Evaluation of the concurrent use of dolutegravir and metformin in human immunodeficiency virus-infected patients

Abstract

An analysis of the interaction between dolutegravir and metformin was conducted in the HIV ambulatory clinic setting. This was a multicenter, retrospective case series evaluating adult, HIV-infected patients concurrently prescribed dolutegravir and metformin. Historical electronic medical records were utilized to collect case-specific data. Laboratory parameters including serum creatinine (SCr), hemoglobin A1c (HgbA1c), plasma HIV RNA, CD4 cell count, and lactate were reviewed. Adverse drug reactions were assessed using patient-reported gastrointestinal intolerance and hypoglycemic symptoms. Metformin dose reduction or discontinuation was also recorded. Nineteen patients identified as concurrently taking metformin and dolutegravir were included. Eighteen patients were on metformin prior to dolutegravir initiation, with 13 having received metformin for at least six months prior to dolutegravir. At the time of dolutegravir initiation, one patient had a preemptive metformin dose reduction. Seven patients were initiated on dolutegravir with a metformin dose greater than 1000 mg daily. Eleven patients had baseline and three- to six-month follow-up HgbA1c. Of those 11 patients, eight had stable or decreased values. Thirteen of the 19 patients had an increase in SCr, with a median increase of 0.3 mg/dl (0.03–0.43). Gastrointestinal distress (N = 3) and hypoglycemic symptoms (N = 3) were reported in a total of five patients. Adverse drug reactions resulted in metformin dose reduction (N = 2) and/or discontinuation (N = 2). There were no reported cases of lactic acidosis. Providers concurrently prescribing dolutegravir and metformin should be aware of potential consequences with this combination and may consider an empiric metformin dose reduction to prevent intolerable adverse drug reactions.

Keywords

HIV AIDS diabetes dolutegravir metformin

Introduction

The prevalence of diabetes mellitus (DM) is 3.8% higher in HIV-infected patients compared to the general United States population.¹ According to Department of Health and Human Services HIV treatment guidelines and the American Diabetes Association, HIV-infected patients should be screened for DM with a fasting glucose or hemoglobin A1c (HgbA1c) at entry into care and three months after antiretroviral therapy (ART) initiation.^2,3 If screening results are normal, an annual fasting glucose or HgbA1c is recommended for all HIV-infected patients. Several drug–drug interactions (DDIs) exist between standard oral DM agents and ART.⁴ Metformin has traditionally been a safe and effective medication to combine with ART and is a first-line oral therapy for DM management.^3,5

Recently, the HIV treatment recommendations shifted to integrase strand transfer inhibitor (INSTI)-based combinations due to their improved adverse drug reaction (ADR) and drug interaction profiles.² Two of the recommended INSTI regimens include dolutegravir in combination with either abacavir/lamivudine or tenofovir/emtricitabine. Dolutegravir is metabolized by uridine diphosphate glucuronosyl-transferase 1A1 resulting in minimal DDIs. However, dolutegravir is an inhibitor of organic cation transporter-2 (OCT-2) and multidrug and toxin extrusion transporter-1 within the renal tubules.^6,7 Medications utilizing either transporters for excretion, such as metformin, may have increased plasma concentrations.^6–9 In a small study examining healthy volunteers, metformin 500 mg twice daily (BID) was administered with dolutegravir 50 mg once daily (N = 14) or BID (N = 13) for seven days compared to metformin alone for five days.^8,9 The metformin area under the concentration time curve (AUC) and the maximum concentration (C_max) were evaluated. The metformin geometric least squares mean ratios with 90% confidence intervals compared to metformin alone increased with both dolutegravir dosing regimens (daily: AUC: 1.79 [1.65–1.93] and C_max: 1.66 [1.53–1.81]) (BID: AUC: 2.45 [2.25–2.66] and C_max: 2.11 [1.91–2.33]). These data suggest close monitoring or empiric dose reduction may be necessary in HIV-infected patients concurrently receiving metformin and dolutegravir. There are minimal data examining HIV-infected patients prescribed this drug combination. The purpose of this paper is to describe clinical experience and outcomes in HIV-infected patients coadministered dolutegravir and metformin.

Methods

This was a retrospective, multicenter descriptive analysis evaluating adult HIV-infected patients receiving ambulatory HIV care in health-system-based infectious diseases clinics with a concurrent prescription for dolutegravir and metformin initiated between 12 August 2013 and 4 May 2015. The primary site for enrollment was an inner-city infectious diseases clinic that provides chronic care for over 2000 HIV-positive individuals. Virginia Commonwealth University Health investigational review board granted exemption for a multicenter site evaluation (HM20004861). Pregnant females and prisoners were excluded.

