Clinical Trials on Diabetic Kidney Disease: What Have We Learned from Landmark Trials?

In the era of evidence-based medicine, high-quality clinical trials are the key to the development of sound practice guidelines. Many landmark trials have enabled us to make significant progress in our approach to diabetic nephropathy, the leading cause of ESKD worldwide, although we are still short of a cure. The two enduring lessons learned from these trials are that glucose control and BP control by renin-angiotensin-aldosterone system (RAAS) antagonists helps reduce the risk of diabetic kidney disease but do not entirely prevent it. The main trials that constitute the basis of this dual approach are briefly discussed here, along with a table summarizing the key findings extracted from them (Table 1).

table 1.PNG

Although the pathophysiology of diabetes is complex, the main factor responsible for kidney and eye damage is glucose toxicity. So, intuitively one would expect that glucose control should make a difference.

Both the Diabetes Control and Complications Trial (DCCT), conducted from 1983 to 1993, and the follow-up study, Epidemiology of Diabetes Interventions and Complications (EDIC), showed that “intensive control” of hyperglycemia (achieving hemoglobin A1c [HbA1c] <7%) is effective in reducing the microvascular complications of diabetes (1). The UK Prospective Diabetes Study (UKPDS), the largest prospective study of patients with newly diagnosed type 2 diabetes, showed similar beneficial effects. A summary review of the major glycemic control trials clearly shows that intensive control achieving an HbA1c level around 6.5% to 7% helps reduce the risk of albuminuria and kidney disease. For example, the ADVANCE trial, which enrolled over 11,000 patients with type 2 diabetes, showed that achieving an HbA1c level of 6.5% led to a reduction of approximately 20% in kidney disease (2, 3). By contrast, ACCORD, a similarly large trial, showed that more aggressive glucose control targeting an HbA1c level of 6% is not beneficial.

The landmark captopril trial published in 1993 (4) was followed by many others that confirmed the beneficial effects of both the angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the course of diabetic nephropathy (Table 1). Thus, based on the lesson learned from these landmark trials the antiangiotensin strategy became the standard of care in patients with both type 1 and type 2 diabetes with kidney disease. It seemed intuitive that by combining angiotensin-converting enzyme inhibitors with angiotensin receptor blockers we might achieve more effective renoprotection, but we learned from the ONTARGET and NEPHRON-D studies that this approach was not viable because of the increased risk of adverse events, including worse renal outcomes (5).

Thus, the combined strategy of intensive glycemic control and blood pressure control by the use of RAAS antagonists offered hope to patients with diabetes and seemed successful—most trials showed a marked decrease in proteinuria and a slower progression of kidney disease. Still, diabetic nephropathy remains the most common cause of ESKD, both in the United States and worldwide. Why? Did we hit a wall with this strategy? Searching for alternative or complementary approaches, other trials using a direct renin antagonist, an antioxidant (bardoxolone), and an endothelin type A receptor antagonist were disappointing and, in fact, yielded adverse outcomes (Table 1).

Medical care has improved much and is organized better since the publication of these landmark trials, and these strategies are now available to larger populations of individuals with diabetes and kidney disease. We are far better at achieving simultaneously better glycemic control and BP control with the novel classes of antidiabetic drugs, including dipeptidyl peptidase-4 antagonists, incretins, and most sodium glucose co-transporter 2 (SGLT-2) inhibitors combined with anti-RAAS drugs.

Although these agents are helpful in achieving better glycemic control, we do not yet have robust data on the benefits of the newer antidiabetic drugs on diabetic kidney disease, except for the SGLT-2 inhibitor canagliflozin. The CREDENCE trial, which included 4401 patients with type 2 diabetes, was terminated prematurely because the early data showed a clear benefit of canagliflozin on renal outcomes, including the doubling of serum creatinine or ESKD (6). The response from the medical community to the recently published results of this trial suggests that the use of SGLT-2 inhibitors may well rise to the level of standard of care in the treatment of patients at risk for diabetic nephropathy.

It could be argued that the landmark trials completed since the early 1990s have shown that the efforts to achieve optimal glucose control (i.e., HbA1c level of 6.5% to 7%; and optimal BP control, usually suggested as <130/80 mm Hg) with the use of RAAS antagonists are rewarded by favorable outcomes. Yet, both of these therapy targets remain controversial. The HbA1c levels may not always be accurate in different populations and may not be the best biomarker of glycemic control. More aggressive BP lowering (i.e., systolic pressure <120 mm Hg) may be better. But, to date, we do not have robust clinical trials to resolve these lingering questions.

Nevertheless, after a long and bumpy road, we have accumulated substantial evidence on which to base our current approach: to contain if not to fend off the diabetic nephropathy epidemic completely. Ongoing work suggests that among the newer antidiabetic agents, the SGLT-2 inhibitors may confer additional benefit for patients with diabetes who are at risk for microvascular complications. Clearly, much additional work is needed to curb the diabetic nephropathy epidemic.

August 2019 (Vol. 11, Number 8)

References

1. DCCT/EDIC Research Group: Effect of intensive diabetes treatment on albuminuria in type 1 diabetes: Long-term follow-up of the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study. Lancet Diabetes Endocrinol 2014; 2:793–800.

2. Zoungas S, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med 2014; 371:1392–1406.

3. Perkovic V, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int 2013; 83:517–523.

4. Lewis EJ, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329:1456–1462.

5. Fried LF, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369:1892–1903.

6. Perkovic V, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–2306.

 

Table References

1. Chan GC and Tang SC. Diabetic nephropathy: Landmark clinical trials and tribulations. Nephrol Dial Transplant 2016; 31:359–368.

2. Diabetes Control and Complications Trial Research Group, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977–986.

3. DCCT/EDIC Research Group. Effect of intensive diabetes treatment on albuminuria in type 1 diabetes: Long-term follow-up of the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study. Lancet Diabetes Endocrinol 2014; 2:793–800.

4. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837–853.

5. Perkovic V, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int 2013; 83:517–523.

6. Action to Control Cardiovascular Risk in Diabetes Study, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559.

7. Lewis EJ, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329:1456–1462.

8. Brenner BM, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861–869.

9. Lewis EJ, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851–860.

10. Haller H, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011; 364:907–917.

11. Mann JF, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): A multicentre, randomised, double-blind, controlled trial. Lancet 2008; 372:547–553.

12. Fried LF, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369:1892–1903.

13. Parving HH, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012; 367:2204–2213.

14. de Zeeuw D, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013; 369:2492–2503.

15. Mann JF, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010; 21:527–535.

16. Perkovic V, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–2306.