The present study has shown that a portion control diet can prevent weight gain in diabetic patients treated with pioglitazone over 16 weeks. Previous studies have shown that the weight gain during treatment with pioglitazone increases with dosage (from 15 to 45 mg/day), ranging from 0.3 to 3.6 kg in monotherapy trials and from 0.9 to 5.5 kg in combination with other antidiabetic drugs [11
]. Thus, the weight gain in our pioglitazone + ADA diet group was comparable to other data and highlights the clinical finding that a portion control diet can prevent this weight gain, offering a potential way to prevent or reduce the weight gain associated with TZDs. A 2.7% (of the initial body weight) weight loss over 16 weeks in the Pio + PC group compares favourably with a 5.24% weight loss over 24 weeks, a 4.35% weight loss over 52 weeks in T2DM [12
] and a 7.8% weight loss in the obese at 12 weeks [13
]. Longer term weight loss studies [14
] have used matched controls gaining weight over time to calculate the weight loss in overweight subjects using a portion control strategy to obtain weight loss.
Although the current trial only lasted 16 weeks, published data would suggest that portion control diets can be effective for a year or more [12
]. In a 4-year study of portion control diets in obese patients in an out-patient setting, weight loss was maintained for 4 years [13
]. In the Look AHEAD trial, diabetic patients lost an average of 8% of their body weight in 1 year using a strategy that included a portion control diet [14
]. Thus, in both diabetic and non-diabetic subjects, this dietary approach may be useful in helping produce and maintain weight loss. This study with pioglitazone suggests a further avenue for use of this strategy to prevent weight gain.
Weight loss is an important component in preventing and treating DM and the MetS [17
]. The Diabetes Prevention Program (DPP) showed that a 7% weight loss along with 150 min of exercise a week reduces the incidence of diabetes by 58% in subjects with impaired glucose tolerance [9
]. Although maintaining increased physical activity is an important measure to help sustain weight loss [19
], the DPP data indicate that almost all the benefit was because of weight loss, not exercise. In the DPP, a kilogram of weight loss resulted in a 16% reduction in risk, after adjustment for changes in diet and activity [9
]. The Look AHEAD trial [16
] also demonstrates that weight loss in diabetic subjects (in the intensive lifestyle intervention group) significantly improves glycaemic control and lipoprotein metabolism along with a reduction of blood pressure, despite a decrease in medications use.
Calorie restriction with or without exercise improves insulin sensitivity and beta-cell function, reduces fat cell size and ectopic lipid deposition in overweight subjects [20
]. Weight loss by calorie restriction, with or without exercise, also results in reduction in fat cell size. Treatment with pioglitazone increased new small fat cells in the subcutaneous compartment [2
]. We would suggest that subjects in the pioglitazone plus portion control group improved insulin sensitivity by decreasing fat cell size and reducing the total quantity of body weight and visceral fat through activation of PPAR-γ receptor.
Metformin is widely used in the treatment of diabetes and is weight neutral or produces weight loss [9
]. In the Diabetes Prevention Program [9
], a double-blind randomized trial of metformin in patients with impaired glucose tolerance showed that it could significantly reduce body weight and reduce the incidence of diabetes over 2.8 years by 31%. Other data also suggest that metformin can reduce body weight [22
]. Metformin was thus selected as the comparator for the pioglitazone-portion control diet group. Although the weight loss with metformin plus the ADA diet and pioglitazone plus the portion control diet were almost identical, there were a number of differences between pioglitazone and metformin, including change in deep subcutaneous fat and a borderline difference in visceral fat. Total body fat measured by DXA and deep subcutaneous fat measured by CT were both significantly higher in the pioglitazone plus ADA group than the metformin + ADA diet group reflecting the weight gain with pioglitazone unless a weight loss therapy similar in effect to the portion control diet is implemented during pioglitazone therapy.
Both pioglitazone and metformin improved insulin resistance, as measured by HOMA-IR [23
]. This was the result of the significant reductions from baseline in both glucose and insulin concentrations in all three groups. However, the subjects treated with pioglitazone had a greater decrease in HOMA-IR than the metformin group, indicating that the weight gain usually associated with pioglitazone does not impair its effect in improving diabetic control.
