Hemoglobin A_1c values below 7.5% were associated with increased all-cause mortality and cardiovascular events in patients with type 2 diabetes in an analysis of nearly 48,000 patients in a U.K. general practice database.

If confirmed, the findings suggest that diabetes guidelines might need revision to include a definition of a minimum HbA_1c value, Dr. Craig J. Currie of Cardiff (Wales) University and his associates said (Lancet 2010 Jan. 27 [doi:10.1016/S0140-6736(09)61969-3

The study also showed that insulin therapy was associated with higher mortality than combination oral therapy. Unadjusted mortality rates were 16.2 deaths per 1,000 person-years of follow-up for the oral combination therapy group and 27.2/1,000 for the insulin group. After exclusion of patients with high cardiovascular risk or renal impairment, insulin-based therapy remained associated with significantly greater all-cause mortality (HR 1.46) than did combination oral agents, the investigators reported.

The study utilized data from November 1986 to November 2008 in the U.K. General Practice Research Database. Two cohorts of patients aged 50 years and older with type 2 diabetes were assessed: 27,965 whose treatment regimen had been intensified from oral glucose-lowering monotherapy to a combination oral regimen with a sulfonylurea plus metformin, and 20,005 on oral hypoglycemic agents alone who were initiated on insulin with or without concomitant oral agents.

All-cause mortality was the primary outcome. The secondary outcome was the occurrence of a major cardiovascular event among those who had no record of cardiovascular disease before the index date. The mean follow-up was 4.5 years in the oral medication group and 5.2 years in the insulin group.

Patients were divided by HbA_1c decile, with the lowest decile (1) having a median HbA_1c of 6.4% and the highest decile (10) at 10.5%. Mortality varied by HbA_1c decile in both treatment groups, with increased mortality seen in both the highest and lowest deciles. Patients in decile 4, who had a median HbA_1c of 7.5%, had the lowest mortality across deciles, Dr. Currie and his associates reported.

In the combination oral therapy group, only those in deciles 1 and 10 had significantly increased mortality, compared with patients in HbA_1c decile 4. However, in the insulin-treated cohort, deciles 1, 2, 3, 9, and 10 all had significantly greater mortality, compared with decile 4.

Progression to large-vessel disease events occurred in 8.2% of 20,817 patients who did not have large-vessel disease at baseline in the oral medication group, and in 11.9% of 13,475 patients in the insulin group. After adjustment for covariates, the adjusted risk of progression to large-vessel disease in both groups was higher for decile 1 (HR 1.54) and decile 10 (HR 1.36). Compared with combination oral therapy, insulin treatment also was associated with an increased likelihood of progression to a first large-vessel disease event (HR 1.31).

The data suggest that for patients on oral combination therapy, a wide HbA_1c range is safe with respect to all-cause mortality and large-vessel events, but a narrower range may be desirable for patients taking insulin, the investigators commented.

Decreased survival in patients achieving low HbA_1c levels might be related to hypoglycemia, a common complication of intensive blood glucose control. Postulated mechanisms include a link between the sympathomimetic or hypokalemic manifestations of hypoglycemia and the onset of cardiac arrhythmia.

Hypoglycemia might also potentiate glucose variability, contributing to increased oxidative stress and vascular inflammation and predisposing patients to atherosclerotic plaque destabilization and vascular function, Dr. Currie and his associates said.

In an accompanying editorial, Dr. Beverley Balkau and Dr. Dominique Simon noted that although this study does lend support to earlier studies, epidemiologic studies cannot show causal relationships. Moreover, observational databases can't provide the detailed information available in a randomized clinical trial, such as the actual frequency of hypoglycemia.

However, this study does have the advantage of real-world observation, said Dr. Balkau and Dr. Simon, of the CESP Centre for Research in Epidemiology and Population Health, Villejuif, France (Lancet 2010 Jan. 27 [doi:10.1016/S0140-6736(09)62192-9

Dr. Balkau and Dr. Simon recommended that priority be given to treatment with insulin sensitizers for as long as possible in patients with type 2 diabetes, because these drugs allow a low HbA_1c to be achieved without risk of hypoglycemia.

For patients with type 2 diabetes using insulin secretagogues or insulin itself, this study provides a rationale for an HbA_1c threshold of 7.5%, which corresponds to the lowest threshold of death and lowest event rate for large-vessel disease, they said.

Disclosures: The study was funded by Eli Lilly & Co. Dr. Currie has received research grants from and consulted for various pharmaceutical companies, including Eli Lilly. Four of the study coauthors are employees of Eli Lilly. Dr. Balkau and Dr. Simon have served as speakers for and been on the advisory panels of several pharmaceutical companies.

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Decreased survival in patients achieving low HbA_1c levels might be related to hypoglycemia.

Source DR. CURRIE

Mortality May Be Increased at HbA1c Below 7.5%

Mortality May Be Increased at HbA_1c Below 7.5%