DM is the most common cause of CKD and progression to ESRD in the United States.2
Patients with CKD and ESRD experience an increased risk of premature death even at early disease stages.3, 4
In addition to the human costs, treatment costs pose an enormous burden on the health-care system. Although the efficacy of OADs on glucose control is well established,13
their effects on long-term kidney function outcomes are less clear.13, 15
Furthermore, whether individual OADs have different effects on kidney function is unknown.
In this large national retrospective cohort study of 93,577 diabetic veterans initiating OAD monotherapy, initiation of sulfonylureas compared with metformin was associated with a 20% increased risk of the composite outcome of an eGFR event or ESRD. This association was consistently observed across all planned sensitivity analyses, including the use of a more stringent GFR event definition, a subgroup analysis of patients with baseline urine protein measurement, and an analysis in which persistent exposure was not required. Supplemental analyses using a propensity score–matched design yielded almost identical results. These results are also consistent with our previous findings in a smaller regional VHA cohort from the southeast United States.14
A number of renoprotective properties of metformin have been recently recognized. Patients with CKD have metabolic disturbances, including insulin resistance,16, 17, 18, 19, 20, 21
and chronic inflammation,23, 24, 25, 26
all of which have been proposed to have a significant role in CKD progression.18, 27
Recent data indicate that metformin has important antioxidant features28
in addition to its known insulin-sensitizing properties. Both of these properties are relevant in early stages of diabetic kidney disease, when beneficial effects can be attained before the development of irreversible glomerular damage. It is also possible that different OADs confer a differential risk of acute renal injury (AKI). Morales et al.28
demonstrated in animal models that metformin prevented gentamicin-induced AKI by normalizing oxidative stress and restoring mitochondrial functional integrity. The contribution of AKI to CKD progression and ESRD has recently been highlighted.29, 30
Thus, metformin could slow CKD progression if it prevented or reduced the severity of AKI.
Another possible explanation for the differences observed is weight gain associated with sulfonylureas vs. metformin. Excess weight has been recognized as a significant risk factor for CKD progression.31, 32, 33, 34, 35, 36
Multiple epidemiological and mechanistic studies have confirmed the adverse effects of obesity on kidney function. The so-called ‘obesity glomerulomegaly' is primarily a model of hyper-filtration associated with the development of proteinuria. Sulfonylureas are well known to promote weight gain.15, 32, 34
In a systematic review, the weighted mean absolute difference in body weight between sulfonylureas and placebo in clinical trials was 3.8
In a previous observational study in a VHA regional cohort, the mean adjusted weight difference between sulfonylurea users and metformin users at 12 months following initiation of treatment was 3.18
Whether differences in weight gain among metformin compared with sulfonylurea users could contribute to differences observed in CKD and death requires further scrutiny.
Recently, the United Kingdom Prospective Diabetes Study (UKPDS)38
10-year posttrial follow-up reported that significant risk reductions (=0.79) persisted for any diabetes-related end point (95% CI=0.83–0.99) for metformin compared with the dietary restriction group, but no difference was observed in risk of microvascular disease (including plasma creatinine or ACR). It is important to highlight that in UKPDS patients were assigned to metformin only if they were more than 120% of ideal body weight. Of 342 individuals randomized to metformin, only 136 (40%) completed the posttrial monitoring. In the sulfonylurea vs. dietary restriction arm, there was a 24% risk reduction for any diabetes-related end point (P
=0.001), including renal microvascular outcomes. Unlike UKPDS, we had sufficient power to directly compare metformin with sulfonylurea therapy.
Our study found that rosiglitazone was associated with a similar risk of kidney decline as metformin and lower risk than sulfonylureas. Both metformin and rosiglitazone are insulin sensitizers.39
Previous studies found that rosiglitazone decreased albuminuria in patients with DM.11, 12, 40, 41
Our results are similar to those from the ADOPT clinical trial, which reported a hazard ratio of 0.91 (95% CI: 0.67, 1.23) for developing eGFR <60
cc/min comparing rosiglitazone with glyburide.42
When using this same outcome, the aHR for the same comparison in our cohort was 0.77 (95% CI: 0.55, 1.10; data not shown). With the more sensitive definition requiring only a persistent decline of GFR of 25% from baseline, the difference in outcome was statistically significant. Although our study suggests that rosiglitazone does not differ from metformin and is associated with slower decline in kidney function compared with sulfonylureas, the sample size for the rosiglitazone group was small, which limits the precision of these estimates.
