Basal Plus Prandial Insulin Gets Results

MONTREAL — Insulin added to oral therapy in patients with long-standing type 2 diabetes is best initiated as a basal formulation and then intensified with prandial doses, according to the 3-year results of the Treat to Target in Type 2 Diabetes (4-T) trial.

“The results of our trial support current guidelines, which suggest that basal and prandial insulin regimens should be considered if adequate glycemic control is not achieved with initial regimens,” reported lead author Dr. Rury Holman of the diabetes trials unit at Oxford (England) University.

The findings were announced at the World Diabetes Congress, with simultaneous publication in the New England Journal of Medicine (2009;361:1736-47).

“We now have very clear evidence that the sequence of basal with added prandial gives you less weight gain and less hypoglycemia,” Dr. Holman said in an interview immediately following his presentation.

“The 4-T study supports the initiation of treatment with basal insulin, which is consistent with the concept that fasting hyperglycemia contributes more than postprandial hyperglycemia to glycated hemoglobin levels during periods of poor glycemic control,” Dr. Michael Roden of the German Diabetes Center and the Heinrich Heine University of Düsseldorf, Germany, said in an editorial in the same issue.

However, “it seems premature to recommend specific insulin regimens for patients with newly diagnosed disease.,” he said.

The 4-T multicenter, open-label trial included 708 patients who had inadequate glycemic control on dual oral metformin and sulfonylurea therapy. Mean patient age oas 61.7 years, wid mean disease duration ofwas 9 years.

They were randomized to one of three regimens in the first year: prandial insulin aspart (NovoRapid) three times daily, biphasic insulin aspart (NovoMix 30) twice daily, or basal detemir (Levemir) once or twice daily.

In the second year, sulfonylureas were replaced by a second insulin if hyperglycemia became unacceptable, which was the case in almost 90% of the patient population, Dr. Holman said.

For patients who had started on biphasic insulin, a midday prandial dose was added. Treatments converged for those who had started on either basal or prandial regimens, so that the basal group added prandial doses (10% of the daily basal dose with a minimum and maximum limit) and the prandial group added a basal dose (10 units at bedtime).

“The importance here is the temporal sequence—they are not identical,” Dr. Holman said. “So basal plus prandial was not the same as prandial plus basal …. Those who started with prandial had substantially more prandial than basal at the end, and those who started with the basal and then added prandial ended up with about 50/50.”

Preliminary results published after the first year of the study did not favor the basal insulin regimen, which was the least successful at bringing hemoglobin A_1c levels to 6.5% or less (N. Engl. J. Med. 2007;357:1716-30).

However, “the difference in outcomes from the first to the third year is startling,” Dr. Roden said in his editorial.

Final results showed that fewer than 45% of all patients achieved the HbA_1c target of 6.5% or less. In addition, significantly fewer patients on the biphasic regimen (31.9%), compared with the prandial (44.7%) and basal (43.2%) groups, reached the target.

The basal group gained significantly less weight (3.6 kg) than did the biphasic and prandial groups (5.7 and 6.4 kg, respectively), and the median number of hypoglycemic events per patient per year was lowest in the basal group (1.7), compared with the biphasic (3.0) and prandial groups (5.5).

“Median glycated hemoglobin levels converged after 1 year and remained stable in all groups, for an overall value at 3 years of 6.9%,” wrote the authors (7.1% for biphasic, 6.8% for prandial, and 6.9% for basal, with no significant differences).

The final mean reduction from baseline was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group.

“The overall message of the [final 4-T results] is that you need complex insulin regimens to obtain adequate glycemic control, Dr. Roden said in an interview.

The 4-T study was supported by Novo Nordisk A/S and Diabetes UK. Dr. Holman reported receiving grants, consulting fees, and lecture fees from pharmaceutical companies including Novartis and Novo Nordisk, and royalties from sale of the Unistik single-use safety lancet. Dr. Roden reported receiving consulting and lecture fees from several drug makers, including Novo Nordisk.

