Billionaire investor Carl Icahn on Tuesday urged Cigna shareholders to vote against the health insurer's $52 billion purchase of Express Scripts, citing regulatory hurdles and the growing threat of Amazon.com.

The Cigna-Express Scripts deal has drawn investor skepticism over concerns that Amazon.com Inc's entry into healthcare will upend the sector, which is already reeling from President Donald Trump's push to lower drug prices.

"When Amazon starts to compete as we believe they will, with their 100 million Prime users and scale distribution system, they will have no trouble breaking into the so-called ecosystem," Icahn wrote in a letter to Cigna shareholders.

"Competitive risk from Amazon, arguably the strongest competitor in the world, will be an existential threat to pharmacy benefit managers like Express Scripts, possibly challenging their very existence."

Icahn also said the Trump administration's push to scale back rebates that PBMs receive from drug manufacturers will hurt their profitability.

The billionaire investor, who has a long position on Cigna and a short position on Express Scripts, said in a letter titled "Cigna's $60 billion folly" that the insurer was overpaying for Express Scripts.

Icahn said Cigna should instead repurchase its shares and pursue partnership with existing pharmacy benefit managers, including Express Scripts.

Icahn has not disclosed his stake in Cigna, but The Wall Street Journal reported on Monday that the investor and his affiliates own about 0.56 percent of the company.

Express Scripts' shares fell last week after the news of Icahn's stake and his opposition to the deal first emerged. Cigna on Thursday said it was confident of winning shareholder approval for its Express Scripts deal. The shareholder vote is due on Aug. 24.

"We strongly believe that the combination (with Express Scripts) is in the best interest of our shareholders," Cigna Chief Executive Officer David Cordani reiterated last week.

Express Scripts shares were down 2 percent in heavy premarket trading, while Cigna shares were untraded.

"We believe we are well positioned for growth and remain confident in the deal," Express Scripts spokesman Brian Henry said. Cigna was not immediately available for comment.

Analysts do not expect shareholders to support Icahn, noting that few shareholders have questioned the strategic rationale of the deal and cited significant overlap in shareholding, with Cigna shareholders through various funds also owning nearly 84 percent of Express Scripts.

"We still expect that Icahn will find it challenging to build support among Cigna shareholders," Leerink analyst Ana Gupte wrote in a note on Monday.