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For years, nephrologists have despised diabetic nephropathy due to its commonality between patients. For the past two decades, patients of diabetic nephropathy have long had to manage their illness by controlling their blood pressure, controlling their glucose, and blocking the angiotensin system. Despite there being little change to the management of diabetic nephropathy, nephrologists remain optimistic due to new studies that show promise. SGLT2 inhibitors, which increase urinary excretion of glucose, have been shown to slow the progression of kidney disease in a secondary analyses. However, the secondary analyses should be viewed with caution because large clinical trials rarely utilize large samples of patients who have chronic kidney disease (CKD). Additionally, CANVAS and EMPA-REG studies have also had the same problem of not having a large sample size of patients with chronic kidney disease.
Yet, the study CREDENCE has shown promise within the first 24 hours of being conducted. This study included 4401 patients with diabetic nephropathy. These patients had diabetic nephropathy that’s been defined by an eGFR of 30 to <90 mL/min/1.73 m² and modest proteinuria of > 300 mg per gram of creatinine. In addition to sharing this definition, the patients also had to be on a stable dose of renin-angiotensin system (RAS) blockade. The results found that this study resulted in doubling of creatinine, dialysis, and death. However, as alarming as death and mortality may be, the doubling of creatinine may enumerate the results at a lower number due to those who initiate dialysis or die before the creatinine has doubled. This result was found in 11% of the patients who were treated with canagliflozin. Yet, funnily enough, the placebo sample of patients had 15.5% share the same outcome. Additionally, the rates of end-stage kidney disease were reduced. It should be noted that the difference in mortality, which was 17% lower in the sample group that was treated with canagliflozin, didn’t necessarily meet the statistical significance, yet doctors have mentioned that this should not discourage using the medication. Patients and doctors should not be quick to put away these medication practices because of the sheer success and various other outcomes of the study that otherwise matters to patients.
Before this study began, there were other studies that made alarming suggestions from the sample that was treated with canagliflozin. Patients from this sample were required to have their feet examined every trial due to the fact that previous studies suggested that there was a risk for amputation for those treated with canagliflozin. Of the 70 participants, 63 of them required amputations of some kind. This was deemed as a nonsignificant different that should provide some reassurance for both patients and their doctors. In addition to these results, the rates of minor kidney injury and urinary tract infections were no different than the rates that the canagliflozin group. Nevertheless, one difference that this test had was there were more genital mycotic infections in the canagliflozin group. But it should be noted that these rates of infections were low with the canagliflozin group having 2% of patients with infections whereas the placebo group had a 0.5% of infections in patients. Another difference was that this group had more episodes of diabetic ketoacidosis with 11 episodes compared to the placebo group. From this, the study deduced that the canagliflozin had side effects on rare occasions.
Although the medication seems to work, it’s hard to pinpoint why exactly it works. Through the sodium-glucose cotransporter, SGLT2 inhibitors have several physiologic effects. The inhibitors promote glucosuria. This can lead to osmotic diuresis which ultimately leads to lower blood pressure. Yet, if there were to be an increase in glucose excretion, there may be a better way of controlling glucose. This holds the potential to induce weight loss which can reduce glomerular hyperfiltration.
Moreover, the A1c levels held no significant differences between the two groups. This gave evidence that improved diabetic control as a mechanism of benefit may have no correlations. Besides this difference, the sample that was treated with canagliflozin had experienced more weight loss which is difficult to achieve. In addition to weight loss, this sample also experienced reduced levels of proteinuria in comparison to the placebo group.
Although physicians believe that the CREDENCE study holds credibility, they also argue that this study should change practice due to the fact that it’s one study. The study does in fact align with the general consensus of the role of SGLT2 inhibitors in diabetes. This pushes the agenda that there should be more studies conducted in order to solidify the evidences that have been found through this study. Additionally, the SGLT2 inhibitors should be adopted into the aid of diabetic nephropathy. Again, it should be noted that all the patients had adequate RAS blockade and the ACE inhibitors should continue to be administered in order to digress the disease.
