Initiating intensive therapy in treatment-naive, newly-diagnosed patients with type 2 diabetes preserved beta-cell function for 3.5 years….
Ildiko Lingvay, MD,assistant professor of internal medicine at University of Texas Southwestern Medical Center, said during her presentation at ADA that, “Everybody knows that type 2 diabetes is a progressive disease and this progression is determined by a progressive decline in beta-cell function over time.” “Our ideal goal as physicians when we treat our patients is to preserve beta-cell function, either by decreasing the slope of decline or, ideally, by stabilizing beta-cell function over time — a disease-modifying effect.”
In view of data from the UKPDS and ADOPT studies, Lingvay and colleagues developed a treatment strategy that they hoped would preserve beta-cell function in treatment-naive patients who were newly diagnosed with type 2 diabetes. They randomly assigned patients to insulin-based treatment or triple oral therapy preceded by a short, 3-month course of insulin-based therapy.
All patients were treated with insulin and metformin during the 3-month run-in, after which they were randomly assigned to treatment continuation or triple oral therapy. The goal of the run-in period, according to Lingvay was to remove the transient stunning of beta-cell function due to glucotoxicity.
All patients were treated with Novolog 70/30 at 0.2 U/kg or metformin at 500 mg daily, which was titrated weekly to 1,000 mg twice daily. Triple oral therapy included glyburide 1.25 mg twice daily, which was titrated throughout the study; metformin 1,000 mg twice daily and pioglitazone (Actos, Takeda) 15 mg titrated during 3 months to 45 mg.
Treatment failure was defined as HbA1c ≥8%. If patients in the triple oral arm achieved this target, they were switched to the insulin group. Similarly, if patients in the insulin group achieved this target, they remained on insulin with the option to change the frequency or type of treatment.
Lingvay and colleagues screened 67 patients; 63 enrolled and 58 finished the 3-month run-in and were randomized in a 1:1 fashion with continued insulin or were switched to triple oral therapy. At the time of diagnosis, the average HbA1c was 10.6%; after the 3 months of the run-in period, HbA1c was reduced to 5.9% and 100% of participants achieved the ADA-recommended goal of HbA1c ≤7%.
At the time of randomization, age was about 45 years, 80% were minorities, average BMI was 36 and the insulin dose was 0.6 U/kg, which was three times the initial dose. There was a rapid improvement in glycemic control within the first 3 months, with normalization of glucose then sustained glycemic control through 3.5 years, regardless of treatment assignment.
Treatment failure occurred in three patients in the insulin group and five in the triple oral therapy group.
In regards to the main outcome of beta-cell function, C-peptide AUC/glucose AUC did not show the expected decline, Lingvay said. Stabilization of beta-cell function occurred in both treatment groups.
Weight increased in both groups, but there was no statistically significant difference. Mild hypoglycemia was defined conservatively (any home glucose measurement of <70 mg/dl associated with any symptoms suggestive of hypoglycemia) and occurred at a rate of one per month during the first 4 months. According to Lingvay, the rate decreased to less than 0.5 events per month and remained low during the course of the study.
“This is a very important finding, in light of a very low HbA1c achieved and maintained throughout the study; and the fact that; all patients were treated with insulin or sulfonylurea.” Lingvay said follow-up continues and 6-year results will be available soon.
Before concluding, she shared some lessons learned while conducting this study. “I suggest we try to achieve glycemic normalization as quickly as possible after diagnosis. Additionally, I recommend we maintain glycemic control long-term. Because diabetes is such a multifactorial disease with so many underlying pathophysiological components, I don’t personally think monotherapy is the answer to change the course of the disease. I recommend combination treatment with complementary mechanisms of action. We also need to anticipate disease progression. Treatment intensification should be done while the patient’s glycemic control is still within the target range; I would not recommend waiting until HbA1c go above target before intensifying treatment.”
Lingvay I. CT-SY26. Presented at the ADA Scientific Sessions June 10, 2012