Basal, prandial insulin added to oral therapy produced greater glycemic control than biphasic insulin regimen

Three-year data support the addition of basal or prandial insulin to oral therapy compared with a biphasic insulin-based regimen in patients with type 2 diabetes.

New data from the Treating-to-Target in Type 2 Diabetes (4-T) trial reveal that the addition of basal or prandial insulin to oral therapy was associated with better HbA1c control, fewer hypoglycemic events and less weight than the addition of biphasic insulin.

“Our results show that using a basal insulin first, then adding prandial insulin as needed, can achieve guideline HbA1c levels with only a modest risk for hypoglycemia or weight gain,” Rury Holman, MD, professor of diabetic medicine and director of the Diabetes Trials Unit at University of Oxford, told Endocrine Today.

Holman and colleagues randomly assigned 235 patients to receive twice-daily biphasic insulin aspart (NovoMix 30, Novo Nordisk), 239 patients to three times-daily prandial insulin aspart (NovoRapid, Novo Nordisk) and 234 patients to once-daily (twice if required) basal insulin detemir (Levemir, Novo Nordisk).

All patients had suboptimal HbA1c levels while on metformin and sulfonylurea therapy. Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or if HbA1c levels were >6.5%.

Holman reported the results of 4-T at a late-breaking clinical trials session at the 20th World Congress of Diabetes, and the data were published simultaneously on The New England Journal of Medicine website.

Differences in therapy regimens

Median HbA1c levels were similar for patients assigned to the biphasic insulin-based regimen (7.1%), prandial regimen (6.8%) and basal (6.9%) regimen (P=.28). However, fewer patients had HbA1c levels ≤6.5% in the biphasic group (31.9%) vs. the prandial group (44.7%; P=.006) and the basal group (43.2%; P=.03).

According to Michael Roden, MD, it was striking that fewer than 45% of patients in the study reached the target HbA1c, and less than one-third assigned to biphasic insulin.

“The difference in outcomes between the first year and the third year is startling. The ratios of prandial to basal insulin suggest that the use of increased doses of prandial insulin contributed to the efficacy of basal-plus-prandial regimens,” Roden, of the Institute for Clinical Diabetology at the German Diabetes Center in Düsseldorf, Germany, wrote in an accompanying editorial.

The researchers observed significant differences in HbA1c levels in patients who replaced sulfonylurea with a second type of insulin in the biphasic group (67.7%), prandial group (73.6%) and basal group (81.6%; P=.002).

The proportion of patients with any type of serious adverse event differed among the groups, and the highest proportion was observed in the biphasic group (P=.01). However, mean weight gain was highest in the prandial group when compared with the biphasic group or the basal group.

Death was reported in seven patients in the biphasic group, nine in the prandial group and three in the basal group (P=.23); four patients in the biphasic group, nine in the prandial group and one in the basal group died from cardiovascular disease (P=.002).

“This pragmatic approach should translate easily into the community care setting, enabling an earlier and easier approach to insulin therapy and by avoiding unnecessary hyperglycemia may help to prevent diabetic complications,” Holman said. – by Jennifer Southall

Holman RR. N Engl J Med. 2009;doi:10.1056/NEJMoa0905479.

These data support the conventional approach to insulin therapy and basal insulin followed by basal plus prandial insulin in patients with type 2 diabetes failing oral metformin plus sulfonylurea therapy. They do not address the relative merits of insulin analogues or of non-insulin approaches. The relatively low rates of hypoglycemia are consistent with the fact that these patients were just failing oral hypoglycemic agent therapy and, therefore, undoubtedly had not yet reached marked absolute endogenous insulin deficiency, perhaps coupled with the challenge of ascertainment (Diabetes. 2008;57:3169-76). Indeed, when measured, the 3:00 a.m. capillary glucose levels were significantly lower with the basal insulin regimen, so the frequency of nocturnal hypoglycemia with that regimen may have been underestimated. The number of deaths did not differ significantly among the groups although the number of those attributed to cardiovascular disease did.

– Philip E. Cryer, MD

Endocrine Today Editorial Board member

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