What Have We Learnt from Cardiovascular Outcome Studies of New Anti-diabetic Therapies in Last Decade?

Diabetes has become a major health concern worldwide with a rapid increase in its prevalence rate. Cardiovascular complications are the leading cause of morbidity and mortality in diabetes. A 2007 meta-analysis of rosiglitazone showed significant increase in the risk of cardiovascular events with rosiglitazone therapy and that raised an alarm regarding cardiovascular safety of anti-diabetic drugs. Post this incidence in 2008, the UF FDA issued a guidance for the industry to conduct CVOT on new anti-diabetic therapies before they are approved for clinical use. Since then, all new anti-diabetic therapies underwent CVOTs for their cardiovascular safety evaluation. The objective of this paper is to review the key learnings from CVOTs of new anti-diabetic therapies published post 2008 FDA guidance.


Introduction
The prevalence of diabetes and associated complications are rising rapidly. Diabetes has become a major health issue worldwide. According to 9th Edition, International Diabetes Federation (IDF) Diabetes Atlas released in 2019, there are 463 million people living with diabetes worldwide, and the number is projected to reach to 700 million by 2045 and this is alarming [1]. Increasing diabetes prevalence is also associated with increasing prevalence of associated comorbidities and complications. A meta-analysis of 102 studies showed that the hazard ratio (HR) for coronary heart disease (CHD) and coronary death were 2.0 (95%CI 1.83 to 2.19) and 2.3 (95%CI 2.05 to 2.60) respectively in people with diabetes compared to those without diabetes [2]. According to a systemic review analysis including more than 4.5 million type 2 diabetes (T2DM) patients, CVD has been observed as a major cause of morbidity (around 32% prevalence of CVD in T2DM) and mortality (accounting for almost 50% of all death) amongst T2DM patients [3]. Looking into this strong positive association between diabetes and CVD, one would always expect the treatment modalities of diabetes to be associated with at least no further increase in the risk of CVD if not reduced.

Rosiglitazone and cardiovascular events
Rosiglitazone was introduced in 1999 and became one of the most widely used medicine either as a monotherapy or in combination with other anti-diabetic drugs in the management of T2DM. In the year 2007, a meta-analysis was carried out including 42 trials showed that the treatment with rosiglitazone was associated with significant increase in the risk of myocardial infarction (odds ratio 1.43; 95%CI 1.03 -1.97) and death due to cardiovascular (CV) causes (odds ratio 1.64; 95%CI 0.98 -2.74) [4]. The results of this meta-analysis triggered a discussion on CV safety of anti-diabetic drugs. As a result, the United States Food & Drug Administration (US FDA) issued a guidance in the year 2008 for pharmaceutical companies to carry out cardiovascular outcome trials (CVOT) for all new anti-diabetic drugs before they get authorization for the clinical treatment of diabetes [5]. After this development, the CVOT became mandatory for all new research molecule in T2DM.

The US FDA 2008 guidance on new anti-diabetic therapy evaluation
According to the 2008 guidance by US FDA, the agency advised that the analysis of premarketing data (either a meta-analysis of phase II and phase III studies or an exclusively conducted large randomized controlled study) comparing the CV events (typically a composite of nonfatal myocardial infarction [MI], nonfatal stroke or CV death) in the test arm with control arm should rule out the upper limit (two-sided 95% CI) of hazard ratio of 1.8. For the new drug therapy whose 95% CI upper limit falls within 1.3 to 1.8 in premarketing studies analysis, completion of post marketing trial or continuation of premarketing trial after approval may be needed to conclusively show that the upper limit of the two-sided 95% CI is 1.3 with a reassuring point estimate of overall CV risk [5]. Post 2008, many new antidiabetic therapies from various categories, like DDP-IV inhibitors, GLP-1 agonists and SGLT2 inhibitors have been evaluated under long-term CVOTs.

Current Research in Diabetes & Obesity Journal
The various CVOTs of new anti-diabetic therapies are briefly summarized in table 1.

DPP-IV inhibitors and CVOTs
None of the studies of DPP-IV inhibitors, as mentioned in table 1, have shown increase or decrease in the risk of MACE (major adverse cardiovascular events) [6][7][8][9][10]. These studies have also endorsed that DPP-IV inhibitors are not associated with increased risk of all-cause mortality. The results from SAVOR-TIMI 53 study showed that saxagliptin therapy is associated with significant increase in the risk of hospitalization for heart failure compared to placebo group (HR 1.27; 95% CI, 1.07 to 1.51; P = 0.007) [6]. All these studies were placebo controlled except for CAROLINA study wherein linagliptin was compared with glimepiride. For primary MACE outcome, linagliptin was found to be non-inferior to glimepiride [10].

