Pharmacological Treatment of the Pathogenetic Defects in Type 2 Diabetes

Abstract

OBJECTIVETo determine the effect of treatment with insulin aspart compared with NPH insulin, together with metformin/placebo and rosiglitazone/placebo. The hypothesis was that combined correction of major pathogenetic defects in type 2 diabetes would result in optimal glycemic control.RESEARCH DESIGN AND METHODSThis study was a 2-year investigator-driven randomized partly placebo-controlled multicenter trial in 371 patients with type 2 diabetes on at least oral antiglycemic treatment. Patients were assigned to one of eight treatment groups in a factorial design with insulin aspart at mealtimes versus NPH insulin once daily at bedtime, metformin twice daily versus placebo, and rosiglitazone twice daily versus placebo. The main outcome measurement was change in A1C.RESULTSA1C decreased more in patients treated with insulin aspart compared with NPH (−0.41 ± 0.10%, P < 0.001). Metformin decreased A1C compared with placebo (−0.60 ± 0.10%, P < 0.001), as did rosiglitazone (−0.55 ± 0.10%, P < 0.001). Triple therapy (rosiglitazone, metformin, and any insulin) resulted in a greater reduction in A1C than rosiglitazone plus insulin (−0.50 ± 0.14%, P < 0.001) and metformin plus insulin (−0.45 ± 0.14%, P < 0.001). Aspart was associated with a higher increase in body weight (1.6 ± 0.6 kg, P < 0.01) and higher incidence of mild daytime hypoglycemia (4.9 ± 7.5 vs. 1.7 ± 5.4 number/person/year, P < 0.001) compared with NPH.CONCLUSIONSInsulin treatment of postprandial hyperglycemia results in lower A1C than treatment of fasting hyperglycemia, at the expense of higher body weight and hypoglycemic episodes. However, insulin therapy has to be combined with treatment of both peripheral and liver insulin resistance to normalize blood glucose, and in this case, the insulin regimen is less important.

Metformin, but Not Rosiglitazone, Attenuates the Increasing Plasma Levels of a New Cardiovascular Marker, Fibulin-1, in Patients With Type 2 Diabetes

“…In this 2-year, investigator-driven, prospective, randomized, partly blinded trial (27), we tested the hypothesis that metformin and/or rosiglitazone modulates the level of plasma fibulin-1 in patients with T2D. We found a significant fibulin-1-lowering effect of metformin, but not of rosiglitazone.…”

“…The HbA 1c results for all eight treatment groups have previously been reported (27). In Table 1, we present baseline patient characteristics for the four treatment groups, which are the main focus in this investigation, i.e., patients treated with insulin only (NPH or aspart, control), metformin only, rosiglitazone only, or a combination of metformin and rosiglitazone.…”

“…Patients between 30 and 70 years of age with T2D were admitted to eight hospital centers participating in the South Danish Diabetes Study (SDDS) conducted between January 2003 and July 2006 (27). Eligibility criteria included BMI .25 kg/m 2 , fasting plasma C-peptide .300 pmol/L, HbA 1c .7% (53 mmol/mol), diagnosis of T2D at least 2 years before participation, and treatment for at least 3 months with stable doses of oral antidiabetics and/ or insulin.…”

“…After a 4-week run-in period, 371 eligible patients were randomized to one of eight treatment groups in a factorial design with NPH insulin versus insulin aspart, metformin versus placebo, or rosiglitazone versus placebo, as previously described (27). The factorial design made it possible, in the present paper, to present the combined results from groups treated with the two different insulins, since these treatment modalities did not influence plasma fibulin-1.…”

Effects of Mealtime Insulin Aspart and Bedtime NPH Insulin on Postprandial Inflammation and Endothelial Cell Function in Patients with Type 2 Diabetes

“…Patients with type 2 diabetes in the outpatient clinics at the Departments of Endocrinology, Hospital of South West Denmark, Esbjerg and Odense University Hospital, Odense, Denmark, were invited to participate in the study, if they at the same time participated in the South Danish Diabetes Study (SDDS) 1-year follow-up period, in which patients with diabetes 2-3 years previously were randomized to insulin NPH or insulin aspart [22]. Seventy-eight patients met the inclusion and exclusion criteria and were recruited for the present meal test study.…”