Talking about "hypoglycemia" and "stability": do sulfonylureas make weight gain?

Hypoglycemic ability, body weight effect, etc.
, have always been the main factors considered by clinicians when prescribing hypoglycemic drugs, and the weight benefits obtained by using hypoglycemic drugs rank in the top three of all considerations [1].

Hypoglycemic drugs sulfonylureas have been classified by major guidelines and consensus as having a positive effect on body weight [2].

Sulfonylureas are the earliest oral hypoglycemic drugs put into use in clinical practice, and since 1955, the first generation of sulfonylurea hypoglycemic drugs have been developed and applied to clinical practice, and have made indelible contributions to reducing the mortality and disability rate of acute hyperglycemic events in diabetic patients [3].

However, as the consensus points out, different hypoglycemic drugs have different effects on body weight, and the same sulfonamide drugs also have different effects on body weight [4].

The UK Prospective Diabetes Study (UKPDS), a multicentre randomized controlled trial design involving 2520 patients with newly diagnosed type 2 (T2DM), compared the efficacy and safety
of diet control alone and the addition of chlorpropamide, glibenclamide, insulin or metformin (in obese patients).
。 The results of the study showed that the average weight of T2DM patients treated with chlorsulfafenclamide and glibenclamide on the basis of controlled diet was 3.
5 kg and 4.
8 kg (P<0.
001), suggesting that chlorpropamide and glibenclamide had a greater impact on the patient's weight and could cause weight gain [5].
<b11>

Overweight or obesity is not only the most important predisposing factor for the development of T2DM, but also an important risk factor
for the development of macrovascular complications such as coronary heart disease.
In patients with T2DM, the accumulation of fat, especially visceral fat, can exacerbate insulin resistance and glucose intolerance, making blood glucose more difficult to control [6].

The effect of traditional sulfonylureas (e.
g.
, chlorpropamide, glibenclamide, etc.
) on weight gain in patients may compromise the benefits of improved glycaemic control
.

Sulfonylureas have been developed to the third generation, glimepiride is the representative of the third generation of sulfonylurea hypoglycemic drugs, what is its impact on weight? Are there differences in the effect of different sulfonylureas on body weight?

The ZODIAC-39 cohort study is a retrospective cohort study of 29195 patients with T2DM who received metformin monotherapy for ≥ 1 year from 1998 to 2012, followed by the addition of sulfonylureas for ≥ year and >were aged 18 years, to investigate the trajectory
of weight change with sulfonylurea addition in metformin-treated T2DM patients.
The primary endpoint was weight change for each year after receiving add-on therapy during the five-year follow-up period; The secondary endpoint was annual change in
HbA_1c after receiving add-on therapy.
After 5 years of follow-up, it was found that the weight of patients in the metformin combined with glimepiride group only increased by 0.
1 kg, while the weight of metformin + gliclazide group and metformin + glibenclamide group increased by 3.
9 kg and 3.
3 kg, respectively (Figure 1).

It can be seen that compared with traditional sulfonylureas, glimepiride treatment has a small effect on body weight, which may be related
to the sensitization mechanism of glimepiride.

The weight of the glimepiride group increased by only 0.
1 kg, the gliclazide group increased by 3.
9 kg, and the glibenclamide group increased by 3.
3 kg

Fig.
1 Change of average weight value after 5 years of treatment

The CAROLINA study also confirmed the above conclusions, in which up to 6 years of follow-up, the number of patients in the glimepiride-treated group was 2998, the average baseline weight was 83.
6 kg, and the number of patients in the linagliptin treatment group was 3014, the average baseline weight was 84.
3 kg, and the patients in the two groups had the same baseline weight of about 84 kg
.
Linagliptin sustained weight reduction throughout treatment, while although there was a tendency to gain weight in the early stages of treatment, weight decreased from baseline in the later stages of the study
.
Of course, at the end of the study, there was still a difference in body weight levels between the two groups, with linagliptin being about 1.
5 kg
lower than glimepiride.
However, looking at the entire study, we can find that although glimepiride treatment resulted in higher body weight than in the lidagliptin group, the before-after control actually resulted in weight reduction (Figure 2).

Fig.
2 Weight changes of glimepiride and linagliptin at 5 years of follow-up

Therefore, the third generation of sulfonylurea hypoglycemic drugs represented by glimepiride bind rapidly to the receptor and can stimulate insulin
faster and more effectively.
Compared to conventional sulfonylureas, glimepiride has a relatively small
effect on body weight.

Citations

【1】 market research, conducted by Interbrand Health.
January 6, 2012

【2】 Garber AJ, et al.
Endocr Pract.
2017 23(2):207-238

[3] Yang Wenying.
Expert consensus on the application of sulfonylureas[J].
Chinese Journal of Endocrinology and Metabolism, 2004, 24(4):255-259

[4] Expert consensus on the clinical application of sulfonylureas (2016 edition)[J].
Drug Evaluation, 2017(1).

【5】 United Kingdom prospective diabetes study (UKPDS) 13: relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years[J].
Bmj, 1995, 310(6972):83-88.

【6】 ZHENG Jingchen.
Effects of sulfonylurea hypoglycemic drugs on body weight[J].
DRUG EVALUATION, 2011, 08(23):14-17.

【7】 Rosenstock J, et al.
JAMA.
2019; 322(12):1155-1166.