How Relevant is the Interaction Between Dolutegravir and Metformin in Real Life? (2017)

To the Editors: Song et al1 have reported recently the results of a phase I parallel-group study aimed to evaluate the effect of dolutegravir on the steady-state pharmacokinetics (PK) of metformin in healthy volunteers. They found that co-administration of dolutegravir dose-dependently (dolutegravir was in fact given at 50 mg q24h or 50 mg q12h) increased metformin area under the curve (AUC) and Cmax by 79%–145% and 66%–111%, respectively. Overall, combined treatment was well-tolerated, with 1 of 29 nondiabetic subjects experiencing clinical signs of hypoglycemia. According to these findings, the authors recommended that dose adjustments of metformin should be considered to maintain optimal glycemic control when HIV-infected patients are starting/stopping dolutegravir while taking metformin. Here, we intend to verify the clinical relevance of this drug-to-drug (DDI) pharmacokinetic interaction in a real-life setting. In this retrospective analysis, we considered all HIV-infected patients from our local database fulfilling the following mandatory criteria: (1) a diagnosis of type II diabetes from at least 1 year; (2) metformin therapy for at least 12 months; and (3) switch from any antiretroviral regimen to dolutegravir-based therapies from at least 6 months. Glycemic control was expressed both as fasting blood glucose concentrations (the last 3 measurements before the switch and the first 3 measurements after the switch to dolutegravir) and glycosylated hemoglobin (HbA1c) (the 2 most recent measurements for each observational period, with the third measurement taken at least 3 months after the switch to dolutegravir). Hypoglycemia was defined as fasting blood glucose concentrations less than 70 mg/dL, in agreement with the definition adopted by Song et al.1 Dolutegravir plasma trough concentrations were assessed by high performance liquid chromatography method with ultraviolet detection.2 Comparative analysis on glycemic control before versus after the switch to dolutegravir were performed by paired t test (significance level was verified for P < 0.05). The association between glycemic control parameters and dolutegravir plasma trough concentrations was investigated by linear regression analyses. All HIV-infected adult patients concomitantly given metformin and dolutegravir identified from our database were included in this study (n = 15). The patients were mainly Caucasians (92%), men (92%), and had mean age of 59 ± 10 years. After the switch to dolutegravir, all patients had a good viro-immunological status (CD4 cell count: 776 ± 423 cells/mL; HIV-RNA <37 copies/mL). None of them had clinical signs of liver (serum alanine aminotransferase: 29 ± 12 IU/mL) or kidney (serum creatinine: 1.1 ± 0.3 mg/dL) dysfunction. Mean body weight and body mass index were 76 ± 13 kg and 26.2 ± 4.0 kg/m2, respectively. As shown in Figure 1, no significant differences were observed while comparing predolutegravir versus postdolutegravir switch on mean fasting blood glucose concentrations (left panel: 140 ± 31 versus 134 ± 43 mg/dL, mean difference −4.0%; P = 0.538) or on HbA1c (right panel: 48 ± 10 versus 47 ± 13 mmol/mol, mean difference +3.0%; P = 0.589).FIGURE 1.: Blood glucose concentrations (the last 3 measurements before the switch and the first 3 measurements thereafter) and HbA1c (2 measurements for each observational period, with the third measurement taken at least 3 months after the switch to dolutegravir) measured in the same HIV-infected patients before versus after the switch to dolutegravir-based antiretroviral therapies.All patients were given dolutegravir at 50 mg/d in combination with abacavir + lamivudine (n = 4), tenofovir + emtricitabine (n = 1), atazanavir/ritonavir (n = 4), darunavir/ritonavir (n = 2), nevirapine (n = 1), or lamivudine (n = 1). A wide distribution of dolutegravir trough concentrations was observed, with values ranging from 197 to 4288 ng/mL. No significant associations were found between dolutegravir trough concentrations and the percentage differences in blood glucose levels (coefficient of correlation = −0.027) or the percentage differences in HbA1c (coefficient of correlation = −0.030) after the switch to dolutegravir. No changes in the hypoglycemic therapy (drugs and/or drug doses) were done after the switch to dolutegravir. Metformin was well-tolerated when either administered without or when administered with dolutegravir. In particular, no patients experienced episodes of hypoglycemia or lactic