Diabetic nephropathy (DN) has a burgeoning pipeline of drugs in late-stage development, which is particularly interesting since, in addition to showing signs of renal benefits, the SGLT-2 inhibitors have shown reductions in CV events, a very important co-morbidity in DN patients. However, in the CANVAS CVOT, the SGLT-2 inhibitor Invokana (JNJ, Daiichi, Mitsubishi) also increased the risk of amputations, for which DN patients are already at a higher risk, whereas Jardiance (Boehringer, LLY) showed no such finding in its EMPA-REG CVOT. Label expansions are particularly important for the class given the potential entrance of an oral GLP-1 agonist (oral semaglutide; NVO) to the type 2 diabetes market.

This 10-question survey of 70 US primary care physicians gauges what benefits they would like to see in a new drug for DN, whether signs of renal benefits for SGLT-2 inhibitors in CVOTs will lead them to increase usage of the drugs prior to pivotal DN trials, concern about Invokana's amputation risk in various segments of DN patients and whether it may be a class effect, projected usage of SGLT-2 inhibitors in various scenarios (including potential outcomes in Farxiga's [AZN] CVOT), and views on the mineralocorticoid receptor antagonist finerenone (Bayer) and endothelin- A antagonist atrasentan (ABBV).

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Survey Questions:

• Screening question: How many type 2 diabetes patients with diabetic nephropathy are you currently treating?
• Screening question (part 2): To what percentage of your type 2 diabetes patients on diabetic medications do you currently prescribe SGLT2 inhibitors?
• Please rank the following features that you would like to see in new treatments for diabetic nephropathy (DN). Please put the highest priority feature at the top.
• The SGLT2 inhibitors Invokana, Farxiga, and Jardiance are being tested in renal trials, because Invokana and Jardiance had signs of renal benefit in their cardiovascular outcomes trials (CVOTs) in high CV risk diabetics, but the data was insufficient for a new indication. The renal and CV benefits from these trials are shown below. How much will the renal benefits themselves (not considering the CV effects) lead you to increase prescribing of SGLT2 inhibitors before results from the new trials?
• In addition to the CV & renal benefits seen in Invokana's CVOT (CV results shown below), it also had an increased rate of amputations (6.3 vs. 3.4 per 1000patient-years) resulting in a black box warning. More amputations occurred in those with certain risk factors for amputations, but the relative risk was increased even in those without these factors. In light of this information, how concerned are you about using Invokana in Type 2 diabetes patients with the following comorbidities?
• In Jardiance's EMPA-REG CVOT (CV results below), the drug showed no difference from placebo in the rate of amputations, though this was not a side effect that was prespecified to look for. Farxiga CVOT results are not yet available to compare. Given the increased risk for amputations seen for Invokana, under the following scenarios for Farxiga's CVOT, please indicate how concerned you will be that Jardiance has an increased risk for amputations, which may just not have shown up in its CVOT.
• To what percent of your Type 2 patients with the following renal stages do you currently prescribe SGLT-2 inhibitors?
• Assume the SGLT2 inhibitors have the results shown below in their pivotal diabetic nephropathy (DN) trials and other trials with data on renal function. Assume also that there is no increased risk of amputations seen in any of the pivotal DN trials or Farxiga's CVOT in Type 2 diabetes, as was seen in Invokana's CANVAS CVOT. To what percent of your DN patients with the following renal stages will you prescribe SGLT2 inhibitors if they are approved for DN?
• Now assume everything is the same as in the last question, but that the SGLT2 inhibitors have an even stronger benefit on cardiovascular death in their DN trials, with CV death reduced by 38% (rather than 14% as in the previous question). To what percent of your DN patients with the following renal stages will you prescribe SGLT2 inhibitors once they are approved for DN?
• Now assume that Invokana does show an increase in amputations in its pivotal DN trial, as it did in its CANVAS CVOT, but other SGLT2 inhibitors do not show an increase in their pivotal DN trials. Relative to the last question (CV death reduced by 38%), how will that impact your prescribing of the overall SGLT2 inhibitor class to DN patients with the following renal stages?
• Finerenone is a selective oral, non-steroidal mineralocorticoid antagonist that may not increase potassium as much as current options (eg spironolactone and eplerenone). Assume it only slightly increases the risk for elevated potassium and without negative clinical consequences in larger pivotal DN outcomes trials looking at both cardiovascular and renal outcomes. Please select which group of patients you would be hesitant to use finerenone in given the following efficacy results?
• Atrasentan antagonizes the endothelin receptor, which can cause edema. To minimize the risk and enhance efficacy on renal outcomes, its pivotal trial has an enrichment phase to screen out patients with fluid retention from the drug and select those who will likely have better efficacy. Assume in the enriched population, edema is not a major issue and efficacy appears greater than other DN drugs. Assuming atrasentan is approved, please indicate if each of the below statements reflects your view.