Pioglitazone also improved HDL-C. In the pio + ADA group HDL-C increased by 13% and in the Pio + PC group it increased 18% when compared with a 4% increase in the metformin group, again indicating that the effect of pioglitazone was independent of weight change. Increase in HDL-C, the driver of the reverse cholesterol transport pathway [24
] has recently been shown to reverse atherosclerosis in the CHICAGO trial [26
]. In this trial of diabetic subjects, there was a significant increase in HDL-C after 24 weeks in the pioglitazone-treated group compared with the glimepiride-treated group. This increase was maintained throughout the follow-up at 72 weeks and was accompanied by a significant slowing in progression of carotid artery intima-media thickness. The Quebec Heart Study has shown that for every 10% reduction in HDL-C, the risk for coronary artery disease (CAD) increased by 13% [27
]. Conversely, a 10% increase in HDL-C should result in 13% reduction in CAD risk. The 13 and 18% increase in HDL-C in the Pio + ADA and the Pio + PC groups, in our study, might thus translate into a reduction of 17 and 23%, respectively, in CVD risk. The GALI study has demonstrated a significant decline in triglycerides, a significant increase in HDL-C and no change in non-HDL-C lipoproteins during treatment with pioglitazone when compared with treatment with rosiglitazone [28
]. A decrease in LDL-C particle number with an increase in particle size (smaller number of large buoyant less atherogenic particles) was also demonstrated in the pioglitazone group. Pioglitazone lowers triglycerides by increasing lipoprotein lipase mass and inhibiting plasma apoC-III production rates [29
]. PPAR-γ stimulation with pioglitazone produces beneficial changes in lipoprotein particle composition with reduction of triglyceride content, in very low-density lipoprotein, intermediate density lipoprotein and high-density lipoprotein (HDL) [30
Although the LDL-C increased in both pioglitazone-treated groups and decreased in the metformin group, cardaic risk ratios (Total-C/HDL-C, LDL-C/HDL-C and TG/HDL-C) declined in all groups. Pio + ADA (from 4.1 to 3.6, from 2.14 to 2.09 and from 3.8 to 2.8), Pio + PC (from 4.2 to 3.9, from 2.3 to 2.2 and 3.7 to 2.9) and Met + ADA (from 3.8 to 3.6, from 2.1 to1.9 and 3.6 to 3.1, respectively) indicating an improved CVD risk profile.
Waist circumference decreased implying a reduction in visceral fat and an improved cardiometabolic risk profile [31
]. Subjects between 40 and 70 years of age, with blood pressures between 115/75 to 185/115, double their cardiovascular disease risk with a rise of 20 mmHg systolic blood pressure (SBP) or a rise of 10 mmHg diastolic blood pressure (DBP) [33
]. There was a significant decrease in blood pressure in the Pio + PC group when compared with the Pio + ADA diet group, the benefit of weight loss. A drop of 8 mmHg in SBP and a 6 mm in DBP in the Pio + PC group could account for a substantial cardiovascular disease risk reduction. The obese T2DM subject in the pioglitazone plus portion group positively modified all the parameters of the MetS, including a reduction in systolic and diastolic blood pressure, triglycerides, glucose, waist circumference and an increase HDL-C.
The strengths of the present study include the fact that participants were randomized to treatment groups and that more than 90% completed the study. In addition, there was a clear separation in weight changes with a loss of weight occurring in the group receiving metformin plus ADA diet and the group receiving pioglitazone plus portion control diet and a gain of weight in the pioglitazone plus ADA diet group. Although the study was only 16 weeks in duration, other data would suggest that the portion control effect can remain effective for more than a year. The Pio + PC group also had a significant decline in visceral adipose tissue (vs. Pio + ADA).
In summary, we found that pioglitazone plus a portion control diet significantly reduced weight gain, visceral fat and waist circumference when compared with pioglitazone used with the ADA diet. Pioglitazone treatment in well-controlled obese T2DM, when compared with metformin treatment, significantly modified the parameters of the MetS and reduced cardiovascular risk.