acidosis after the switch to dolutegravir. One patient stopped dolutegravir 8 months after its introduction because of virological failure (2 consecutive plasma HIV-RNA levels ≥200 copies/mL); no change in glucose concentrations and HbA1c was observed after the dolutegravir withdrawal. Here, we have documented that in a real-life setting, co-administration of dolutegravir did not alter the response of HIV-infected patients with diabetes to metformin. Out of mention, no differences on the glycemic control were also found in patients exposed to high versus low dolutegravir concentrations. This is apparently an unexpected finding in light of the results of a pharmacokinetic study in healthy volunteers showing a highly significant dose-dependent increase in metformin concentrations when co-administered with dolutegravir.1 Indeed, if metformin exposure increases, one should eventually expect that also its hypoglycemic effect increases, eventually resulting in worsening of the glycemic control. How to reconcile these discrepant findings? First, it should be understood whether a clear definition exists in the therapeutic concentrations of metformin. Indeed, a systematic review on this topic has recently concluded that there is great variability and heterogeneity in the reported “therapeutic” plasma metformin concentrations, with proposed values ranging from 0.13 to 90 mg/L and threshold values for metformin intoxication set up to 270 mg/L.3 This very wide range of drug concentrations seems to suggest that, once those evident risk factors for inadequate drug exposure are excluded (such as renal dysfunction), most patients are likely to fall within the “therapeutic range”. Second, it should be clarified whether a clear correlation exists between metformin PK and its pharmacodynamics. Although the PK of metformin has been extensively reported, studies dealing with its association with glycemic control are scarce and not conclusive. New evidence seems to argue against a strong PK/pharmacodynamics relationship based on the following: (1) findings in patients with polycystic ovary syndrome, showing that in this clinical condition the therapeutic effects of metformin are independent of the administered dose/exposure4; (2) a population pharmacokinetic analysis showing no correlation between metformin concentrations with either lactate concentration or HbA1c levels.5 Taken together, these findings may challenge the belief that altered metformin PK may adversely impact on glycemic control. Third, available data on the clinical relevance of already known DDIs involving metformin should be looked at. Indeed, other DDIs leading to increased metformin exposure have been reported to date.6,7 For instance, cimetidine, pyrimethamine, trimethoprim, and cephalexin have been shown to significantly increase the AUC of metformin by reducing its renal clearance through competitive inhibition of renal tubular secretion acting on specific renal transporters, with mechanisms very similar to the one proposed for dolutegravir (that is, a concentration-dependent inhibition of renal organic cation transporters 2 (OCT2) resulting in impaired metformin tubular secretion). As a matter of fact, these interactions, some of which have been known from more than 20 years, are actually scored as “minor clinical relevance”.7 The limited clinical impact of reduced metformin tubular secretion is indirectly supported also by recent findings by Dujic et al8 which, by performing a large-scale meta-analysis of available data on polymorphisms in transporter genes (also including OCT2) in nearly 8000 individuals, found that none of the variants showed significant effect on metformin response, suggesting that altered activity of candidate transporter genes involved in the renal elimination and disposition of metformin have, if any, little contribution to variability in the glycemic response to this drug in type 2 diabetes. In conclusion, here, we have provided preliminary evidence from real-life setting that, even if pharmacokinetic DDIs may take place between dolutegravir and metformin ultimately resulting in increased drug exposure, its clinical relevance may be limited. Therefore, instead of proposing a priori adjustments in metformin dose1—with unnecessary potential reduction of drug efficacy—we suggest just to monitor, as per clinical practice, glycemic control in HIV-infected patients on metformin who start or stop dolutegravir. We would like to reassure physicians that, in most cases, it is likely that nothing happens and no dose adjustment may be required.