Major Finding: HbA1c values below 7.5% were associated with increased all-cause mortality and cardiovascular events.
Data Source: A general practice database analysis of 47,970 type 2 diabetes patients with recently intensified glucose-lowering therapy.
Disclosures: Funding by Eli Lilly & Co. The investigators disclosed ties to numerous manufacturers of diabetes treatments, including Eli Lilly.
Hemoglobin A1c 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 HbA1c 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 (hazard ratio 1.46) than did combination oral agents, the investigators reported.
The study used 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 HbA1c decile, with the lowest decile (1) having a median HbA1c of 6.4% and the highest decile (10) at 10.5%. Mortality varied by HbA1c decile in both treatment groups, with increased mortality seen in both the highest and lowest deciles. Patients in decile 4, who had a median HbA1c of 7.5%, had the lowest mortality across deciles.
In the combination oral therapy group, only those in deciles 1 and 10 had significantly increased mortality, compared with patients in HbA1c 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 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 HbA1c 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 said.
In an editorial, Dr. Beverley Balkau and Dr. Dominique Simon noted that although this study lends support to earlier studies, epidemiologic studies cannot show causal relationships. Moreover, observational databases cannot provide the detailed information available in a randomized clinical trial, such as the actual frequency of hypoglycemia.
This study has the advantage of real-world observation, added 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 said priority should be given to treatment with insulin sensitizers for as long as possible in patients with type 2 diabetes, because these drugs allow a low HbA1c 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 HbA1c threshold of 7.5%, which corresponds to the lowest threshold of death and lowest event rate for large-vessel disease, they said.
Disclosures: Dr. Currie has financial ties to Eli Lilly and other drug companies. Four study coauthors are employed by Eli Lilly. Dr. Balkau and Dr. Simon have financial ties to several drug companies.
Diabetes guidelines might need revision to include a definition of a minimum HbA1c value.