Our comparative effectiveness study has noteworthy strengths. We assembled a large national cohort of diabetic patients who allowed detection of small differences in risk. This study applied a new-user design43
and strict criteria to minimize misclassification of exposures, outcomes, and covariates. Our analyses accounted for available laboratory and physiological measurements that complemented administrative data, reducing concerns about residual confounding. Our previous studies evaluating the associations between the choice of first OAD and intermediate outcomes, using a regional VHA cohort, showed results consistent with those from a recent systematic review on comparative effectiveness and safety of medications for Type 2 diabetes.13
Our group estimated that after 1 year, compared with sulfonylurea use, metformin initiators had 3.2
kg lower weight; a nonsignificant 5
mg/dl lower low-density lipoprotein; 8.7
mg/dl lower triglycerides; and no difference in HbA1c.37, 44
The consistency of our findings in the primary, secondary, and sensitivity analyses, as well as with the small amount of informative data from randomized clinical trials42
and our previous study using data from the southeastern region of the United States,14
lends further credibility to these results and suggests a lack of systematic bias in the present cohort study.
Although an intention-to-treat analysis is considered the gold standard in clinical trials, trials are designed to minimize non-adherence, crossover, and differential use of co-therapies. We required persistent exposure on the OADs of interest to best address the effect of these drugs. To avoid confusion with clinical trials, we termed the analysis that kept patients in their initial exposure group as persistent exposure not required. In this analysis, the associations we observed were similar to those of the primary analysis but attenuated suggestive of increasing exposure misclassification.
If the observed more rapid decline in renal function with sulfonylureas compared with metformin is indeed causal, then our observed hazard ratio would mean that, in clinical practice, for every 1000 patients begun on sulfonylureas rather than metformin therapy, an excess of about 8 persons annually will experience a 25% or more decline in GFR.
Our study is not without limitations. First, although all individuals had a GFR
ml/min, there were no major differences in measured characteristics between exposure groups at baseline, and patients were censored after reaching a serum creatinine
mg/dl; confounding by indication is still of concern if patients who initiated sulfonylurea or metformin were systematically different in ways that make them more likely to be diagnosed with kidney disease. Second, our cohort consisted mainly of male veterans, and findings should be generalized to other populations with caution. Third, only a minority of the cohort had data on proteinuria, a key predictor of CKD progression. The subgroup analysis restricted to individuals with a baseline measurement of urine protein strengthens our findings. Fourth, in this retrospective study, some individuals with reversible AKI may have been misclassified as having CKD progression. We attempted to minimize such misclassification by requiring a confirmatory eGFR measurement 3–12 months after the first measurement.
Given the known limitations of using creatinine alone for estimating kidney function,45
we used eGFR (Modification of Diet in Renal Disease four-component equation) as the measurement of kidney function, although it is less accurate in a range of values >60
ml/min. Nevertheless, we performed a sensitivity analysis with a more stringent definition of eGFR event, requiring not only a persistent 25% drop of baseline eGFR but also reaching an eGFR
ml/min, which should mitigate these concerns. Finally, we used refill data as a proxy for medication exposure. Although exposure misclassification cannot be ruled out, our group has previously demonstrated that prescription fills are a good proxy for medication use, and we anticipate that this potential misclassification would be non-differential with regard to exposure group, and thus would tend to bias our estimates toward the null hypothesis.37, 44
In summary, in this large national retrospective cohort study, initiation of sulfonylureas was associated with an increased risk of a clinically significant decline in kidney function or death compared with initiation of metformin. Our data support the current recommendations by the American Diabetes Association and the International Diabetes Federation in their recommendation of metformin as the first-line therapy for DM, in patients with earlier stages of kidney disease. More data are needed on risks and benefits of specific OADs in more advanced CKD.