ACC – Jardiance heart benefit looks like a class effect

Astrazeneca and Johnson & Johnson can rest easier knowing that their glucose lowering pills Farxiga and Invokana will not be completely outmatched by Boehringer Ingelheim and Lilly’s Jardiance.

A six-country registry analysis suggests that all the marketed SGLT2 pills have prevented heart failure hospitalisations and death compared with other glucose lowering drugs. As Astra and J&J await major outcomes trials in the next two years that they hope will match Jardiance's Empa-Reg Outcome study, the findings of this massive meta-analysis should give hope of positive data (Event – J&J needs to paint a heartening picture with Canvas, February 7, 2017).

Staying out of the hospital

The CVD-Real analysis covered 300,000 patients in the US, UK, Germany, Norway, Denmark and Sweden taking either one of the SGLT2 inhibitors or another glucose-lowering drug, defined as insulin, GLP-1, DPP-IV or older generic. Most patients were on multiple glucose-lowering medications, with nearly 80% of patients in the trial taking metformin in addition to other drugs.

In the SGLT2 arm, the risk of a single heart failure hospitalisation was reduced by 39%, and when patients taking thiazolidinediones, sulfonylureas and insulin were excluded from the non-SGLT2 arm the risk was cut by 43%. The risk of all-cause mortality was 51% lower and, and in a composite analysis of heart-failure hospitalisation and all-cause mortality the risk was reduced 46%.

Across the entire analysis, 54% of patients’ exposure time was from Invokana, 37% from Farxiga and the rest from Jardiance; among European patients more than 90% of the exposure was to Farxiga.

The researchers cautioned that, because this was not a clinical trial, unmeasured factors could have affected the results. In addition, the analysis did not look at other cardiovascular complications like heart attacks, was not able to adjudicate events and did not look at adverse events.

Evaporating advantage

Boehringer and Lilly have done well in translating Jardiance’s cardiovascular benefit into sales growth, and the drug is now forecast to overtake Invokana to be the biggest-selling SGLT2 by 2022 (EASD – Lilly blooms with full Jardiance outcomes data, September 18, 2015).

Jardiance’s 2020 forecast has doubled since the Empa-Reg Outcome results were announced, but with these data – along with what may be confirmatory results from the Canvas trial of J&J’s Invokana later this year – analysts might want to take a new look at their models.

The SGLT2 outlook
Global sales ($m)
Product Company 2016 2017 2018 2019 2020 2021 2022
Jardiance Boehringer Ingelheim/Lilly 395 918 1,453 2,064 2,617 3,049 3,456
Invokana Johnson & Johnson/Mitsubishi Tanabe 1,347 2,021 2,321 2,556 2,779 3,012 3,244
Farxiga Astrazeneca/Ono 908 1,255 1,586 1,833 2,006 2,099 2,204
Ertugliflozin Pfizer - 9 66 138 203 260 311
Suglat Astellas Pharma 90 115 132 141 164 215 304
Lusefi Taisho Pharmaceutical Holdings 26 33 41 49 55 62 69

Jardiance now has a cardiovascular claim on its label. Should Canvas, and the Declare-Timi58 trial of Farxiga due in 2019, prove similarly beneficial J&J and Astra should also be able to begin marketing to physicians on the basis of averting cardiovascular death, although Jardiance has a good head start.

If this proves to be a class effect, growth of the SGLT2s could come at the expense of another fast-growing diabetes class, the GLP-1s, especially since the benefit here has appeared more modest (Novo slumps as Leader looks more like a follower, June 14, 2016).  

Showing a cardiovascular benefit is now the baseline expectation for the SGLT2s, and in the future perhaps for all diabetes drugs. This meta-analysis suggests that Invokana and Farxiga will rise to this challenge, but the only way to be sure is with readout of well-controlled clinical trials.

To contact the writer of this story email Jonathan Gardner in Washington DC at jonathang-us@epvantage.com or follow @ByJonGardner on Twitter

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