SGLT2 inhibitors and weight loss

Weight loss and SGLT inhibitors

Weight loss can occur with the use of SGLT inhibitors (1,2,3,4,5,6).

What is the mechanism of this weight loss - how does it relate to the renal excretion of glucose that occurs with these agents?

• does the caloric deficit caused by glucose elimination induce a higher lipid catabolism with a consequent body mass loss?
• does glucose, more concentrated in the glomerular filtrate, promote higher water retention in the urine, which constituted the weight effectively lost?

A 24- week study comparing 2 groups was carried out to help answer these questions (3):

• placebo and metformin versus use of dapagliflozin 10 mg and metformin
  • fhe first obtained result was a more intense polyuria in the second group, which contributed to a greater fluid loss
  • by the end of the study, waist circumference and fat mass index were analyzed, and the following results were found:
    • waist circumference, placebo group = -0.99 cm and dapagliflozin group = - 2.51 cm;
    • fat mass index, placebo group= - 0.74 kg and dapagliflozin group = -2.22 kg
  • the conclusion was that weight loss occurred due to the confluence of both theorized factors there was a greater reduction in a visceral fat deposition in the second group

The average proportional weight loss measured for dapagliflozin and canagliflozin stands between 1 and 3% (1,2,3).

A study was undertaken to determine the effects of empagliflozin on adiposity indices among patients with type 2 diabetes mellitus (4):

• changes in weight, waist circumference, estimated total body fat, index of central obesity and visceral adiposity index were assessed using analysis of covariance and testing of treatment by strata for age, sex and baseline waist circumference in patients with type 2 diabetes mellitus randomized to blinded treatment with empagliflozin versus placebo in clinical trials of 12 weeks (cohort 1) or 24weeks (cohort 2) duration
  • study comprised 3300 patients (cohort 1, =823; cohort 2, N=2477)
    • empagliflozin reduced weight, waist circumference and adiposity indices versus placebo in both cohorts
      • adjusted mean (95% confidence interval) change from baseline in empagliflozin versus placebo was -1.7kg (-2.1 to -1.4kg) and -1.9kg (-2.1 to -1.7kg) for body weight in cohorts 1 and 2 respectively
      • reduction in visceral fat -0.3 (-0.5 to 0.0; p=0.07) and -0.4 (-0.7 to -0.1; p=0.003) for visceral adiposity index in cohorts 1 and 2, respectively

The time at which weight stabilization occurs seems to vary between SGLT2 inhibitors:

• in a 2-year study, which involved the administration of both dapagliflozin (2.5-10 mg) and metformin, weight loss stabilization occurred around week 26, with a reduction of approximately 3.0 kg of mass over this period of time (5)
• in a study which compared such parameters between empagliflozin 10 mg, empagliflozin 25 mg and metformin, stabilization was observed around week 12, with a lower average weight loss value (approximately 2.1 kg)
  • when comparing this average in the monotherapy administration of empagliflozin with the complementary metformin
    • monotherapy with empagliflozin revealed weight loss was 2.1 kg
    • in the co-administration, the average value was 3.3 kg
    • differences remained significant throughout the 90-week study (6)

Reference:

• Sanz-Serra P et al. Dapagliflozin: Beyond glycemic control in the treatment of type 2 diabetes mellitus. Clin Investig Arterioscler 2015; 27: 205-211
• Bode B et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab 2015; 17: 294-303.
• Bolinder J et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab 2012; 97: 1020-1031.
• Neeland IJ et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus Diab Vasc Dis Res. 2016 Mar; 13(2): 119-126.
• Nauck MA et al. Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes Metab 2014; 16: 1111-1120
• Ferrannini E et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care 2013; 36: 4015-4021