Clinical Efficacy of Metformin HbAlc Lowering But No Weight Gain

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In placebo-controlled trials, metformin lowered HbAlc concentrations by about 1.0-2.0% [8,9]. The efficacy of metformin monotherapy was equivalent to the monotherapy of sulfonylurea or thiazoliden-diones [10,11]. The greatest advantage of metformin compared with other anti-diabetic agents (insulin, sulfonylureas or thiazolidendiones) has been the fact that it is associated with weight loss but not with weight gain [1,9-14]. This has been shown for drug-nai've patients as well as for patients already receiving other oral anti-diabetic drugs. In the UKPDS, weight gain was modest with met-formin and very similar to the diet group, whereas treatment with insulin and sulfonylureas was associated with a significant weight gain of 4-8 kg over 10 years [14]. The effect of metformin to pioglitazone or gliclazide in monotherapy or combination therapy was recently studied in large randomized head-to-head studies (QUARTET

Studies) [11-13]. Table 1 shows that the HbA1c-lowering effect was very similar among the different oral anti-diabetic drugs, whereas weight change versus baseline and the frequency of symptomatic hypoglycaemic events was quite different. In the -head-to-head comparison of metformin with pioglitazone in 1,199 drug-nai've patients using a parallel-group, double-blind study design, HbA1c decreased similarly by 1.4% and 1.5% in both groups from baseline after 52 weeks [11]. However, the glycaemic improvement in the piogli-tazone group was associated with an increase in body weight of 1.9 kg, whereas body weight decreased by 2.5 kg in the metformin group, resulting in a difference of 4.4 kg after 1 year.

Recently, the data of the ADOPT (A Diabetes Outcome Progression Trial) study confirmed the significant difference in weight loss or weight gain when either metformin, glibenclamide or rosiglita-zone was used as first-line monotherapy in patients with recently diagnosed type 2 diabetes [15]. The mean HbA1c level at 4 years was only 0.13% less in the rosiglitazone group than in the metformin group and 0.42% less than in the glibenclamide

Table 1. Effects of oral anti-diabetic drugs on HbAlc, hypoglycaemic events and weight change in four randomized double-blind studies (QUARTET) results after 1 year.

%

Weight change (kg)

Weight difference (kg)

aMetformin

597

-1.5

1.3

-2.5

4.4 0.1

aPioglitazone bMetformin +

597 317

-1.4 -1.5

1.5 1.3

+1.9 +1.5

pioglitazone bMetformin + SU

317

-1.4

11.2

+1.4

cSU + pioglitazone cSU + metformin

320

-1.35 -1.43

10.7 14.1

+2.8 -1.0

3.8

SU = Sulfonylureas

aSchernthaner et al. J Clin Endocrinol Metab 2004;89:6068 [11]. bMatthews et al. Diab Metab Res Rev 2005;21:167 [12]. cHanefeld et al. Diabetes Care 2004;27:141 [13].

aSchernthaner et al. J Clin Endocrinol Metab 2004;89:6068 [11]. bMatthews et al. Diab Metab Res Rev 2005;21:167 [12]. cHanefeld et al. Diabetes Care 2004;27:141 [13].

group. Over a period of 5 years, the mean weight increased from baseline by 4.8 kg in the rosiglita-zone group, but decreased by 2.9 kg in the metformin group, resulting in a difference in body weight of 7.7 kg at the end of the study. Based on these data David Nathan concluded in his editorial [16] that metformin remains the logical choice when initiating pharmacotherapy for type 2 diabetes given the modest glycaemic benefit of rosiglitazone (with the risk of fluid retention and weight gain) and higher cost (including the need for more statins and diuretics). Surprisingly, the proportions of patients with cardiovascular events were similar in the rosiglitazone and metformin groups but were higher than in the glyburide group. This observation differs from the UKPDS findings, which suggested that metformin reduces overall mortality and may reduce coronary events [17]. This difference may be related to the shorter follow-up period of the ADOPT study compared with the UKPDS. In addition, the patients in ADOPT were younger and had better glycaemic control at study entry.

The mechanism for the weight loss associated with metformin therapy despite significant improvement of glycaemic control in contrast to other anti-diabetic drugs is not known, but an anorectic effect has been accused since many years. Several studies have shown that metformin reduces hunger and food intake [18,19]. Interestingly, metformin attenuates hypoglycaemia-induced hunger, but does not appear to influence post-hypoglycaemic food intake [18]. Recent studies may now explain why patients treated with metformin show weight loss or no weight gain despite significant lowering of glycosuria and HbA1c levels. Metformin enhances GLP-1 secretion in experimental animal studies [20] and inhibits DPP IV activity in type 2 diabetic patients [21], suggesting that the drug may have potential for future combination therapy with incretin hormones.

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