MONTREAL — Insulin added to oral therapy in patients with long-standing type 2 diabetes is best initiated as a basal formulation and then intensified with prandial doses, according to the 3-year results of the Treat to Target in Type 2 Diabetes (4-T) trial.

“The results of our trial support current guidelines, which suggest that basal and prandial insulin regimens should be considered if adequate glycemic control is not achieved with initial regimens,” reported lead author Dr. Rury Holman of the diabetes trials unit at Oxford (England) University.

The findings were announced at the World Diabetes Congress, with simultaneous publication in the New England Journal of Medicine (2009;361:1736-47).

“We now have very clear evidence that the sequence of basal with added prandial gives you less weight gain and less hypoglycemia,” Dr. Holman said in an interview immediately following his presentation.

“The 4-T study supports the initiation of treatment with basal insulin, which is consistent with the concept that fasting hyperglycemia contributes more than postprandial hyperglycemia to glycated hemoglobin levels during periods of poor glycemic control,” Dr. Michael Roden of the German Diabetes Center and the Heinrich Heine University of Düsseldorf, Germany, said in an editorial in the same issue.

However, “it seems premature to recommend specific insulin regimens for patients with newly diagnosed disease.,” he said.

The 4-T multicenter, open-label trial included 708 patients who had inadequate glycemic control on dual oral metformin and sulfonylurea therapy. Mean patient age oas 61.7 years, wid mean disease duration ofwas 9 years.

They were randomized to one of three regimens in the first year: prandial insulin aspart (NovoRapid) three times daily, biphasic insulin aspart (NovoMix 30) twice daily, or basal detemir (Levemir) once or twice daily.

In the second year, sulfonylureas were replaced by a second insulin if hyperglycemia became unacceptable, which was the case in almost 90% of the patient population, Dr. Holman said.

For patients who had started on biphasic insulin, a midday prandial dose was added. Treatments converged for those who had started on either basal or prandial regimens, so that the basal group added prandial doses (10% of the daily basal dose with a minimum and maximum limit) and the prandial group added a basal dose (10 units at bedtime).

“The importance here is the temporal sequence—they are not identical,” Dr. Holman said. “So basal plus prandial was not the same as prandial plus basal …. Those who started with prandial had substantially more prandial than basal at the end, and those who started with the basal and then added prandial ended up with about 50/50.”

Preliminary results published after the first year of the study did not favor the basal insulin regimen, which was the least successful at bringing hemoglobin A_1c levels to 6.5% or less (N. Engl. J. Med. 2007;357:1716-30).

However, “the difference in outcomes from the first to the third year is startling,” Dr. Roden said in his editorial.

Final results showed that fewer than 45% of all patients achieved the HbA_1c target of 6.5% or less. In addition, significantly fewer patients on the biphasic regimen (31.9%), compared with the prandial (44.7%) and basal (43.2%) groups, reached the target.

The basal group gained significantly less weight (3.6 kg) than did the biphasic and prandial groups (5.7 and 6.4 kg, respectively), and the median number of hypoglycemic events per patient per year was lowest in the basal group (1.7), compared with the biphasic (3.0) and prandial groups (5.5).

“Median glycated hemoglobin levels converged after 1 year and remained stable in all groups, for an overall value at 3 years of 6.9%,” wrote the authors (7.1% for biphasic, 6.8% for prandial, and 6.9% for basal, with no significant differences).

The final mean reduction from baseline was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group.

“The overall message of the [final 4-T results] is that you need complex insulin regimens to obtain adequate glycemic control, Dr. Roden said in an interview.

The 4-T study was supported by Novo Nordisk A/S and Diabetes UK. Dr. Holman reported receiving grants, consulting fees, and lecture fees from pharmaceutical companies including Novartis and Novo Nordisk, and royalties from sale of the Unistik single-use safety lancet. Dr. Roden reported receiving consulting and lecture fees from several drug makers, including Novo Nordisk.

