Metformin is a widely used and effective drug for the treatment of type 2 diabetes [1]. Thiazide diuretics are recommended as first-line treatment for hypertension [2]. People with hypertension associated with diabetes are usually treated with combination antihypertensive treatment, which often includes thiazides [3].
In a local study (submitted for publication), which included assessment of metformin pharmacokinetics, two patients on hydrochlorothiazide (HCTZ) had increased plasma metformin concentrations (mean 81% increase in AUC), suggesting the possibility of a drug interaction. Both patients were wildtype for organic cation transporter-1 (OCT1) genotype. No pharmacokinetic interactions have been reported previously between thiazides and metformin. Although a clear theoretical mechanism is not obvious, and metformin and the thiazides interact with different transporters, thiazides could affect transporter activity through altered ionic balance.
We undertook a metformin pharmacokinetic study to determine whether HCTZ interacts with metformin. HCTZ was used as the representative thiazide diuretic as it was the diuretic used by the two patients with a suggestive signal.
It was calculated that if HCTZ altered the area under the plasma concentration–time curve (AUC) of metformin by >20% (which would represent a clinically significant interaction), six subjects would provide sufficient power (>80%) to detect this effect (α = 0.05).
Six patients with diabetes were recruited, including the two patients (5 and 6) who provided the initial ‘signal’ from the previous study. Baseline demographics were as follows: four men, two women, mean age 50 years (range 37–69), mean body mass index (BMI) 35.3 kg m−2 (range 34.5–36.4) and blood pressure (BP) 154/86 mmHg (range 112–180/69–96). There was no significant change in BMI, BP or electrolytes during the study period. Four patients were already stabilized on metformin 1 g twice daily. The remaining two patients (1 and 4) were stabilized on this dose 2 weeks before the first study day (day 1). HCTZ was then commenced for 2 weeks and the study day was repeated (day 2). Patients 5 and 6 were already on HCTZ as part of a combination tablet with quinapril (Accuretic™) and did the study days in reverse order. Accuretic™ was changed to quinapril alone for the 2 weeks during the study period. All other medications were unchanged.
On both study days, plasma metformin concentrations were sampled at six time points over the 12-h dosing interval (predose, 1, 2, 3, 4 and 7 h post dose). After fasting bloods were taken for metformin measurement, patients were observed to take 1 g metformin with their breakfast.
Medications were provided in a blister pack to aid compliance and to confirm compliance by pill counting at the end of the study. A telephone call was made a few days before the study day to remind patients of the appointment day, and for them to arrive without taking their metformin or breakfast that day.
Metformin concentrations were analysed by a validated high-performance liquid chromatography method [4].
The results are shown in Figure 1. The mean AUC of metformin based on the six time points was 9.48 mg l−1 h−1 without HCTZ and 10.14 mg l−1 h−1 with HCTZ. The mean change in AUC was 0.66 mg l−1 h−1, with standard error of the difference 0.39, P = 0.16 (paired two-tailed t-test), and 95% confidence interval of the difference, −0.12–1.19 mg l−1 h−1 (−1.25% −12.59%).
Figure 1
Individual patient's average metformin AUC (mg l−1 h−1) with and without HCTZ. Patient 1 (–•–); Patient 2 (); Patient 3 (–▪–); Patient 4 (); Patient 5 (); Patient 6 (–▴–); ...
Two weeks’ therapy with HCTZ had no significant effect on the AUC of metformin, and therefore no effect on the clearance (CL) of metformin (since CL = Dose/AUC). In addition, five out of the six patients showed no suggestion of signal. In patient 3, an apparent increase in metformin AUC was evident with HCTZ. On the ‘without HCTZ’ study day the predose concentration of metformin was lower than on the study day ‘with HCTZ’. The small AUC (when without HCTZ) might therefore be the result of omission of the preceding dose of metformin, or the drug may have been taken at an earlier time. The patient did not acknowledge any deviation from the protocol.
In conclusion, we believe that a clinically significant interaction between metformin and HCTZ is unlikely.