Electronic medical records were reviewed beginning at dolutegravir–metformin initiation with a six-month follow-up period. Data collection included current metformin and dolutegravir dosing regimens and additional DM pharmacotherapy regimens. DM management was evaluated using HgbA1c values at baseline dolutegravir–metformin therapy, three and six months to assess changes in blood glucose control. Safety outcomes included provider documentation of patient-reported gastrointestinal (GI) intolerance, hypoglycemic symptoms, and metformin dose adjustment or discontinuation. GI intolerance was defined as nausea, vomiting, and/or diarrhea. Laboratory safety analysis included serum lactate and creatinine (SCr) alterations. HIV viral suppression and immunologic response were recorded at baseline, three and six months by plasma HIV RNA viral load, and CD4 cell count. Descriptive statistics including median and interquartile range were utilized.

Results

A total of 25 patients were initially identified with concomitant dolutegravir and metformin prescriptions. Six patients were excluded for the following: lost to follow-up after the initial visit (N = 1), or, upon further chart review, dolutegravir and metformin were not used concurrently (N = 5). Of the 19 patients included, patients were primarily black males with a median age of 55 years and suppressed HIV viremia (Table 1). Seven patients were prescribed additional medications for DM. All seven were prescribed long-acting insulin, of which, four were also using short-acting insulin and two were taking sitagliptin. Eighteen patients were prescribed metformin prior to dolutegravir initiation, 13 having received metformin for six months or more prior to dolutegravir initiation. At dolutegravir initiation, one patient receiving a total daily metformin dose of 2000 mg had a preemptive 50% dose reduction. Eighteen of the 19 patients received once daily dolutegravir (eight prescribed fixed dose combination tablets), and one patient received twice daily dolutegravir.

Table 1.

Baseline demographics and patient characteristics.

Characteristics	N (%)
Age (years)
45–50	2 (10.5)
51–59	15 (79)
60–65	2 (10.5)
Gender
Males	14 (74)
Females	5 (36)
Race
Black	12 (63)
Hispanic	1 (5)
White	6 (32)
Weight at metformin initiation (kg)
70–79	4 (26.7)
80–100	7 (46.7)
>100	4 (26.7)
Dolutegravir oral TDD^a (mg)
50	18 (95)
100	1 (5)
Metformin oral TDD (mg)
500	3 (15.8)
1000	9 (47.4)
1500	1 (5)
1700	2 (10.5)
2000	4 (21.1)
SCr (mg/dl)
0.5–0.99	10 (52.6)
1.0–1.5	9 (47.4)
CrCl (ml/min)^a
40–60	3 (15.8)
61–80	6 (32)
81–100	3 (15.8)
>100	7 (36.8)
HgbA1c (%)
<6	2 (18.2)
6–8	7 (63.6)
>8	2 (18.2)
CD4 cell count (cells/mm³)
<200	1 (5.6)
200–500	8 (44.4)
501–1000	6 (33.3)
>1000	3 (16.7)
% CD4 cell count
<20	7 (38.9)
20–40	9 (50)
>40	2 (11.1)
HIV RNA (<20 copies/ml)	9 (47.4)

TDD: total daily dose; SCr: serum creatinine; CrCl: creatinine clearance.

Calculated using the Cockcroft–Gault equation.

HgbA1c measurements at three and six months remained stable or decreased from baseline (Table 2). Thirteen patients had an increased SCr, with a median rise of 0.3 mg/dl (0.03–0.43). GI distress (N = 3) and hypoglycemic symptoms (N = 3) (all on concurrent insulin) were reported in a total of five patients. The daily metformin dose was reduced (N = 2) and/or subsequently discontinued (N = 2) with no dose alterations in two patients. No lactate concentrations were drawn during the study period as they are not routinely drawn in the ambulatory setting. Furthermore, there were no provider notes suggesting concern for increased serum lactate concentrations or lactic acidosis.

Table 2.

Concurrent metformin and dolutegravir use in HIV-infected patients (median [interquartile range]).

Laboratory	3 mo	6 mo
CD4 cell count, cells/mm³ (%)	493 (26) (289–777 [17–35]) (N = 15)	492 (29) (419–842 [19–39]) (N = 13)
HIV RNA, <20 copies/ml – N	11 (N = 16)	10 (N = 13)
HgbA1c (%)	6.7 (6.4–7.3) (N = 9)	6.5 (6–8.8) (N = 9)
SCr (mg/dl)	1.21 (0.88–1.3) (N = 16)	1.2 (0.94–1.33) (N = 16)
CrCl (ml/min)^a	72.7 (60.6–88.6) (N = 16)	73.1 (69.3–94.9) (N = 16)

Calculated using the Cockcroft–Gault equation.

