Summary

• Insulin resistance is not a pharmacologic target of canagliflozin.^1-3 The pharmacology of canagliflozinis sodium-glucose cotransporter 2 (SGLT2) inhibition.
• By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RT_G), and thereby increases urinary glucose excretion (UGE).⁴
• Patients with insulin resistance were not excluded from INVOKANAphase 3 clinical trials.
• The effect of INVOKANAon insulin resistance was not evaluated as a secondary efficacy endpoint in Johnson & Johnson Research and Development-sponsored phase 2/3 studies.
• In a pooled analysis of four^5-8 phase 3 placebo-controlled studies, a higher proportion patients with a triglyceride/high-density lipoprotein-C (TG/HDL-C) ratio ≥3.5 at baseline treated with INVOKANAattained a TG/HDL-C ratio of <3.5 treatment versus placebo at 26 weeks.⁹
• Other relevant literature identified pertaining to INVOKANA and its effect on insulin resistance are listed in the REFERENCE section.^10-13

BACKGROUND

• Insulin resistance is indicated by the decreased response or sensitivity of peripheral tissues (ie, skeletal muscle, liver, and adipocytes) to the metabolic effect of insulin. In response, secretion of insulin increases to offset the insulin resistance.¹⁴
• Hyperglycemia resulting from the decline in beta-cell function and increase in peripheral insulin resistance leads to a further decline in insulin sensitivity.¹⁵

EFFECT OF INVOKANA ON INSULIN RESISTANCE

Insulin resistance is not a pharmacological target of canagliflozin.^1-3 The effect of INVOKANAon insulin resistance as a secondary efficacy endpoint was not evaluated in Johnson & Johnson Research and Development-sponsored phase 2/3 studies.

Effect of INVOKANAon TG/HDL-C Ratio: A Marker of Insulin Resistance^9,16

In a pooled analysis of four^1-3 phase 3 placebo-controlled studies, Wyne et al (2015)⁹ evaluated the effects on INVOKANA100 mg and 300 mg on select lipid endpoints in patients with T2DM, including the change from baseline in plasma TG and HDL-C levels, and TG/HDL-C ratio, in the overall population.

• Greater least squares mean change from baseline in TG/HDL-C ratio was seen in patients treated with INVOKANA100 mg (-0.5) and 300 mg (-0.8) compared to placebo (-0.03) at week 26.
• In patients with TG/HDL-C ratio ≥3.5 at baseline, a greater percent of patients attained TG/HDL-C ratio <3.5 with INVOKANA100 mg (28.8%) and 300 mg (33.8%) compared to placebo (21.0%).⁹ A TG/HDL-C ratio >3.5 is considered elevated in male patients and  >2.5 is considered elevated in female patients.¹⁷
• Greater reduction in the TG/HDL-C ratio were reported in female patients treated with INVOKANAcompared to male patients treated with INVOKANA.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 22 October 2024.