Dolutegravir

Metformin

Dose adjustment and closer monitoring may be required.

No pharmaceutical opinion available for this interaction.

Mechanism

Dolutegravir can inhibit the renal transport (OCT2 and MATE 1) and increase plasma concentration of Metformin.

Dolutegravir

Pharmacodynamic effects

Recommendations

Alternative solution(s)

Metformin

Pharmacodynamic effects

Possible increase of adverse effects.

Recommendations

If patient is already receiving dolutegravir, start with a low metformin dose and gradually increase.

If patient is starting/stoping dolutegravir while receiving metformin, a dose adjustment may be necessary.

Closely monitor metformin adverse effects and potential effects of hyperlactatemia, particularly in elderly patients, malnourished or with impaired renal function.

If the patient has been taking dolutegravir and metformin for a long time, check for side effects associated with hyperlactataemia and adjust the dose if deemed necessary.

Choose an alternative if it is considered necessary.

Alternative solution(s)

Monitor

Monitor signs and symptoms of lactic acidosis: nausea, vomiting, stomach pain, weight loss, shortness of breath, and great fatigue.

Adverse effects of metformin: gastrointestinal effects and symptoms related to hypoglycemia.

Tests

Blood Sugar

Pharmacokinetic parameters
Parameters
Reference number
# patients
HIV
Dose
Frequency
Duration (days)
Cmax
AUC
T1/2
Dolutegravir
3075 3075
15 14
- -
50 mg 50 mg
QD BID
7 (6-12) 7 (6-12)
   
   
   
Metformin
3075 3075
15 14
- -
500 mg 500 mg
BID BID
22 22
+ 66% (1.7x) + 111% (2.1x)
+ 79% (1.8x) + 145% (2.5x)
+ 9% (1.1x) + 14% (1.1x)
Comment

Observations on pharmacokinetics suggest an interaction. However, observations in observational cohorts are contradictory as to clinical implications. See references.

Ref #3384 : In a retrospective analysis, patients (n=15) did not experience any adverse effects associated with metformin while they were on dolutegravir 50 mg QD. The study author states that there was no evidence on the increased risk of hypoglycemic events when dolutegravir was associated with metformin. However, he mentions that hyperglycemia was observed when doses of metformin were decreased. In light of these findings, the author recommended monitoring glucose levels and adverse effects of metformin rather than decreasing metformin doses.

Ref #3386 : Hyperlactatemia case report in a 77-year-old female patient. The patient on dolutegravir/lamivudine/abacavir (prescribed in December 2015) presented with weight loss and severe lipoatrophy. It is documented as a history: diabetes, hypertension, osteoporosis, sarcoidosis, asthma and chronic pain. NRTIs were withdrawn and antiretroviral therapy modified for dolutegravir + rilpivirine. Metformin, which was prescribed at 1000 mg BID for 3 years, was temporarily suspended and then decreased at a dose of 500 mg BID. There was improvement of lactates. The author concludes that the combination of dolutegravir and metformin and the presence of impaired renal function (advanced age and low muscle mass) may have contributed to the accumulation of metformin and hyperlactatemia. However, there was no dosage of metformin.

Ref #3387 : Retrospective analysis in outpatients. Different laboratory data were listed as serum creatine, hemoglobin A1c, viral load and CD4. Gastrointestinal side effects, hypoglycaemia, and dose changes of metformin were also collected. Nineteen files were analyzed. 3/19 patients had gastrointestinal effects and 3/19 had symptoms of hypoglycemia. A dose reduction of metformin was necessary in 2/19 patients and a cessation of metformin for 2/19. No cases of lactic acidosis have been reported.

The US product monograph suggests limiting the daily dose of metformin to 1000 mg.

Reference
  • 2868
    Dolutegravir (Tivicay), ViiV Healthcare, Quebec, Canada, 31 janv. 2020.
  • 2858
    Dolutegravir (Tivicay), US Prescribing Information, ViiV Healthcare, August 2013.
  • 3441
    Dolutegravir/Rilpivirine (Juluca), ViiV Healthcare ULC, Quebec, Canada, 5 fév. 2020.
  • 3497
    Dolutegravir/Lamivudine (Dovato), ViiV Soins de santé ULC, Québec, Canada, 29 septembre 2020.
  • 3075
    Song IH, Zong J, Borland J, Jerva F, Wynne B et al. The Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects. J Acquir Immune Defic Syndr. 2016 Aug 1;72(4):400-7.
  • 3173
    Metformin (Glucophage), Sanofi-Aventis, Québec, Canada, 2 mars 2018.
  • 3384
    Gervasoni C, Minisci D, Clementi E, Rizzardini G, Cattaneo D. How Relevant is the Interaction Between Dolutegravir and Metformin in Real Life? J Acquir Immune Defic Syndr 2017; 75: E24-26.
  • 3386
    Naccarato M, Yoong D and Fong IW. Dolutegravir and metformin : a case of hyperlactemia. AIDS 2017; 31(15) : 2176-77.
  • 3387
    Masich A, Badowski ME, Liedtke MD and Fulco PP. Evaluation of the concurrent use of dolutegravir and metformin in human immunodeficiency virus. Int J STD AIDS 2017; 28(12): 1229-123.
  • 3388
    Ribera E, Podzamczer D. Mechanisms of action, pharmacology and interactions of dolutegravir. Enferm Infec Microbiol Clin. 2015; 33: suppl 1: 2-8.
  • 3389
    Zong J, Borlan J, Jerva F et al. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Int Aids Soc. 2014; 17(4 suppl 3): 19.