Discussion

Pharmacokinetic studies in healthy subjects have documented a decrease in metformin clearance when coadministered with dolutegravir primarily due to renal OCT-2 inhibition.^8,9 Based on this study, HIV-infected patients concurrently using dolutegravir 50 mg once daily with metformin should have a 60–70% increase in the metformin AUC and C_max.^8,9 Furthermore, a twofold increase in the metformin pharmacokinetic profile results with a dolutegravir 100 mg daily dose. As dolutegravir is a first-line antiretroviral agent in the treatment of HIV infection and metformin is an initial agent for DM, this combination is difficult to avoid. The question then becomes how this interaction will affect patients clinically. Should this combination be considered an absolute or a relative contraindication? The results of this small retrospective, case series provide some insight into the clinical implications of this interaction.

Among this cohort of patients, as expected, diabetes control was maintained when metformin and dolutegravir were concurrently prescribed, with some patients experiencing an improved HgbA1c. Five patients (26%) reported either hypoglycemic symptoms (N = 3) or GI intolerance (N = 3). Two of these patients had their metformin dose reduced, and two, ultimately, discontinued therapy. Specifically, one patient in this analysis with a baseline HgbA1c of 7.7% was initiated on dolutegravir 50 mg daily while prescribed metformin 1700 mg daily. Although the HgbA1c improved to 6.7%, the patient described severe diarrhea, which led to a metformin dose decrease to extended release 750 mg. Metformin was subsequently discontinued and resulted in diarrhea resolution. Of patients who experienced ADRs, three were prescribed a metformin daily dose >1000 mg at dolutegravir initiation. In an additional patient, with a baseline HgbA1c of 5.2%, who was stable on metformin 1000 mg BID, a preemptive dose reduction to 1000 mg once daily was documented by the provider. In this patient, the HgbA1c remained stable at 5.7% without issue and there were no reported adverse events.

After the initial data collection period (12 August 2013 to 4 May 2015), an additional patient reported GI intolerance for a total of six patients describing adverse effects. Unknown to the HIV clinic, an outside provider increased the patient’s daily metformin dose from 1000 to 2000 mg. The dolutegravir regimen was subsequently changed to raltegravir to avoid any interactions with the diabetes regimen. The patient reported improvement in symptoms at a follow-up visit. This patient demonstrates the importance for healthcare providers to understand this interaction and its potential clinical implications.

It is difficult to know whether increased metformin plasma concentrations truly have any correlation with increased adverse effects in these patients. Metformin 3000 mg daily has been compared to a 1500 mg dose and demonstrated improved glucose control with similar GI-reported adverse effects.¹⁰ The pathogenesis of GI intolerance with metformin is not fully elucidated, but several hypotheses suggest an alteration on intestinal serotonin secretion, increased incretin concentrations, or reduced bile acid salt absorption, not related to systemic plasma concentrations.¹¹ Metformin is transported into enterocytes via OCT-1 and plasma membrane monoamine transporters (PMAT).^8,9 Decreasing transporter activity results in higher intestinal concentrations and increased adverse effects.¹² However, dolutegravir does not appear to inhibit OCT-1 or PMAT as metformin uptake within intestinal cells was not altered with concurrent administration.^8,9,13 This would lead one to believe that there should not be an increase in GI adverse effects with no change in intestinal metformin concentrations and only an increase in the plasma concentrations. Of the four patients (one discovered post hoc) with GI intolerance, additional review of concurrent medications that inhibit OCT-1 (e.g. citalopram, proton pump inhibitors) was not performed and may be a contributing variable to the increased metformin GI effects.

An increase in hypoglycemic events is also difficult to correlate to metformin plasma concentrations as this adverse effect is rare when metformin is used without concurrent hypoglycemic agents.¹⁴ One healthy subject in the metformin–dolutegravir pharmacokinetic analysis had a drug-related hypoglycemic event and three in the present study.^8,9 All of the patients in the present study with hypoglycemic events were concurrently receiving insulin therapy and one was on a 2000 mg total daily metformin dose.

The most worrisome effect of metformin overdose is the possibility of lactic acidosis, but is rarely reported, and was not documented in the present study.¹⁴ Additionally, recent evaluations have led to metformin labeling changes in patients with renal disease due to the minimal risk of lactic acidosis in patients with lower glomerular filtration rates.¹⁵ All patients in the present study had preserved renal function throughout the study.

For patients with poor diabetes control (HgbA1c >7%), close monitoring for ADRs may be preferable to empiric metformin dose reduction with concurrent dolutegravir.^6,7 Only one patient in the current study was using dolutegravir 50 mg BID and no ADRs were reported. Additional data in HIV patients receiving high-dose dolutegravir are needed with concurrent metformin to determine the optimal dosing regimen.