MONTREAL — Insulin added to oral therapy in patients with long-standing type 2 diabetes is best initiated as a basal formulation and then intensified with prandial doses, according to the 3-year results of the Treat to Target in Type 2 Diabetes (4-T) trial.

“The results of our trial support current guidelines, which suggest that basal and prandial insulin regimens should be considered if adequate glycemic control is not achieved with initial regimens,” reported lead author Dr. Rury Holman of the diabetes trials unit at Oxford (England) University.

The findings were announced at the World Diabetes Congress, with simultaneous publication in the New England Journal of Medicine (2009;361:1736-47).

“We now have very clear evidence that the sequence of basal with added prandial gives you less weight gain and less hypoglycemia,” Dr. Holman said in an interview immediately following his presentation.

“The 4-T study supports the initiation of treatment with basal insulin, which is consistent with the concept that fasting hyperglycemia contributes more than postprandial hyperglycemia to glycated hemoglobin levels during periods of poor glycemic control,” Dr. Michael Roden of the German Diabetes Center and the Heinrich Heine University of Düsseldorf, Germany, said in an editorial in the same issue.

However, “it seems premature to recommend specific insulin regimens for patients with newly diagnosed disease.,” he said.

The 4-T multicenter, open-label trial included 708 patients who had inadequate glycemic control on dual oral metformin and sulfonylurea therapy. Mean patient age oas 61.7 years, wid mean disease duration ofwas 9 years.

They were randomized to one of three regimens in the first year: prandial insulin aspart (NovoRapid) three times daily, biphasic insulin aspart (NovoMix 30) twice daily, or basal detemir (Levemir) once or twice daily.

In the second year, sulfonylureas were replaced by a second insulin if hyperglycemia became unacceptable, which was the case in almost 90% of the patient population, Dr. Holman said.

For patients who had started on biphasic insulin, a midday prandial dose was added. Treatments converged for those who had started on either basal or prandial regimens, so that the basal group added prandial doses (10% of the daily basal dose with a minimum and maximum limit) and the prandial group added a basal dose (10 units at bedtime).

“The importance here is the temporal sequence—they are not identical,” Dr. Holman said. “So basal plus prandial was not the same as prandial plus basal …. Those who started with prandial had substantially more prandial than basal at the end, and those who started with the basal and then added prandial ended up with about 50/50.”

Preliminary results published after the first year of the study did not favor the basal insulin regimen, which was the least successful at bringing hemoglobin A_1c levels to 6.5% or less (N. Engl. J. Med. 2007;357:1716-30).

However, “the difference in outcomes from the first to the third year is startling,” Dr. Roden said in his editorial.

Final results showed that fewer than 45% of all patients achieved the HbA_1c target of 6.5% or less. In addition, significantly fewer patients on the biphasic regimen (31.9%), compared with the prandial (44.7%) and basal (43.2%) groups, reached the target.

The basal group gained significantly less weight (3.6 kg) than did the biphasic and prandial groups (5.7 and 6.4 kg, respectively), and the median number of hypoglycemic events per patient per year was lowest in the basal group (1.7), compared with the biphasic (3.0) and prandial groups (5.5).

“Median glycated hemoglobin levels converged after 1 year and remained stable in all groups, for an overall value at 3 years of 6.9%,” wrote the authors (7.1% for biphasic, 6.8% for prandial, and 6.9% for basal, with no significant differences).

The final mean reduction from baseline was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group.

“The overall message of the [final 4-T results] is that you need complex insulin regimens to obtain adequate glycemic control, Dr. Roden said in an interview.

The 4-T study was supported by Novo Nordisk A/S and Diabetes UK. Dr. Holman reported receiving grants, consulting fees, and lecture fees from pharmaceutical companies including Novartis and Novo Nordisk, and royalties from sale of the Unistik single-use safety lancet. Dr. Roden reported receiving consulting and lecture fees from several drug makers, including Novo Nordisk.