Diabetic nephropathy: A condition with scant therapeutic options
Management of diabetic nephropathy continues to be a daunting task for endocrinologists and nephrologists around the world. Glycemic control and blood pressure (BP) management are the primary steps taken to delay chronic kidney disease progression. Therapy guidelines recommend lowering HbA1c to <6.5% and a BP target of 140/90 mm Hg (International Diabetes Federation, 2012). However, the prevention of disease progression to ESRD (end-stage renal disease) or reversal of disease remains a herculean task. RAAS (renin-angiotensin-aldosterone system) inhibitors are the most commonly prescribed class of drugs for the prevention of diabetic nephropathy disease progression.
The SGLT-2 (sodium-glucose cotransporter 2) inhibitors are available in the U.S. and Europe for the treatment of type 2 diabetes (T2D) and are in clinical trials for chronic kidney disease. By preventing glucose reabsorption the proximal convoluted tubule (PCT) and thus promoting excretion of glucose, SGLT-2 inhibitors lower blood glucose levels. Along with their efficacy in the management of glycemia, SGLT-2 inhibitors also demonstrate efficacy in lowering body weight and BP (Kalra S, 2014).
Johnson and Johnson make the first move into renal protection
In April 2019, Johnson and Johnson presented the results of the landmark CREDENCE trial. In the trial, canagliflozin (brand name Invokana) demonstrated a 34% reduction in relative risk of a renal specific composite of ESKD, doubling of creatinine level or death due to renal causes. Also, canagliflozin group patients showed 32% reduction in relative risk of ESKD (Janssen Pharmaceuticals, press release, April 14, 2019). In March 2019, Johnson & Johnson submitted a supplemental New Drug Application (sNDA) to the FDA for a canagliflozin label expansion for the reduction in the risk of ESKD, doubling of serum creatinine and renal or CV death. With the data from the CREDENCE trial and revised labeling, we expect a boost in the commercial potential of canagliflozin.
In two previously conducted trials, CANVAS (canagliflozin cardiovascular assessment study) and CANVAS-R (cardiovascular assessment study on adult participants with diabetes mellitus), patients in the canagliflozin group had around twice the number of leg and foot amputations compared to the patients in the placebo group. Subsequently, the FDA gave canagliflozin a boxed warning describing the potential risks on the use of the drug. However, in CREDENCE, a significant canagliflozin did not cause a significant increase in amputation or fracture events. Hence, it is likely the FDA will remove the boxed warning in the future.
The American Diabetes Association (ADA) updated its 2019 Standard of Care guideline recommendations for treatment of DN patients after the CREDENCE trial was published. ADA now recommends the use of SGLT-2 inhibitors in DN patients with eGFR equal or higher than 30 mL/min/1.73 m2 and albuminuria over 300 mg/g for lowering the risk of disease progression and prevention of cardiovascular events.
Other manufacturers with ongoing renal trials
With the release of CREDENCE trial results, Johnson & Johnson canagliflozin is leading in renal protection but competitors aren’t far behind. Now, companies are conducting a wide range of trials for the evaluation of SGLT-2 inhibitors for CV and renal outcomes. AstraZeneca is conducting the DapaCare clinical programme to evaluate Farxiga (dapagliflozin) across a wide range of CV and renal diseases. Under DapaCare, Dapa-CKD trial is being conducted to evaluate dapagliflozin for renal outcomes and cardiovascular mortality in patients with chronic kidney disease irrespective of diabetes status (differentiating from the CREDENCE trial, where all patients had type 2 diabetes). While we await the completion of the Dapa-CKD trial, expected November 2020 AstraZeneca is stoking interest in its SGLT-2 inhibitor, dapagliflozin (Farxiga). ln June 2019, AstraZeneca released the renal data of its cardiovascular outcomes trial, DECLARE-TIMI 58. In the pre-specified investigative analysis, patients in the dapagliflozin group showed a 24% reduction in relative risk of a cardio-renal composite of decline in kidney function, ESRD, or renal or CV death compared to placebo. The magnitude of effect and endpoint is comparable to that observed in the CREDENCE. Arguably canagliflozin will accumulate more diabetic nephropathy-specific data, dapagliflozin a broader CKD evidence base. Either way, competition will continue to be fierce in the emerging market segment.
Merck & Co. in collaboration with Pfizer is conducting VERTIS CV study for evaluation of CV outcomes in patients with T2D and vascular disease who underwent ertugliflozin therapy. The VERTIS CV trial which is expected to be completed by December 2019 is also tracking renal outcomes as secondary endpoints. If the trial meets the primary and secondary outcomes, we can expect another exclusive renal outcome trial with ertugliflozin.
Sanofi is conducting the Phase 3 SCORED trial evaluating the effect of sotagliflozin for CV and renal outcomes in patients with T2D and renal impairment who are also at CV risk. The trial is expected to be completed by March 2022. In the SCORED trial, time to the first composite renal event, and renal event in patients with macroalbuminuria are secondary outcomes. It must also be said that the SCORED trial is being conducted over a large patient pool of 10,500 patients with T2D. A positive result from the SCORED trial could help later-to-market sotagliflozin compete at the top table.
In the VERTIS CV trial, diabetes mellitus is a primary inclusion criterion while in SCORED trial along with T2D eGFR parameters has also been considered. In DAPA-CKD and EMPA-KIDNEY trials, eGFR parameters are the primary inclusion criteria. Hence, we can understand that most of the SGLT-2 inhibitors are being evaluated for renal effects in clinical trials. The CREDENCE trial remains a torchbearer in the clinical trials with SGLT-2 inhibitors in patients with diabetic nephropathy. With the release of positive CREDENCE data, it is reasonable to expect similar results with other members in the same class and several new treatment options in diabetic nephropathy.