Kombiglyze (metformin and saxagliptin)‐induced hepatotoxicity in a patient with non‐alcoholic fatty liver disease

Abstract

A 33‐year‐old man was referred with hyperosmotic symptoms of 4 weeks. Clinical examination showed palpable hepatomegaly and no stigmata of liver disease. Findings were random glucose 16.6 mmol/L, HbA1c 12.4%, triglyceride 6.2 mmol/L, normal LFTs and ultrasound liver: increased echogenicity. Management consisted of dietician referral and commencement of metformin 500 mg bd, diamicron MR 60 mg od, and fenofibrate 145 mg od. He was non‐compliant, complaining of “heaviness of head” after consuming oral diabetic agents, without symptoms of hypoglycemia. Treatment was switched to Kombiglyze XR (saxaglipitin 5 mg + metformin 1000 mg) and empagliflozin 25 mg od. He presented 1 week later with generalised pruritus with ALT 307 IU/L and serum GGT 808 IU/L. Following this, a percutaneous liver biopsy was performed, revealing steatohepatitis and marked intra‐hepatic cholestasis. Kombiglyze XR was withheld, with resolution of LFTs to baseline. Phenotypes of liver injury are categorised according to R value, defined as ratio ALT/ULN:ALP/ULN. R value of ≥5:hepatocellular injury, ≤2:cholestatic injury, 2–5:mixed‐type injury. Here, R value points toward mixed type (R = 3.203). Hepatotoxicity in patients with NASH is difficult to diagnose, based on laboratory parameters. Liver histology was useful in indicating additional changes apart from NASH, causing liver derangement. The Rousal Uclaf Causality Assessment Method is a scoring method to determine the probability of drug induced liver injury. RUCAM score for this case was 6 (probable adverse drug reaction). Hepatotoxicity from saxagliptin not been reported prior. Clinicians need to be more vigilant, particularly in patients with NASH.

Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats

“…As for saxagliptin, one case of hepatotoxicity has been reported to date. Thalha et al (2018) revealed that Kombiglyze (metformin with saxagliptin) induced cholestasis in a patient with nonalcoholic steatohepatitis [13]. Therefore, further studies are required to confirm the covalent binding of saxagliptin to the cysteine residues of endogenous proteins in animals and humans to precisely predict the potential of DILI from saxagliptin in clinics.…”

“…However, saxagliptin-induced liver injury has been reported in rare cases. Thalha et al recently presented a case of hepatotoxicity caused by Kombiglyze (saxagliptin of 5 mg plus metformin of 1000 mg) in Malaysia [ 13 ]. The patient, showing palpable hepatomegaly and no stigmata of liver disease, demonstrated increased alanine aminotransferase (307 IU/L) and gamma-glutamyltransferase (808 IU/L) levels one week after the first Kombiglyze administration.…”

Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients

“…Some preclinical models may provide insight into a single characteristic of NASH, but none can provide a comprehensive overview of all changes in enzyme and transporter expression or function 15 . A small number of studies have reported drugs that present risk of ADRs in patients with preexisting liver diseases ( Table 1 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , ...…”

“…A small number of studies have reported drugs that present risk of ADRs in patients with preexisting liver diseases ( Table 1 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ,…”

“…Among the 71 drugs reported with ADRs in patients with hepatic impairment, 54 are substrates of major drug transporters ( Table 1 ) and/or metabolizing enzymes ( Tables 2 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 39 , 70 , 78 , 123 , 128 , 143 , 144 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , …”