Journal of Diabetes and Its Complications xxx (2014) xxx–xxx

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Editorial

Lessons from SAVOR and EXAMINE: Some important answers, but many open questions☆,☆☆ Type 2 diabetes is a progressive complex metabolic disease associated with both microvascular and macrovascular complications. The risk of cardiovascular (CV) disease is around two times as high in people with diabetes as in people without diabetes (Emerging Risk Factors Collaboration et al., 2010). Improved glycemic control can reduce the risk of many microvascular complications of diabetes such as diabetic nephropathy, retinopathy and neuropathy (UKPDS, 1998), but three recent studies have not individually shown a favorable effect of intensive glycemic control in reducing macrovascular events in patients with type 2 diabetes (Action to Control Cardiovascular Risk in Diabetes Study Group, 2008; ADVANCE Collaborative Group, 2008; Duckworth et al., 2009) During the last 25 years all-cause mortality, CV death and CV events were reduced in patients with type 2 diabetes by more than 50% (Gregg et al., 2012; Lind et al., 2013; Preis et al., 2009), mainly by the wide use of lipid lowering and blood pressure lowering drugs. In the secondary prevention of CV events antiplatelet drugs are effective and therefore also standard therapy in diabetic patients presenting with CVD (Grove & Gregersen, 2012). Based on the proven effect of HbA1c lowering on microvascular complications but some uncertainty over CV benefits, most clinical development programs for novel antidiabetes drugs have focused mainly on glucose lowering. Most patients recruited for regulatory approval have had limited duration of diabetes and few complications. Although these types of confirmatory studies established the glucose-lowering properties of novel drugs, CV safety assessment in the context of the clinical development of glucose-lowering agents has been largely neglected until recently. Concerns regarding adverse cardiovascular outcomes with antidiabetic agents, in particular for rosiglitazone, prompted the Food and Drug Administration (FDA) to issue guidance in December 2008 that included specific requirements for cardiovascular safety assessment before and after the approval of new antidiabetic therapies (http://www. fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ UCM334550.pdf). Specifically, sponsors were informed that they must rule out an upper 95% CI of the hazard ratio (HR) for cardiovasuclar events of 1.8 for their medication before approval and 1.3 after approval. As a consequence more than 180,000 patients with type 2 diabetes will be included in about 18 CV outcome studies with new antidiabetic drugs (GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2Inhibitors, Acarbose). In addition to previously published studies with

☆ Declarations of interest: Guntram Schernthaner has consulted for: Amgen, Astrazeneca, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, MSD. ☆☆ Naveed Sattar has consulted for: Astrazeneca, BMS, Sanofi, Amgen, Boehringer Ingelheim. http://dx.doi.org/10.1016/j.jdiacomp.2014.02.011 1056-8727/© 2014 Elsevier Inc. All rights reserved.

pioglitazone (PROactive; Dormandy et al., 2005), rosiglitazone (RECORD; Home et al., 2009) and basal insulin glargine (ORIGIN Trial Investigators et al., 2012), we have now also evidence from two recently published DPP-4 inhibitor studies, which investigated saxagliptin (SAVOR; Scirica et al., 2013) and alogliptin (EXAMINE, White et al., 2013). Patients randomized to active therapy or placebo in the SAVOR and EXAMINE studies differed in many aspects. Whereas SAVOR recruited two types of patients, one with establised CVD and other with multiple risk factors (MRF), all patients in EXAMINE had an history of acute coronary syndrome (Table 1). Thus, prior stroke and PAD was considerably lower in EXAMINE, whereas heart failure at baseline was documented in 28% of patients included in EXAMINE, but in only 14.8% and 5.1% respectively in the two groups of patients recruited into SAVOR. About two thirds of all patients received metformin at baseline and sulfonylureas were used by 37–46% of participants (Table 2). Insulin was more often used in SAVOR patients with established CVD (42.2%) compared with patients included in EXAMINE (30%), which is likely in part explained by the fact that median duration of diabetes was longer in SAVOR vs. EXAMINE (10.3 vs. 7.3 years). Treatment for reducing CV risk factors was extremely good in both studies; statins and ACE/ARB were used in 80 to 90% and antiplatelet in almost all patients (89–97%), however ß-blocking agents were less used in SAVOR vs. EXAMINE (68 vs. 82%). As expected the 25% of patients in SAVOR presenting only with MRF received less cardioprotecive therapy (Table 2). A recently published metanalysis of DPP-4 inhibitors and CV risk showed rather promising results (Monami, Ahrén, Dicembrini, & Mannucci, 2013). The MH–OR (95% CI) for DPP-4 inhibitors versus comparators (placebo or active control) was 0.71 [0.59;0.86], 0.64 [0.44;0.94], 0.77 [0.48;1.24] and 0.60 [0.41;0.88] for MACE, myocardial infarction, stroke and mortality, respectively. More specific, the MH-OR for MACE with saxagliptin was 0.67 [0.45;0.99] based on 15 studies and 0.86 [0.25;2.93] for alogliptin based on only 5 studies. However, the mean observation period of the 63 trials was only 44 weeks, and the CV event rate was extremely low in both the DPP-4 inhibitor arms (263 events in 23 451 patients years; 0.73%) and comparator arms (232 events in 16 962 patient years; 0.89%). Taking into account the rather small difference in the event rate of only 0.16% and the fact that these studies were not controlled for the use of cardioprotective drugs, the value of such information is potentially limited and could even be misleading, hence the need for robustly adjudicated randomised placebo-controlled clinical trials. The SAVOR study was originally designed as a superiority study testing the hypothesis that treatment with saxagliptin is safe and reduces CV events in high-risk patients with T2DM (Scirica et al., 2013), whereas the primary objective of EXAMINE (White et al., 2013) was to

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Editorial / Journal of Diabetes and Its Complications xxx (2014) xxx–xxx

Table 1 Cardiovascular history at baseline (%). SAVOR

Number MI ACS Stroke PAD CHF

EXAMINE

Established CVD

MRF

Acute coronary syndrome

12.927 47.9 0 16.0 14.9 14.8

3.573 1.3 0 0.8 1.1 5.1

5.380 77.0⁎ 23.0 7.2 9.5 28.0

MRF: multiple risk factors; MI: myocardial infarction; *acute myocardial infarction. PAD: peripherial arterial disease; CHF: congestive heart failure. Scirica BM, et al. N Engl J Med. 2013; 369: 1317-1326, White WB et al. N Engl J Med. 2013; 369:1327-1335.

demonstrate the noninferiority of MACE on alogliptin versus placebo in the treatment of type 2 diabetes in a high-risk CV patient group. The primary endpoint - composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was not different between the DPP-4 inhibitor and the placebo arms in both SAVOR and EXAMINE (Table 3) irrespective of the small difference in the median exposure time (25 versus 18 months). These findings demonstrate that saxagliptin and alogliptin are safe concerning CVD, but cannot further reduce the risk of the primary endpoint when added to other antidiabetic and cardioprotective drugs in type 2 diabetic patients with a high CV risk. Are these data surprising? Not at all. The HbA1c lowering potency of saxagliptin and alogliptin at study end versus baseline or the control groups was rather modest in both studies (0.30 and 0.36%), although one must accept that neither study was designed as a glycaemia-differential trial. In addition the reported pleiotropic CV effects of DPP-4 inhibitors on lipid or blood pressure lowering are quite modest (Scheen, 2013). It appears from this work that reducing glucose by a small or even modest amount is highly unlikely to lead to CV risk reduction, at least in the short period over which trials are conducted. One might also conclude that in order to meaningfully reduce CV events in patients with diabetes, cholesterol and BP reduction together with smoking cessation are of paramount importance. In this way, the results of the SAVOR and EXAMINE reinforce the need to re-challenge the glycamia paradigm in diabetes, as has been recently done (Sattar, 2013). Neutral data for the clinically important endpoint of death, nonfatal myocardial infarction and stroke (Table 4) were not only seen for saxagliptin and alogliptin, but previously also for basal insulin (ORIGIN) and for canagliflozin in the preliminary analysis of the CANVAS trial (Janssen Research & Development LLC, 2012; Neal et al., 2013).). In PROactive (Dormandy et al., 2005) the use of pioglitazone was associated with a significant reduction of the triple endpoint, but the primary endpoint including peripheral and coronary revascularisation was not significantly reduced. In contrast to the newer studies

Table 2 Antidiabetic and cardiovascular medication at baseline (%). SAVOR

Number Metformin Sulfonylureas Insulin Statins ACE/ARB β-blockers Antiplatelet therapy

EXAMINE

Established CVD

MRF

Acute coronary syndrome

12.927 65.5 37.4 42.2 82.7 78.8 68.3 88.7

3.573 74.4 42.3 30.7 62.2 77.4 36.4 54.4

5.380 66.0 46.0 30.0 90.5 81.5 82.0 97.2

MRF: multiple risk factors. Scirica BM, et al. N Engl J Med. 2013; 369: 1317-1326, White WB et al. N Engl J Med. 2013; 369:1327-1335.

Table 3 Effect of saxagliptin or alogliptin versus placebo on the primary endpoint (composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) in SAVOR and EXAMINE. Saxagliptin (n = 8280)

Placebo (n = 8212)

Hazard ratio (95% Cl)

p Value

no (%) 613 (7.3)

609 (7.2)

1.00 (0.89–1.12)

0.99

Alogliptin (n = 2679)

Placebo (n = 2701)

Hazard ratio (95% Cl)

p Value

no (%) 316 (11.8)

305 (11.3)

0.96 (≤1.16)

0.32

statins were far less used in PROactive which might explain why pioglitazone was able to show some antiatherogenic effects in that trial. The HbA1c lowering observed with saxagliptin in SAVOR was associated with a small increase in hypoglycemic events, which was related to the combination with sulfonylureas as reported at the EASD 2103. An increased risk of hypoglycemia associated with the use of saxagliptin was only seen in those patients presenting with HbA1c at baseline b 7.0% (HR 1.40; 95% CI 1.17, 1.69; p b 0.001), but not in patients presenting with HbA1c N 7.0% at baseline (as reported at the AHA). Perhaps the most notable findings was the observation of more patients in the saxagliptin group than in the placebo group being hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; p = 0.007). As expected the risk for heart failure hospitalisation (HF) was closely related to NT-proBNP levels at baseline in both the saxagliptin and control arms. In patients with the highest quartile of NT-proBNP levels at baseline (333–46,627) the risk for HF hospitalisation was10.9% in the saxagliptin group and 8.9% in the placebo arm (HR 1.31 95%CI 1.0–1.6; p = 0.021). The risk for HF hospitalisation associated with the use of saxagliptin was highest in the first 6 months (HR 1.80; 1.29–2.54; p b 0.001) and declined thereafter, HR 1.48 after 1 year and 1.28 after 2 years (Scirica et al. (2013). As expected prior HF was the strongest predictor of HF hospitalisation during the study (HR 4.17; 3.48–4.99; p b 0.001), followed by impaired kidney function (eGFR b 50 ml/min) (HR 2.39; 1.98–2.88; p b 0.001) and increased (N30 mg/g) albumin/creatinine ratio (HR 2.18; 1.81–2.63; p b 0.001). Other variables such as high age (N75 years) or previous myocardial infarction were less predictive (Scirica et al. (2013)). The overall risk of hospitalization for HF in the SAVOR study was ~ 2% annually, 289 cases of HF hospitalisation were observed in the saxagliptin arm and 228 in the placebo arm. A similar trend was also observed in EXAMINE, 106 patients in the alogliptin arm and 89 patients in the placebo arm were hospitalised for HF. Fig. 1 shows the metaanalyis combining data from both studies and indicates an increased risk of HF hospitalisation with the use of DPP-4 inhibitors, 395 cases of HF with DPP-4 inhibitors versus 317 with placebo (HR 1.24 (1.07–1.44). It may be somewhat surprising that the increase in HF hospitalisation risk associated with alogliptin was apparently less clear cut despite prior HF being almost doubled in EXAMINE versus SAVOR. The higher use of ß-blocking agents and the more frequent medical controls with treatment adapations in EXAMINE might be one of the potential explanations, amongst other explanations.

Table 4 Effect of glucose lowering drugs on the combined endpoint of CV mortality, nonfatal myocardial infarction and stroke.

• PROactive • ORIGIN • SAVOR • EXAMINE • CANVAS

Antidiabetic drug

HR

Pioglitazone Insulin Glargine Saxagliptin Alogliptin Canagliflozin

0.84 1.02 1.00 0.96 1.00

p value (Cl 0.72–0.98) (Cl 0.94–1.11) (Cl 0.89–1.12) (Cl 0.80–1.15) (CI 0.72, 1.39)

0.02 NS NS NS NS

Editorial / Journal of Diabetes and Its Complications xxx (2014) xxx–xxx

Study of Subgroup

Gliptin Events Total

Placebo Events Total Weight

Odds Ratio

Odds Ratio M-H, Random, 95% CI

EXAMINE

106

2701

89

2679 27.4 %

1.19 [0.89, 1.58]

SAVOR-TIMI

289

8280

228

8212 72.6 %

1.27 [1.06, 1.51]

10891 100.0 %

1.24 [1.07, 1.45]

10981

Total (95% CI)

Total events

395

3

M-H, Random, 95% CI

317 0.5

0.7

Favours Gliptin

1

1.5

2

Favours Placebo

Fig. 1. Metaanalysis of heart failure events observed in SAVOR and EXAMINE.

Of course, whether there could be a class effect of DPP-4 inhibitors on risk for HF or HF hospitalisation, is an obvious next question. In the VIVIDD (Vildagliptin in Ventricular Dysfunction Diabetes) trial 254 patients with type 2 diabetes mellitus (mean age 63 years; HbA1c 6.5 to 10%), and NYHA class I (9.8%), II (52.8%) and III (37.4%) were randomized to either vildagliptin 50 mg bid (n = 128) or placebo (n = 126). After 52 weeks the mean increase in the ejection fraction was 4.1 in the vildagliptin versus 3.5 in the placebo group (P = NS), and BNP had fallen by 14%, relative to baseline, in the placebo group versus 28% in the vildagliptin group (McMurray, 2013). Surprisingly, patients taking vildagliptin, in comparison to those taking placebo showed unexpected increases in left ventricular end-diastolic volume (LVEDV, p = 0.007), end systolic volume (LVESV, p = 0.06) and stroke volume (p = 0.002). By 52 weeks worsening of HF occurred in 22 patients in the placebo group versus 23 in the vildagliptin group; and death from any cause occurred in four patients in the placebo group versus 11 in the vildagliptin group. Larger and longer studies are needed to exclude a negative effect of DPP-4 inhibitors on heart function, since increases in LVEDV and LVESV would usually be considered unfavourable effects in context of unchanged LVEF. If there is a genuine adverse effect of DPP-4 on HF (whether new development or, as it appears most likely currently, worsening in those with existing HF), the mechanisms are unknown. Very recently, a large number of biologically active proteins with putative truncation sites for DPP4 has been identified, presenting many unanswered questions regarding how this ubiquitous enzyme may modulate many different hematopoietic and other cell functions through its effects on different cytokines, chemokines, and other proteins (Ou, O'Leary, & Broxmeyer, 2013). Irrespective of mechanisms, the observations have led the FDA to review relevant data [http://www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm385471.htm]. There is an ongoing debate, whether the risk for acute pancreatitis or pancreatic cancer is increased in diabetic patients exposed to incretin-based therapies (Butler, Elashoff, Elashoff, & Gale, 2013; Nauck, 2013). In the SAVOR study the number of patients with acute or chronic pancreatitis was similar in the two groups (24 patients [0.3%] in the saxagliptin group and 21 patients [0.3%] in the placebo group, p = 0.77). However, definite acute pancreatitis occured in 17 patients (0.2%) in the patients receiving saxagliptin and in only 9 patients (0.1%) in the placebo group (p = 0.17). In EXAMINE the number of patients with acute or chronic pancreatitis was 17 in the alogliptin and 12 in the placebo arm; an acute pancreatis occured in 12 patients receiving alogliptin and in 8 patients on placebo. Taking both studies together 29 patients exposed to DPP-4 inhibitors and 17 patients receiving placebo had an acute pancreatitis. In the SAVOR

study 5 cases of pancreatic cancer were observed in the saxagliptin group and 12 cases in the placebo group (p = 0.095), whereas in EXAMINE there were no reports on pancreatic cancer. The data of the DPP-4 inhibitor outcome studies concerning the risk of severe pancreatic events are somewhat reassuring, but cannot be conclusive. The incidence of acute pancreatitis in nondiabetic subjects is about 30 (range 16–40) per 100,000 patients years (Yadav & Lowenfels, 2013), and there is general agreement that the risk is about two-fold higher in diabetic patients (Yang, He, Tang, & Liu, 2013). Thus, the annual risk of diabetic patients for acute pancreatis is only about 6 in 10,000 per year. The annual incidence of pancreatic cancer is even lower and about only 5.5 to 6.7 per 100,000 subjects as reported from two large epidemiological studies performed in the US (Lau, Davila, & Shaib, 2010)) and Shanghai (Luo, Xiao, Wu, Zheng, & Zhao, 2013). Although the incidence of pancreatic cancer in diabetic patients is almost doubled (Huxley, Ansary-Moghaddam, Berrington de Gonzalez, Barzi, & Woodward, 2005) the relatively low number of patients exposed to incretin-based therapies and the short obervation period of about two years in the available RCTs cannot prove or exluded whether long-term therapy with GLP-1 based therapies may have some negative impact on the risk of acute pancreatitis and/or pancreatic carcinoma. In summary, SAVOR and EXAMINE data are extemely valuable from many standpoints, not least because large trials get us closer to the truth. The results provide moderate reassurance on several aspects related to DPP-4 inhibitors. However, they also suggested a potential unexpected side effect of DPP-4 inhibition on risk for heart failure hospitalisation, findings which, whilst not definitive at the moment, have to be taken seriously.

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Guntram Schernthaner Department of Medicine I, Rudolfstiftung Hospital, Vienna, Austria E-mail address: [email protected] Naveed Sattar Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University Of Glasgow Available online xxxx