAD trial: intensive lifestyle intervention clinically effective
Comprehensive diet and physical activity counselling resulted in a loss of 8.6% of initial weight in a 12-month trial of 5145 people with type 2 diabetes. The comparator group received diabetes support and education only, and exhibited a weight loss of 0.7%. The strongest correlate of weight loss was greater self-reported physical activity followed by treatment attendance and consumption of meal replacements. Orlistat use marginally increased weight loss in participants from the intensive intervention group who had lost <5% of initial weight during the second half of the year.

Expert committee recommends diagnosing diabetes using HbA_1c
HbA_1c should be used to diagnose diabetes, an International Expert Committee assembled by the American Diabetes Association, International Diabetes Federation and the European Association for the Study of Diabetes is recommending.

The committee examined the relationship between long-term glycaemic exposure and complications, and suggested that because HbA_1c is a measure of mean glucose levels over the preceding 3 months, it may serve as a better marker of diabetes than fasting plasma glucose (FPG) levels or oral glucose tolerance tests. They concluded that an HbA_1c value ≥6.5% (≥48 mmol/mol) be used for the diagnosis of diabetes, although it should not be seen as an absolute dividing line between normal glycaemia and diabetes.

David Nathan, Chair of the Expert Committee and Director of the Diabetes Center at Massachusetts General Hospital said “HbA_1c values vary less than FPG values and the assay for HbA_1c has technical advantages compared with the glucose assay. Also, testing for diabetes using HbA_1c is more convenient and easier for patients who will no longer be required to perform a fasting or oral glucose tolerance test”.

The committee announced their recommendation at the conference and published a report online in Diabetes Care.

Sitagliptin/metformin combination tablet compared with metformin
A fixed-dose combination of sitagliptin and metformin has been shown to reduce blood glucose levels significantly more than metformin treatment alone in people with type 2 diabetes.

The results of this large randomised double-blind study, comprising 1250 people with type 2 diabetes and a mean baseline HbA_1c of 9.8% (84 mmol/mol), were presented at this year’s conference. While the combination therapy is not yet licensed for use in the UK, the significant reduction in HbA_1c after week 18 of the 44-week study period is of interest for future clinical practice.

Participants were randomised to either sitagliptin/metformin (50/1000 mg twice-daily) or metformin (1000 mg twice-daily).

Those taking the fixed-dose combination of sitagliptin and metformin as initial therapy achieved mean HbA_1c reductions from baseline of 2.4 percentage points (26.2 mmol/mol) compared with 1.8 percentage points (19.7 mmol/mol) for participants taking metformin alone – a significant between-group difference of 0.6 percentage points (6.6 mmol/mol) (P<0.001).

Professor John Wilding, Head of Diabetes and Endocrinology Clinical Research Unit at the University Hospital Aintree, Liverpool, said: “These latest data for sitagliptin continue to support the use of this flexible class of medicines and develop our understanding of their potential use in the future.”

LEAD 6: Liraglutide compared with exenatide
HbA_1c levels in people with type 2 diabetes treated with liraglutide decreased significantly more than in those treated with exenatide, results of the Liraglutide Effect and Action in Diabetes (LEAD 6) study have shown.

The randomised, open-label study compared the efficacy and safety of once-daily liraglutide with twice-daily exenatide.

Participants taking liraglutide experienced a decrease in HbA_1c of 1.12 percentage points (12.2 mmol/mol) compared with 0.79 (8.6 mmol/mol) for those treated with exenatide (P<0.0001). Liraglutide was also significantly better than exenatide at lowering fasting plasma glucose (–0.16 mmol/L versus –0.60 mmol/L) (P<0.0001).

Greater reduction in HbA_1c using insulin glargine than NPH insulin
Results of a pooled analysis that examined the safety and efficacy of insulin glargine compared with neutral protamine Hagedorn (NPH) insulin in people with type 2 diabetes were presented.

In those aged 65 years or over, insulin glargine treatment resulted in a statistically significantly greater reduction in HbA_1c levels – 1.21 percentage points (13.2 mmol/mol) versus 0.99 percentage points (10.8 mmol/mol) in those treated with NPH insulin. These older participants also experienced significantly greater reductions in fasting plasma glucose with insulin glargine than with NPH insulin.

Low HbA_1c does not account for excess deaths in ACCORD
New analyses have confirmed that low HbA_1c levels did not cause the 20% increased risk of death associated with the intensive treatment strategy in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study published last year.

Matthew Riddle, Professor of Medicine, Oregon Health Science University, and member of the Glycaemia Management Group of ACCORD, explained that an HbA_1c level below 7% (53 mmol/mol) is not necessarily a predictor of mortality risk. His research group found that for every 1 percentage point increase in HbA_1c over 6% (42 mmol/mol), risk of death actually increased by 20%. This suggests that “lower blood glucose levels may be a worthy target in some patients,” he said.

Denise Bonds, Medical Officer for ACCORD at the National Heart, Lung and Blood Institute at the National Institutes of Health, investigated hypoglycaemia as a potential explanation for the increased risk of death.

She said: “We found that severe hypoglycaemia in both groups was associated with a higher risk of death but, among those who had severe hypoglycaemia in the intensive arm, it was associated with a lower risk of death compared to those who had severe hypoglycaemia in the standard group.”