Unexpected Finding with SGLT2 Inhibitor

Short-term treatment with canagliflozin is linked to increases in the adipokine FABP4 (fatty acid binding protein 4) despite improvements in glycemic control and weight loss, according to a small study published online on April 28, 2016 in PLoSOne. ¹

The study is the first to show a link between canagliflozin treatment and increased FABP4 levels, even though the drug improves adiposity and glycemic control.

 “[T]reatment with canagliflozin paradoxically increases serum FABP4 level in some patients with type 2 diabetes mellitus despite amelioration of glucose metabolism and reduction of adiposity, and this effect is possibly mediated by catecholamine-induced lipolysis in adipocytes,” wrote first author Masato Furuhashi, MD PhD, of Sapporo Medical University (Sapporo, Japan) and colleagues.

“Increased FABP4 level by canagliflozin may partly offset the benefit of improvement in glucose metabolism and might be a possible mechanism of increased hepatic glucose production by inhibition of SGLT2,” he continued.

FABP4 belongs to a class of intracellular lipid chaperones that are thought to be involved in the transport of lipids to compartments within the cell. Adipocytes release FABP4 during catecholamine-induced lipolysis. Increased serum FABP4 levels have been linked to obesity, atherosclerosis, hypertension, cardiac dysfunction, renal dysfunction, dyslipidemia, type 2 diabetes, and insulin resistance. Studies have also linked elevation of FABP4 to hepatic insulin resistance and increased hepatic glucose production, according to background information in the article.

SGLT2 inhibitors promote improved glycemic control through increased urinary glucose excretion.  However, they have also been linked to a paradoxical increase in hepatic glucose production, though the mechanism remains unknown.^2,3

The study included 39 participants (11 female, 28 male, mean age 63, mean BMI 27.9) with T2DM who were being seen at outpatient clinics of the Fujita Health University between October 2014 and March 2015.

Key results after 12 weeks of treatment with canagliflozin 100 mg/day:

• Adiposity:

♦ BMI significantly decreased from 27.9 to 26.5 (P<0.001)

♦ Waist circumference significantly decreased from 94.4 cm to 90.0 cm (P<0.001)

• Fasting glucose: Significantly decreased from 145.9 mg/d to 115.8 mg/d (P<0.001)

• HbA1c: Significantly decreased from 7.4 to 6.5 (P<0.001)

• Average serum FABP4: Increased by 10.3% (P = 0.008)

♦ Elevated FABP4 occurred in 26/39 (66.7%) patients

♦ Decreased FABP4 occurred in 13/39 (33.3%) of patients

• Insulin resistance (HOMA-R): Significantly smaller reduction in patients with increased FABP4 compared to those with decreased FABP4 (-0.53 vs. -2.02, P = 0.009)

The authors noted that changes in FABP4 levels were positively linked to changes in fasting glucose (r = 0.329, P = 0.044), and HbA1c (r = 0.329, P = 0.044), indicating that patients with elevated FABP4 had less improvement in HbA1c and fasting glucose during canagliflozin treatment than those with decreased FABP4. Changes in FABP4 levels were also positively linked to changes in noradrenaline (r = 0.329, P = 0.041), but not to changes in BMI (r = -0.021, P = 0.901) and waist circumference (r = 0.135, P = 0.425).

“These findings suggest that the paradoxical increase in FABP4 concentration by inhibition of SGLT2 is independent of alteration of adiposity and undermines the improvement of glucose metabolism since circulating FABP4 leads to hepatic insulin resistance,” the authors concluded.

The small size and lack of placebo group may have limited the study. In addition, most participants were on several drugs at baseline, including angiotensin II receptor blockers, antidyslipidemic drugs, and DPP-4 inhibitors, which may have had an impact on changes in FABP4. That could complicate determination of the relative contribution of canagliflozin to changes in FABP4 levels.

Take-home Points

• Increased levels of the chaperone protein FABP4 has been linked to obesity, atherosclerosis, hypertension, cardiac dysfunction, renal dysfunction, dyslipidemia, type 2 diabetes, hepatic insulin resistance, and increased hepatic glucose production.

• A small, short-term study in Japan found that canagliflozin significantly increased FABP4 levels in some patients, but not all.

• Patients with increased FABP4 had smaller reductions in insulin resistance than those with decreased FABP4.

• Increased levels of FABP4 during SGLT2 inhibitors treatment might undermine improvements in glycemic control.

The authors report no conflicts of interest.

References:

1. Furuhashi M, et al. Possible increase in serum FABP4 level despite adiposity reduction by canagliflozin, an SGLT2 inhibitor. PLoS One. 2016 Apr 28;11(4):e0154482.

2. Ferrannini E, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499-508.

3. Merovci A, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509-514.