Free fatty acid kinetics during long-term treatment with pioglitazone added to sulfonylurea or metformin in Type 2 diabetes.
BACKGROUND
Free fatty acids (FFAs) are linked to impaired insulin action, but their role in mediating long-term insulin sensitization during diabetes treatment is unclear.


OBJECTIVE
To examine the effect of pioglitazone addition to existing therapy on FFA dynamics and insulin action.


METHODS
Two 2-year, randomized, parallel-group, double-blind, double-dummy, clinical trials.


METHODS
One hundred and seventy-one centres in Europe, Australia and Canada.


METHODS
Male and female patients with Type 2 diabetes inadequately managed with metformin or sulfonylurea.


METHODS
Patients were randomized to pioglitazone (15-45 mg day(-1); n=319) or metformin (850-2550 mg day(-1); n=320) as add-on therapy to gliclazide or pioglitazone (n=317) versus gliclazide (80-320 mg day(-1); n=313) as add-on therapy to metformin.


METHODS
Plasma FFA profiles during oral glucose tolerance tests in selected centres before and during treatment (n=588).


RESULTS
At Week 104, pioglitazone treatment decreased fasting FFAs by 0.08 mmol L(-1) when added to sulfonylurea and by 0.11 mmol L(-1) when added to metformin versus the respective sulfonylurea + metformin groups (0.03 mmol L(-1), P=0.05 and 0.04 mmol L(-1), P<0.05), and this was accompanied by significant improvements in fasting adipose tissue insulin sensitivity. Changes in postchallenge FFAs were similar between groups and not related to changes in liver transaminases, insulin action and secretion. However, the sensitivity of FFA to insulin was affected by treatment (P<0.001) and visit (P<0.05). Insulin sensitivity of FFA rose when pioglitazone was added to sulfonylurea (P<0.05), but decreased for gliclazide + metformin (P<0.05).


CONCLUSIONS
Long-term improvements in adipose tissue insulin sensitivity and reduction in fasting FFAs with pioglitazone may help to reduce lipotoxicity in Type 2 diabetes.
Roden
M
M
Department of Medicine/Metabolic Diseases, Institute for Clinical Diabetology, German Diabetes Center, Heinrich Heine University, Düsseldorf, Germany. michael.roden@ddz.uni-duesseldorf.de
Mariz
S
S
Brazzale
A R
AR
Pacini
G
G
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D005907:Gliclazide / Q000627:therapeutic use; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D000077205:Pioglitazone; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use*
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D005907:Gliclazide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D000077205:Pioglitazone; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones