CKD stage 3 or higher was common in this study population, affecting 31.4% of older adults with type 2 diabetes mellitus prescribed metformin at an urban tertiary care setting. This can neither be directly compared to previously reported estimates of CKD among all adults with diabetes mellitus, which range from 15.1% in the U.S. , 27.5-31% in the UK [20, 22] and 38% in urban Japanese adults ; nor can this result be directly compared to a previous UK study which reported that 49% of adults ≥70 years old with diabetes had CKD stage 3 or higher , or a recent Canadian study that showed 38.7% of adults aged ≥66 years with a new metformin prescription for diabetes had CKD stage 3 or higher . However, this study result may reflect kidney function of older adults with type 2 diabetes.
The Cockcroft-Gault, abbreviated MDRD and CKD-EPI equations were comparable in estimating CKD prevalence in the study population, though the Cockcroft-Gault equation identified more subjects as having CKD. Median serum creatinine was in the normal range and median eGFR was lower among subjects with CKD identified by the Cockcroft-Gault equation compared to those with CKD identified by the other equations. This demonstrates some discrepancy between estimated kidney function results using the Cockcroft-Gault equation and either the abbreviated MDRD Study equation or the CKD-EPI formula (Figure 1). This may be due to our study population consisting of older adults and racial/ethnic minorities, which were not well represented in the original populations used to derive these equations [1–3]. Additionally, some discrepancy may be due to the fact that the CKD-EPI equation is reported to be more accurate for estimating GFR >60 mL/min/1.73 m2.
The multivariable logistic regression models showed differences in the association between CKD, sex and race/ethnicity, particularly in the comparison of CKD estimated by each equation. All three equations showed that increased age was consistently associated with potentially inappropriate metformin prescription due to CKD as expected. However, the Cockcroft-Gault equation did not demonstrate statistically significant increased odds of potentially inappropriate metformin prescription due to CKD for female sex compared to the abbreviated MDRD and CKD-EPI equations. It also did not show statistically significant decreased odds of potentially inappropriate metformin prescription due to CKD for non-Hispanic blacks compared to the other equations. This is likely due to the sex and racial/ethnic differences in our study population, as the Cockcroft-Gault equation was derived mostly from Caucasian males . In contrast, the abbreviated MDRD and CKD-EPI equations both showed significant associations between CKD, female sex and non-Hispanic black race.
It is worth noting that the Cockcroft-Gault equation is generally used to adjust medication doses for impaired kidney function and creatinine clearance is used in drug labeling. Clinical pharmacists primarily use the Cockcroft-Gault equation rather than the MDRD or CKD-EPI equations to estimate kidney function according to pharmaceutical manufacturer recommendations; a small survey of U.S. clinical pharmacists showed that nearly all used the Cockcroft-Gault equation to adjust dosing in kidney impairment and use of the abbreviated MDRD equation varied . However, prescribing clinicians may be more likely to use eGFR (calculated from either the abbreviated MDRD equation or CKD-EPI formula) automatically reported by laboratories to evaluate kidney function, because creatinine clearance must be calculated.
It is questionable whether these eGFR discrepancies would significantly impact clinical practice in prescribing metformin. Changes in kidney function would affect a prescribing clinician’s decision to use metformin, or possibly decreasing the metformin dose due to decreasing kidney function. However, these results may indicate that using eGFR calculated from the Cockcroft-Gault equation may lead clinicians to discontinue metformin earlier than using eGFR calculated from either the abbreviated MDRD or CKD-EPI equations. It may be worthwhile to consider whether larger studies would help determine if a different CKD threshold could be used to safely prescribe metformin to older adults given the rarity of serious adverse events. Metformin-associated lactic acidosis is infrequently reported: a 2010 Cochrane review did not identify any cases of lactic acidosis from pooled data including 70,490 patient-years of metformin use, and estimated the incidence of lactic acidosis as 4.3 cases per 100,000 patient-years . A recent observational study reported no increased risk of metformin-associated lactic acidosis among 51,675 Swedish adults with type 2 diabetes and kidney dysfunction . Bodmer et al. reported 6 cases of lactic acidosis in a nested case–control analysis of UK subjects with type 2 diabetes taking oral medications; the estimated crude incidence rate was 3.3 cases per 100,000 patient-years . Kamber et al. reported 5 cases of lactic acidosis in the Fremantle Diabetes Study group with an estimated incidence of 57/100,000 patient-years . A study of U.S. adults with type 2 diabetes and CKD stage 3 nephropathy (N = 237) did not report any cases of lactic acidosis . Thus, it may be inferred that the majority of older adults with diabetes and kidney impairment continue to use metformin safely.
Potential advantages for using metformin in older adults include that it is usually well-tolerated; GI adverse effects are typically dose-related and may be reduced with concurrent food intake. Metformin has a low likelihood of causing hypoglycemia as a single-drug treatment and causes less weight gain, both of which may be advantages for use in older adults. Its use may potentially delay the need for insulin, which may be difficult for older adults to administer and impact ability to live independently. Risk of metformin-associated lactic acidosis in this population may be reduced by routinely discontinuing it for anticipated changes in kidney function during acute illness and surgical procedures. Additional larger studies would be helpful to assess the benefits and risks of using metformin in older adults with type 2 diabetes.
This study has several potential limitations of note. A single serum creatinine value was used to calculate creatinine clearance and eGFR, as some subjects only had one serum creatinine value during the study period; 6 subjects had no recorded serum creatinine during the study period. This may have led to over-estimation of CKD, as we were unable to determine whether serum creatinine values were stable for ≥3 months. However, prescribing clinicians and pharmacists are more likely to use the most current serum creatinine value to guide clinical decision-making. Another limitation is that the study sample may not be representative of the general population in the United States with a greater number of Asian and Pacific Islanders who live in the Seattle area. This may under-estimate the prevalence of CKD as calculated by the MDRD and CKD-EPI equations. Lactic acidosis was not evaluated as an outcome due to difficulty identifying true metformin-associated lactic acidosis in a retrospective electronic medical record review as well as the rare frequency of metformin-associated lactic acidosis.
Despite the study’s limitations, we found a high CKD prevalence in older adults aged ≥65 years who were prescribed metformin for type 2 diabetes. CKD prevalence differed by the estimating equation used, but metformin was potentially inappropriately prescribed in a large proportion of this study population. The discrepancy between estimated kidney function calculated by the Cockcroft-Gault equation, the abbreviated MDRD Study equation and the CKD-EPI equation highlights the need for better methods to easily and accurately evaluate kidney function in the clinical practice setting with results readily available to all providers, including pharmacists. Prescribing clinicians and pharmacists may use different equations to estimate kidney function, which affects prescribing practices and evaluation of medication safety. Systems changes may also be useful to help clinicians and pharmacists determine when it is appropriate to prescribe metformin for those with CKD, especially in older adults. Possible future studies would include a longitudinal assessment of this population’s kidney function and lactic acidosis events, as well as comparing kidney function measurements with older adults taking other diabetes medications.