GLP-1 receptor agonist and CVOTs
The results from available CVOTs as briefed in table 1. have established that GLP-1 receptor agonist is not associated with increase in the risk of CV events [11][12][13][14][15][16][17][18]. Certain studies have shown significant CV risk reduction with certain GLP-1 agonist compared to placebo arm. LEADER, SUSTAIN-6, HARMONY OUTCOMES and REWIND studies showed significant reduction in the risk of MACE with liraglutide, semaglutide, albiglutide and dulaglutide respectively [12,13,16,18]. Two studies, LEADER and PIONEER 6 studies, have additionally shown significant reduction in the risk of all-cause mortality with liraglutide and oral semaglutide respectively compared to placebo group [12,17].

SGLT-2 inhibitors and CVOTs
First published CVOT with SGLT-2 inhibitor was EMPA-REG outcome study with empagliflozin [19] and it showed that the treatment with empagliflozin is associated with significant reduction in the risk of MACE and all-cause mortality compared to placebo arm. Empagliflozin and placebo arms were not significantly different in terms of incidence of MI or stroke, however, empagliflozin significantly reduced the risk of CV death by 38% compared to placebo arm. Based on the results from EMPA-REG outcome study, empagliflozin is also indicated to reduce the risk of CV death in adult patients with type 2 diabetes and established CVD. After EMPA-REG outcome study, the results from many CVOTs with different SGLT-2 inhibitors were published and they showed that SGLT-2 inhibitors are not associated with increased risk of CV events [20][21][22][23][24].
The primary objective of CREDENCE study was to evaluate the renal outcome with canagliflozin compared with placebo. The results of this study showed that canagliflozin produced significant 20% relative risk reduction in one of the secondary objectives of 3-point MACE [22]. DAPA-HF study is an exceptional study, evaluating the effect of dapagliflozin in NYHA class II, III, and IV heart failure with or without diabetes [23]. The results showed that dapagliflozin produced significant 26% relative risk reduction in primary outcome of composite of worsening of heart failure or CV death and 17% significant relative risk reduction in all-cause mortality compared to placebo arm in patients with NYHA II, III and IV patients irrespective of presence of diabetes [23]. As a result of DAPA-HF study, dapagliflozin is additionally approved to reduce the risk of CV death and hospitalization for heart failure in adults with NYHA II-IV heart failure with reduced ejection fraction.
So, what do we learn from all these CVOTs published in 2010s? One common learning from all these studies is that "these drugs are safe and none of the studies showed increase in the risk of MACE compared to placebo". Hence, the point of discussion now in 2020 is "Do we require to conduct CVOTs for new drug therapies in Diabetes?" This is important as conducting CVOT before the drug approval has its own impact on the cost of drug development. Finally, in March 2020, the US FDA has eliminated the previous 2008 guidance for the industry which was asking the sponsor to conduct CVOT mandatorily before they get new anti-diabetic drug approval. After eliminating the previous 2008 guidance, the US FDA has now issued a new draft guidance "Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control" for public comment on its revised proposal for broad safety evaluations before new drug approval [25]. Once this new safety evaluation guidance March 2020 is implemented, we will come to know more about its implications on new anti-diabetic drug development in future.

Summary
Diabetes and associated complications are rising, and CVD has become the leading cause of morbidity and mortality in people with diabetes. Hence, it would always be considered counterproductive if any drug therapy in diabetes increases the risk of CV events. The rosiglitazone matter in the year 2007 raised a CV safety alarm and subsequently the US FDA made CVOT mandatory for all new anti-diabetic therapies in 2008. After this, many CVOTs have been conducted with various new anti-diabetic therapies and none of them showed increase in the risk of MACE, instead some of the studies have shown beneficial effect on MACE/CV mortality/ all-cause mortality. After reviewing all these CVOTs, the US FDA has eliminated the 2008 guidance of CVOT for new anti-diabetic therapies and issued a new draft guidance for soliciting public comment on its revised proposal for broader safety evaluation of new drugs before approval.