Diabetes DPP-4 inhibitor drugs convey no increased risk of cardiovascular death

New results from post-marketing cardiovascular outcome studies regarding diabetes drugs were recently published in The New England Journal of Medicine and presented at the European Society of Cardiology (ESC) in Amsterdam yesterday (2 September). The two drugs in question – UK firm AstraZeneca and US firm Bristol-Myers Squibb's (BMS's) Onglyza (saxagliptin) and Japanese firm Takeda's Nesina (alogliptin) – both belong to the dipeptidyl peptidase-4 (DPP-4) inhibitor class of diabetes medication. Both studies revealed that the drugs presented no added cardiovascular risk of death, but they fail to demonstrate significant improvements in cardiovascular outcomes in diabetes patients, and may raise concerns over the risk of hospitalisation due to heart failure.

AstraZeneca and BMS's Onglyza

In the first study (SAVOR-TIMI 53) enrolling 16,492 diabetes patients, Onglyza met its primary safety endpoint and did not increase the risk of cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal ischaemic stroke when compared with placebo – 7.3 % in the Onglyza arm compared with 7.2% in the placebo group (see United States - United Kingdom: 2 September 2013: AstraZeneca, BMS announce Onglyza meets primary safety endpoint). However, the study also looked at a secondary composite endpoint of cardiovascular events and revealed that although most events were comparable with placebo, hospitalisation for heart failure had a higher occurrence in patients taking Onglyza (3.5% in the Onglyza arm compared with 2.8% in the placebo arm). Results from SAVOR also revealed that Onglyza led to a higher frequency of hypoglycaemia, but it did not convey any added risk of pancreatitis – in fact, it demonstrated reduced rates of pancreatic cancer compared with placebo. AstraZeneca and BMS had previously announced negative efficacy results from the Phase IV study, as Onglyza failed to demonstrate superiority in a composite endpoint looking at cardiovascular death, non-fatal MI, and non-fatal ischaemic stroke.

Takeda's Nesina

The other study (EXAMINE) investigated Nesina compared with placebo, enrolling 5,380 diabetes patients who had recently experienced an acute coronary event. The results demonstrated that patients taking Nesina had comparable cardiovascular outcomes to those on placebo in the composite endpoint of cardiovascular death, non-fatal MI, and non-fatal stroke (11.3% in the Nesina arm versus 11.8% in the placebo group). The study met its non-inferiority endpoint, according to Takeda. In addition, the study demonstrated no significant difference between patients on Nesina and placebo with regards to hypoglycaemia, malignancy, pancreatitis, or kidney failure.

Although the Nesina study did not pick up a significant increase in hospitalisation due to heart failure, as was demonstrated in the Onglyza study, the surprising, yet small, difference may be due to the increased sensitivity in the SAVOR trial that recruited over 16,000 patients in the study. However, further analysis of that sub-group of patients is required to characterise the risk further and understand the patient population that may have an increased predisposition to such events.

Incretin mimetics, pancreatitis, and sales performance

Additionally, DPP-4 inhibitors belong to a larger class of diabetes treatments referred to as incretin mimetics, and they too have come under scrutiny for the potential increased risk of pancreatitis, or pancreatic cancer, as revealed in various studies. The US FDA and the European Medicines Agency continue to monitor the long-term effects of incretin mimetics, although it seems that the risks are far less pronounced than originally reported (see Europe: 27 March 2013: EMA follows FDA with investigation into safety of DPP-4 inhibitors and GLP-1 analogues; United States: 15 March 2013: US FDA investigates incretin mimetic diabetes type 2 drugs for increased pancreas-related risks; and Europe: 29 July 2013: Eight candidate drugs receive CHMP backing for commercialisation in EU).

To date, the DPP-4 inhibitor class of diabetes drugs has performed particularly well in the market. Onglyza generated over USD1 billion in combined sales in 2012, with double-digit growth year-on-year, as reported by AstraZeneca and BMS's individual full-year financial results (see United Kingdom: 31 January 2013: AstraZeneca reports 17% fall in full-year revenues and United States: 25 January 2013: Tax benefit boosts profits for BMS in Q4). Nesina generated JPY7.3 billion (USD73 million) in the first quarter of 2013, as it continues to expand into new markets, following its recent approval in the United States in January (see Japan: 1 August 2013: Takeda's Q1 results show sales up 3.0%; CFDA grants Nesina approval in China and United States - Japan: 28 January 2013: US FDA grants Takeda approval for three type 2 diabetes drugs). Notably, US firm Merck & Co's DPP-4 inhibitor, Januvia (sitagliptin), has demonstrated solid performance, generating over USD4 billion in sales for the US pharmaceutical in 2012 (see United States: 4 February 2013: Merck & Co posts sharp Q4 sales decline, signals odanacatib development delay). However, growth has been slightly reduced in 2013, which may be related to pancreatitis concerns that are still under question (see United States: 4 February 2013: Merck & Co posts sharp Q4 sales decline, signals odanacatib development delay).

Outlook and implications

Diabetes drugs have come in the spotlight for various safety concerns, including cardiovascular risks, particularly following the safety concerns and controversy surrounding UK firm GlaxoSmithKline's (GSK's) Avandia (rosiglitazone; see United States - United Kingdom: 19 May 2011: FDA Updates REMS for Avandia; United States: 3 July 2012: GSK Concludes USD3-Bil. Settlement with US Government; and United Kingdom - United States: 7 June 2013: US FDA panel votes in favour of reducing restrictions on Avandia). As such, the FDA has mandated outcome studies to confirm diabetes drugs' cardiovascular safety.

On that front, Onglyza and Nesina have both demonstrated a positive safety profile, but questions remain as to whether or not DPP-4 inhibitors are, in fact, effective in reducing cardiovascular outcomes – one of the leading causes of death in diabetes patients – despite their well-documented efficacy in regulating glucose levels. However, it may be worthwhile to note that the studies were conducted over two years, and more time may be needed to properly assess cardiovascular outcomes in the long term.

It remains to be seen if the FDA and other regulatory bodies will continue to assess efficacy of diabetes drugs based on improved cardiovascular outcomes, as Januvia's large post-marketing outcomes trial is due next year. The association between cardiovascular disease and diabetes may be more linked to lifestyle and other risk factors, rather than hyperglycaemia. Germany's Health Technology Assessment agency, Institute for Quality and Efficiency in Healthcare (IQWIG), has recently taken a stringent position against most DPP-4s, except Januvia, which, it says, conveys "minor" benefit (see Germany: 2 July 2013: Germany's IQWIG takes tough line on DPP-4 inhibitors in first retrospective benefit assessment). The assessment casts a shadow on the class of diabetes drugs that may continue to face added pressures securing regulatory and reimbursement approval in the future.