Dolutegravir is well known to increase SCr on average by 0.12–0.15 mg/dl (−0.32 to 0.65 mg/dl) without affecting glomerular filtration rate.^6,7,16–20 As expected in this evaluation, the SCr change was within the normal range (0.3 mg/dl [−0.07 to 0.43]). Some non-HIV providers may be unaware of this SCr rise and may discontinue metformin inappropriately due to concerns for metformin accumulation. Thus, dissemination of this expected renal ADR is needed to avoid unnecessary diabetes pharmacotherapy adjustments.

No issues were noted with regard to the antiretroviral regimens in the study. HIV viral suppression and immunologic response remained stable or improved throughout the study period.

Limitations to this study include the retrospective case-series study design and the small sample size. Statistical analysis only included patients with at least two laboratory values. Thirteen patients (68%) had incomplete laboratory results, with eight patients excluded from at least one statistical analysis. Additionally, subjective information was not always documented in the patient’s historic records used for data collection.

Providers concurrently prescribing dolutegravir and metformin may need to consider an empiric metformin dose reduction to prevent intolerable ADRs, but an evaluation of the patient’s DM pharmacotherapy plan, a review of all concurrent prescriptions (OCT-1 inhibitors), and current DM control should be considered. These results offer clinical data in HIV-infected patients supporting a maximum metformin daily dose of 1000 mg for patients initiating dolutegravir.^6,7 Providers should be aware of the potential for increased adverse effects (hypoglycemia and GI intolerance) when metformin and dolutegravir are concurrently prescribed. Lactic acidosis did not occur in any patients included in this study and serum concentrations were not routinely drawn. However, lactic acidosis should be considered if patients present with symptoms concerning for elevated serum lactate concentrations (unexplained abdominal pain, fatigue, and fever). Additional caution is warranted in patients prescribed a dolutegravir 100 mg total daily dose as metformin AUC and C_max increase with dose escalation.^8,9 A larger clinical trial is necessary to determine the impact of metformin with dolutegravir (50 and 100 mg daily doses) in HIV patients with concurrent diabetes.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Hernandez-Romieu AC, Garg S, Rosenberg ES, et al. Is diabetes prevalence higher among HIV-infected individuals compared with the general population? Evidence from MMP and NHANES 2009–2010. BMJ Open Diabetes Res Care 2017; 5: e000304.

Department of Health and Human Services. Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (accessed 21 May 2015).

American Diabetes Association. Strategies for improving care – 2016. Diabetes Care 2016; 39: S6–S12.

Monroe

Glesby

Brown

. Diagnosing and managing diabetes in HIV-infected patients: current concepts. Clin Infect Dis 2015; 60: 453–462.

American Diabetes Association. Approaches to glycemic treatment – 2016. Diabetes Care 2016; 39: S52–S59.

ViiV Healthcare. Tivicay (package insert). Research Triangle Park, NC: ViiV Healthcare, 2015.

ViiV Healthcare. Triumeq (package insert). Research Triangle Park, NC: ViiV Healthcare, 2015.

Zong

Borland

Jerva

et al.

The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Int AIDS Soc 2014; 17: 19584–19584.

Song

Zong

Borland

et al.

The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Int AIDS Soc 2016; 72: 400–407.

10.

Grant

. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 1996; 19: 64–66.

11.

Bouchoucha

Uzzan

Cohen

. Metformin and digestive disorders. Diabetes Metab 2011; 37: 90–96.

12.

Dujic

Zhou

Donnelly

et al.

Association of organic cation transporter with intolerance to metformin in type 2 diabetes: a GoDARTS Study. Diabetes 2015; 64: 1786–1793.

13.

Reese

Savina

Generaux

et al.

In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos 2013; 41: 353–361.

14.

Bristol-Myers Squibb. Glucophage (package insert), Princeton, NJ: Bristol-Myers Squibb Company, 2008.

15.

Food and Drug Administration. Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function (April 2016), http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm (accessed 8 May 2016).

16.

Clotet

Freinberg

Van Lunzen

et al.

For the ING114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naïve adults with HIV-1 infection (FLAMINGO): 48 week results from the randomized open-label phase 3b study. Lancet Infect Dis 2014; 383: 2222–2231.

17.

Koteff

Borland

Chen

et al.

A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br J Clin Pharmacol 2012; 75: 990–996.

18.

Raffi

Jaeger

Quieros-Roldan

et al.

Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naïve adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomized, double-blind, non-inferiority trial. Lancet Infect Dis 2013; 13: 927–935.

19.

Walmsley

Antela

Clumeck

et al.

For the SINGLE investigators. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013; 369: 1807–1818.

20.

Lindeman

Duggan

Sahloff

. Evaluation of serum creatinine changes with integrase inhibitor use in human immunodeficiency virus-1 infected adults. Open Forum Infect Dis 2016; 3: owfd53–owfd53.