In search of answers in diabetes

Blair Hesp questions the inconsistent cardiovascular (CV) benefit of dipeptidyl peptidase-4 (DPP4) inhibitors in diabetes across phase III and IV studies.

(Continued from ‘Have we confirmed that controlling hyperglycaemia is not the magic bullet for preventing macrovascular disease in patients with type 2 diabetes?‘)

Patients with type 2 diabetes have an approximate 80% probability of dying of CV disease.1 Therefore, there were high expectations that prospective studies of DPP4 inhibitors in patients with type 2 diabetes would confirm a reduced risk of major adverse CV events, as was consistently reported in meta-analyses of data from the corresponding phase III clinical trial programmes.2–6 However, no significant improvement in CV outcomes has been observed in reports from the first two prospective trials of DPP4 inhibitors in patients with type 2 diabetes, SAVOR (saxagliptin) and EXAMINE (alogliptin).7,8 In fact, a signal suggesting a greater risk of heart failure was observed in patients treated with saxagliptin.7

Where has the discrepancy come from?

A reduced risk of major CV events was consistently observed in retrospective meta-analyses from the phase III clinical trial programmes for all DPP4 inhibitors, although the magnitude of this reduction varied wildly from 12–66%.2–6 Despite this, the absence of any effect in two prospective studies of CV events in patients with diabetes treated with DPP4 inhibitors still begs an explanation.7,8

“…the absence of any effect in two prospective studies of CV events in patients with diabetes treated with DPP4 inhibitors still begs an explanation…”

Interestingly, a crude comparison of the patient characteristics in the SAVOR study and saxagliptin CV meta-analysis reveals clear differences between the patient populations, and in this context, it may be less surprising to see a different outcome in SAVOR compared with the meta-analysis of phase III saxagliptin data.

*This differs from the originally published primary endpoint of CV death, MI or ischaemic stroke10

Notably, both SAVOR and EXAMINE targeted patients who were at a ‘high risk’ of major adverse CV events, and perhaps this enrichment is not only reflected by the differences highlighted in the table above, but may also be responsible for the lack of CV benefit. Intriguingly, data from a meta-analysis of CV outcomes from the vildagliptin phase III clinical trial programme suggested that patients with a high risk of a CV event who were treated with vildagliptin may have improved CV outcomes, whereas elderly patients may not, further muddying the waters given that advanced age is a risk factor for CV events.4

How does this change the diabetes treatment landscape?

For the time being the neutral results should not have a major influence on the diabetes treatment landscape. By contrast, the hoped for positive result would have significantly improved the value proposition for DPP4 inhibitors as second-line oral antidiabetic therapy compared with cheaper generic drugs, such as sulphonylureas. Likewise, a proven CV benefit would have been a major competitive advantage for saxagliptin and / or alogliptin versus other DPP4 inhibitors, at least in the short term, as first-reporters.

What do the currently known results mean for DPP4 inhibitors?

Firstly, the manufacturers of sitagliptin, vildagliptin and linagliptin now face a nervous wait before the outcomes of their own prospective CV outcomes studies are known. Notably, the threat of saxagliptin and/or alogliptin gaining a significant competitive advantage by being the first to publish positive prospective CV outcomes data no longer exists. Therefore, while SAVOR and EXAMINE have cast a dark shadow over any expectations of CV benefits being a characteristic of DPP4 inhibitors as a class, the potential prize for any single drug that prospectively demonstrates a CV benefit has become much larger.


“For the time being the neutral results should not have a major influence on the diabetes treatment landscape…”


Secondly, a consistent observation of no improvement in CV outcomes may have ramifications for the sales of DPP4 inhibitors, particularly if some prescribers read too deeply into the phase III meta-analyses and favoured DPP4 inhibitors on the basis of a presumed CV benefit. Accordingly, consistent observations of no CV benefit could lead some healthcare professionals to reassess the cost:benefit ratio of DPP4 inhibitors compared with other treatment options for patients with type 2 diabetes.

Thirdly, given that heart failure adverse events led to the withdrawal of rosiglitazone from the market and the introduction of a CV safety regime for new type 2 diabetes therapies, the SAVOR data is likely to fuel more than a passing interest in the risk of heart failure for patients treated with DPP4 inhibitors.

Could this be game over for DPP4 inhibitors, glycaemic control and CV benefits?

As hypothesised in my earlier article on this topic, insulin resistance could be a key factor in CV events in patients with type 2 diabetes, and increased insulin resistance in patients with a longer duration of disease could potentially influence outcomes in the patient groups mentioned here. However, the data released so far does not suggest a complete dead end. Perhaps this data signals an inability to ‘rescue’ high-risk patients with type 2 diabetes from CV disease. This may be another question that could be answered by future investigations of CV outcomes in patients with type 2 diabetes treated with SGLT-2 inhibitors – is any CV benefit associated with the mechanism of action of antidiabetic agents or is the timing of antihyperglycaemic treatment integral to outcomes. In other words, trying to use antihyperglycaemic agents to control the risk of a CV event in a high-risk patient may be futile, whereas early intervention may be the key to a significant level of protection for lower risk patients with type 2 diabetes.


1. Buse JB, et al. Primary prevention of cardiovascular disease in people with diabetes mellitus: A scientific statement from the American Heart Association and the American Diabetes Association. Circulation 2007;115:114–126.

2. Frederich R, et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 2010;122:16–27.

3. Engel SS, et al. Safety and tolerability of sitagliptin in type 2 diabetes: Pooled analysis of 25 clinical studies. Diabetes Ther 2013;4:119–145.

4. Schweizer A, et al. Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large Phase III type 2 diabetes population. Diabetes Obes Metab 2010;12:485–494.

5. Johansen OE, et al. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol 2012;11:3.

6. White WB, et al. Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab 2013;668–673.

7. Scirica BM, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–1326.

8. White WB, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–1335.

9. Mosenzon O, et al. Baseline characteristics of the patient population in the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus (SAVOR)-TIMI 53 trial. Diabetes Metab Res Rev 2013;29:417–426.

10. Scirica BM, et al. The design and rationale of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study. Am Heart J 2011;162:818–825.

About the author:

Blair Hesp is a Director of Kainic Medical Communications Ltd., a New Zealand-based medical communications agency that specialises in providing on-demand, overnight medical communications resource to overseas agencies and pharmaceutical companies. Blair has a PhD in Pharmacology from the University of Otago and a New Zealand Diploma in Business. In addition to several years’ experience working in the Global and European medical communications industry in the United Kingdom, he has also spent several years working in the international intellectual property industry.

Where did the cardiovascular benefit of DPP4 inhibitors in diabetes go between phase 3 and 4?