This study population included adult patients with chronic kidney disease who had an eGFR, a kidney function, between 25 and 75 ml's per minute and urinary albumin excretion in the urine between 200 and 5,000 milligrams per gram creatinine. These patients could have type 2 diabetes, but patients without type 2 diabetes could also participate.
It was about 2/3 of your study population that had diabetes, if I remember correctly. Is this about what you would find in clinical practice, that the majority of patients with kidney disease would also have diabetes, or was this a result of your recruitment criteria?
That's a very good question. We know that in clinical practice about 40% of all patients with type 2 diabetes will develop diabetic kidney disease. Then there's about 20% to 25% of patients who also have hypertension, with or without type 2 diabetes, and of course a number of other diseases. So in clinical practice, we see that these proportions are a little bit different. And the fact that we recorded 2/3 of the population with type 2 diabetes is likely because of the recruitment process and the fact that we are testing a drug that is originally developed for the treatment of diabetes. So perhaps patients with diabetes were more likely to participate compared to patients without diabetes. We did however pre-specify in the trial protocol, that at least 30% of patients should not have type 2 diabetes, and that's what we have reached because one third did not have diabetes.
Can you very briefly recap the main findings?
Yes. So this study was conducted to assess whether dapagliflozin compared to placebo reduced the risk of kidney failure or death due to cardiovascular cause. After 2.2 years of 2.4 years of follow up, the data monitoring board recommended that the trial be stopped due to overwhelming efficacy. When we analyzed the data, we found that 312 participants in the placebo group reached the primary endpoint first, 197 in adaptive dosing which led to a 39% relative risk reduction or a hazard range of 0.61 which was highly, statistically significant.
The secondary outcomes included a kidney specific outcome, namely kidney failure, or 50% eGFR decline, which was also significantly reduced by 44%. Cardiovascular death, or heart failure hospitalization, was the secondary endpoint, which was significantly reduced by 29%. And finally, of course, mortality was also significantly reduced by dapagliflozin by 31% and thus, overall, all the primary and secondary outcomes were met with statistical significant reductions in each endpoint.
Now an important question in our trial was whether these effects were consistent in patients with and without type 2 diabetes. When we analyzed the primary endpoint in patients with type 2 diabetes, we found a 36% relative risk reduction, and in patients without type 2 diabetes, a 50% relative risk reduction for the primary outcome. The p value for interaction for this endpoint in these populations was not statistically significant, indicating that there was no evidence to suggest that dapagliflozin on the primary outcome was different in patients with or without type 2 diabetes. So in other words, dapagliflozin is equally effective in reducing the primary endpoint in these patients, in patients with or without type 2 diabetes.
And finally, we pre-specified eight subgroups in the trial. And these were subgroups defined by age, gender, region, race, eGFR, albuminuria, blood pressure, and whether this patient had type 2 diabetes. Overall, the results showed that dapagliflozin was consistent in every subgroup analysis and that the effects were statistically significant in each circle when analyzed alone. So we therefore concluded dapagliflozin significantly reduced the risk of kidney failure, cardiovascular death, heart failure hospitalization, and prolonged survival. With respect to the safety, dapagliflozin was well-tolerated in this population of patients with chronic kidney disease. And the number of patients with adverse events, or discontinued the study drug due to adverse events, were similar. And importantly, there were no diabetic ketoacidosis in the dapagliflozin arm and only two in a placebo.
I seem to remember there were originally concerns that SGLT2 inhibitors might actually be damaging for kidneys. Why did people think this?
This was based on an idea that by increasing glucose or by-- inhibition of glucose reabsorption in the proximal tubal would lead to high exposure of glucose further in the distal tubal. And people were concerned that high glucose could damage the kidney. Well I think that concern is completely taken away. now with the results from this trial, the results from the CREDENCE trial, which was a trial specifically in patients with type 2 diabetes and kidney disease, and the cardiovascular outcome trials. All these trials have shown the safety of SGLT2 inhibitors and the fact that they significantly reduce or slow the progression of kidney function decline.
And now we're in the reverse situation, where they actually seem to be renal protective. So what do you think the mechanisms are?
I believe that one of the driving mechanisms for kidney protection is the fact that these drugs reduce the pressure in the glomeruli. They do that through a special mechanism and namely tubuloglomerular feedback. Because SGLT2 inhibitors block the inhibition of proximal tubal sodium reabsorption, they actually deliver more sodium to the distal tubal in the kidney, and that leads to a signal to the efferent arteriole at the efferent blood vessel to the glomeruli that is going to be constricted. Thereby, the renal blood flow decreases, the pressure in the kidney decreases, and therefore the GFR acutely decreases. This is, in the long term, associated with preservation of kidney function. We know this mechanism from ACE inhibitors, angiotensin receptor blockers, and it's an important mechanism that can also drive and explain the benefits of SGLT2 inhibitors.
So DAPA-CKD and CREDENCE were in people who already had overt kidney decline. So if you gave a SGLT2 inhibitors to people before they developed that decline, if you were giving them, just as a glucose lowering drug, quite early in the disease process, would you also prevent that kidney decline and maybe prevent them from developing overt renal disease at all?
Yes, that's correct because we know that the DECLARE study, which was a clinical trial in 18,000 patients with type 2 diabetes at early stage of disease, trial was reported two years ago, demonstrated that in these patients with early stages of chronic kidney disease, we can significantly slow the progression of kidney function decline. We now extend these findings to patients with established chronic kidney disease. So SGLT2 inhibitors, specifically dapagliflozin, is beneficial across the spectrum of kidney function.