Robert EJ Ryder,1 Ralph A DeFronzo2
1 City Hospital, Birmingham, UK
2 University of Texas Health Science Center, San Antonio, Texas, USA
Address for correspondence: Dr Bob Ryder
Diabetes and Endocrine Unit, City Hospital, Dudley Road,
Birmingham B18 7QH,
UK E-mail: bob.ryder@nhs.net
Br J Diabetes 2016;16:103-106
http://dx.doi.org/10.15277/bjd.2016.096
We suggested in a previous editorial that the combination of metformin, pioglitazone and empagliflozin would likely improve cardiovascular outcomes in patients with type 2 diabetes at high cardiovascular risk.1 This conclusion was 15 years in the making: 7 years between the UK Prospective Diabetes Study (UKPDS) in 19982 and the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study in 2005,3 and then another 8 years from there to the landmark moment when we saw the results of the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME™) at the European Association for the Study of Diabetes (EASD) 2015 in Stockholm.4,5 Against this background, it is remarkable that we needed to wait only another 9 months for a similar moment at American Diabetes Association (ADA) 2016 in New Orleans. This 4th landmark event, when the finding shown in Figure 1 was greeted with loud applause, was the presentation of the results of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER®) study, which evaluated the effect of the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide on cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk.6,7 Once again though, as the results unfolded, we realised that we were to be left with as many questions as answers.
Our previous editorial concluded that the accumulated evidence from multiple studies suggests that pioglitazone (PROactive) probably exerts its beneficial effects by slowing down – or even reversing – the atherosclerotic process.1 Empagliflozin (EMPA-REG OUTCOME™), which reduced cardiovascular death but not myocardial infarction or stroke, seemed to have an entirely different mechanism, more haemodynamic in nature and involving the combined effects of a decrease in blood pressure (after load reduction) and volume depletion (preload reduction).1,8 Other hypotheses have now been proposed, including the possibility that empagliflozin, by increasing circulating ketone bodies, provides the failing myocardium with a more efficient fuel source.9 Further evidence for pioglitazone as an agent of cardiovascular protection has also emerged from a study in an insulin resistant (but non-diabetic) population with recent prior ischaemic stroke or transient ischaemic attack; in this study the risk of recurrent stroke plus myocardial infarction was reduced by 24% in patients who received pioglitazone versus those who received placebo.10 These mechanisms of cardiovascular benefit are potentially complementary. Accordingly, we proposed that combination therapy with pioglitazone and empagliflozin might provide additive, or even multiplicative, cardiovascular benefits in people with diabetes at high cardiovascular risk compared with either given alone.1
Figure 2 shows side-by-side the effects of empagliflozin in EMPA-REG OUTCOME™ and liraglutide in LEADER® on three-point major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction and stroke).4-7 In Figure 3 the individual components of the three-point MACE endpoint, in addition to the primary composite outcome, are shown side-by-side for the two studies.4,6 The improvement in three-point MACE in EMPA-REG OUTCOME™ was clearly driven by the reduction in cardiovascular death. This is less striking for LEADER®, although it is noticeable that the greatest benefit is once again on cardiovascular death. Moreover, empagliflozin markedly reduced the risk of hospitalisation for heart failure in EMPA-REG OUTCOME™, while liraglutide did not in LEADER® (Figure 4).4-7 As only empagliflozin reduced heart failure but both empagliflozin and liraglutide reduced cardiovascular death, it is possible that liraglutide acted, at least in part, by different mechanisms to those of pioglitazone and empagliflozin. An extensive list has been put forward as to what these different mechanisms might be,8,9,11 and hopefully future research will narrow this down. In the meantime, we have the intriguing possibility that pioglitazone, empagliflozin and liraglutide might work synergistically to improve cardiovascular outcomes by different mechanisms in patients with type 2 diabetes at high cardiovascular risk.
The Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide (ELIXA) study did not show cardiovascular benefit for the GLP-1RA lixisenatide.12 However, the ELIXA patients were a less broad-based high cardiovascular risk group than the LEADER® patients as they had all had an acute coronary event in the last 180 days and the trial was of shorter duration. Further, lixisenatide is short-acting (4–6 hours) and patients are thus not covered by the drug for the majority of the day. At present it is unclear whether other longer acting GLP-1RAs will demonstrate a similar cardiovascular benefit to that observed in LEADER®. However, the preliminary dissemination of the top-line results for Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) indicate that treatment with once-weekly semaglutide for 2 years was associated with a statistically significant reduction in cardiovascular risk.13
When considering the combination of pioglitazone and empagliflozin, we proposed the possibility that sodium-glucose cotransporter-2 (SGLT2) inhibitors might mitigate the fluid retention associated with pioglitazone,1 and clinical evidence for such an effect of SGLT2 inhibitors has recently emerged.14 When considering the combination of pioglitazone and liraglutide, the weight gain associated with pioglitazone might be mitigated by the weight loss associated with liraglutide, as well as with an SGLT2 inhibitor. Indeed, the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study showed that a combination of metformin, pioglitazone and exenatide resulted in overall weight loss.15 As exenatide and liraglutide have similar weight-reducing effects in people with type 2 diabetes,16 it is likely that the same would apply to liraglutide in such a combination. Meanwhile, evidence is accumulating to support the early use of a triple-therapy combination of metformin, pioglitazone and a GLP-1RA as optimal initial antidiabetic therapy.15 This approach achieved lower HbA1c, weight loss and much less hypoglycaemia compared with the traditional approach of sequential escalation through metformin, sulphonylurea and insulin; the traditional approach also led to weight gain.15 In the wake of EMPA-REG OUTCOME™ and LEADER®, a combination of metformin, pioglitazone, empagliflozin and liraglutide now appears to be the optimum cocktail of medications for improving both glycaemic control and cardiovascular outcomes for people with type 2 diabetes at high cardiovascular risk. The evidence we have today suggests that the agents in this combination could complement each other to prevent cardiovascular events and save lives.
Conflict of interest REJR has received speaker fees, consultancy fees and/or educational sponsorships from AstraZeneca, Janssen, Merck, Novo Nordisk and Takeda.
RAD: Advisory Board: AstraZeneca, Novo Nordisk, Janssen, Lexicon, Boehringer-Ingelheim; Research Support: Bristol-Myers Squibb, Boehringer-Ingelheim, Takeda, AstraZeneca; Speaker's Bureau: Novo Nordisk, AstraZeneca
1. Ryder REJ, DeFronzo RA. Diabetes medications with cardiovascular protection in the wake of EMPA-REG OUTCOME™: the optimal combination may be metformin, pioglitazone and empagliflozin. Br J Diabetes Vasc Dis 2015;15:151–4. http://dx.doi.org/10.15277/bjdvd.2015.045
2. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–65. http://dx.doi.org/10.1016/S0140-6736(98)07037-8
3. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–89. http://dx.doi.org/10.1016/S0140-6736(05)67528-9
4. EASD Virtual Meeting. Webcast: Results of the EMPA-REG OUTCOME™ study. http://www.easdvirtualmeeting.org/contentsessions/2030 (accessed 7 July 2016)
5. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. http://dx.doi.org/10.1056/NEJMoa1504720
6. ADA 76th Scientific Sessions Webcasts. Results of the Liraglutide Effect and Action in Diabetes-Evaluation of Cardiovascular Outcome Results (LEADER®) trial. http://professional.diabetes.org/search/site?f[0]=im_ field_dbp_ct%3A7&f[1]=sm_field_wcast_mname%3Anode%3A120&f[2]=sm_field_wcast_sname%3Anode%3A144635&retain-filters=1 (accessed 8 July 2016)
7. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22. http://dx.doi.org/10.1056/NEJMoa1603827
8. Abdul-Ghani MA, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study. Diabetes Care 2016;39:717–25. http://www.ncbi.nlm.nih.gov/pubmed/27208375. http://dx.doi.org/10.2337/dc16-0041
9. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care 2016;39:1108–14. http://www.ncbi.nlm.nih.gov/pubmed/27289126. http://dx.doi.org/10.2337/dc16-0330
10. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321–31. http://dx.doi.org/10.1056/NEJMoa1506930
11. Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab 2016;24:15–30. http://dx.doi.org/10.1016/j.cmet.2016.06.009
12. Pfeffer, MA, Claggett, B, Diaz, R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247–57. http://dx.doi.org/10.1056/NEJMoa1509225
13. Novo Nordisk A/S (DK). Company Announcement, Bagsværd, Denmark, 28 April 2016. Semaglutide significantly reduces the risk of major adverse cardiovascular events in the SUSTAIN 6 trial. https://www.novonordisk.com/bin/getPDF.2007805.pdf (accessed 9 July 2016)
14. Gautam A, Agrawal PK, Prakash P, Hazra DK. Pioglitazone associated pedal edema resolved by adding sodium glucose co-transporter 2 inhibitor. ADA 76th Scientific Sessions 2016. Late Breaking Poster Session, Poster 140-LB. Abstract available at http://www.abstractsonline.com/pp8/#!/4008/presentation/44543 (accessed 9 July 2016)
15. Abdul-Ghani MA, Puckett C, Triplitt C, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab 2015;17:268–75. http://dx.doi.org/10.1111/dom.12417
16. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;374:39–47. http://dx.doi.org/10.1016/S0140-6736(09)60659-0