- Heart failure
Summary of key points
New drugs for the treatment of type 2 diabetes have contributed new knowledge for clinical treatment when cardiac aspects are considered.
Metformin is still a first-line choice when lifestyle treatment fails, but updated meta-analyses have not shown superiority of metformin compared to other anti-diabetes drugs for cardiovascular outcomes.
DPP-4 inhibitors are generally regarded as clinically safe as compared to placebo, and a previous suspicion of increased heart failure risk (SAVOR-TIMI 55) was not confirmed in later studies (EXAMINE, TECOS).
GLP-1 analogue/agonist therapy is also regarded as clinically safe as compared to placebo (ELIXA), and even able to prevent cardiovascular disease (LEADER).
Treatment with an SGLT2 inhibitor versus placebo reduced the primary cardiovascular composite endpoint, an effect largely driven by a reduction of heart failure risk (EMPA-REG Outcome Study).
The treatment of type 2 diabetes (DM2) rests on the principles of initial lifestyle intervention followed by the (early) addition of metformin. Later on, if hyperglycaemia persists, there is a choice of using other oral anti-diabetic drugs (OAD) such as sulphonylureas (SU), DPP-4 inhibitors, or injection drugs such as GLP-1 analogues/agonists or even insulin therapy, and occasionally other OADs such as glitazones, glinides or acarbose, all according to international guidelines. In a recent statement from the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) an algorithm was presented and developed giving the order of introduction of these OADs and insulin . These recommendations are expected to undergo changes based on the results of new drug intervention studies contributing to the evidence base. As cardiovascular disease (CVD) represents a major health threat to patients with diabetes, modern guidelines emphasize a strategy for prevention, addressing all major cardiovascular risk factors, including hypertension, hyperlipidaemia, smoking, hyperglycaemia, and obesity .
During 2015 we saw the publication of a few very important drug intervention studies with results of great importance for the treatment of DM2 patients. These were the randomized treatment studies TECOS  and EMPA-REG  and, in addition, there was another new study with an injectable GLP-1 agonist, ELIXA . In 2016 we also had new data from another study with a GLP-1 analogue, LEADER . The study results from these trials will be of great importance for clinicians treating DM2 patients, not only because of the proven and now well-documented safety aspects, but also for the new available evidence for the prevention of CVD, the most important category of diabetes (macrovascular) complication.
These four new studies provide data from interventions with new anti-diabetes drugs [3-6]. Most likely, these study results will sooner or later find their way into national as well as international guidelines for the treatment of DM2 patients. We want to relate the main results from these important trials and also try to evaluate the data and implications, in our opinion, for clinical practice. One aspect of this is to discuss the potential mechanisms behind the favourable effects documented with an SGLT2 antagonist (empagliflozin) in the EMPA-REG Outcome trial . In addition, we would like briefly to summarize the evidence from older trials and meta-analyses concerning metformin, SU, and insulin treatment.
The topic of intensity of glycaemic control in general is also of importance. In fact, given the clear associations between hyperglycaemia and incremental CVD risk deriving from analyses of observational data, the prevalent thinking for decades was that lowering blood glucose in patients with DM2 would result in a reduction in CVD risk and events. However, with few exceptions, this has not been borne out in the majority of the more recent randomized controlled trials completed to date. The differences between the UKPDS and DCCT/EDIC studies compared with the three more recent studies (ACCORD, ADVANCE, and VADT) could at least partially be attributed to the very different study populations enrolled. UKPDS and DCCT/EDIC enrolled patients with newly diagnosed diabetes, while ACCORD, ADVANCE, and VADT enrolled high-risk patients with pre-existing CVD, longer disease duration, and of a more advanced age. It is plausible that early intervention with intensive glycaemic control has a primary prevention role, but it is now clearly established that glycaemic intensification late in the course of the disease is not beneficial in general with traditional anti-diabetes drugs and could potentially be harmful, as in ACCORD.
Cardiovascular effects of established anti-diabetes drugs
In the UKPDS it was shown that SU and insulin had equal effects on cardiovascular events, but that metformin was more beneficial in a subgroup of overweight/obese subjects . Later on, however, a meta-analysis could not show substantial differences between metformin and other OAD for cardiovascular prevention . This was recently updated with a similar conclusion based on an extensive literature search . A corresponding review on cardiovascular effects of SU has also been published . The results from this review even suggested that SU use may elevate the risk of cardiovascular disease among patients with diabetes . This finding warrants consideration in clinical practice when other treatment options may be available.
On the other hand, some evidence from a recent systematic review  suggests that, compared with metformin, second- and third-generation SU may not affect all-cause or cardiovascular mortality but may decrease the risk of non-fatal macrovascular outcomes among patients with DM2. SU may also increase the risk of hypoglycaemia. The authors of the review concluded that too few studies were available to contribute solid evidence for the comparison .
Glitazones are not very much in use currently but were shown to be equal to placebo in terms of effect for secondary CVD prevention in the PROactive Study by use of pioglitazone , or equal to other OADs such as rosiglitazone in the RECORD Study .
A traditional approach for the treatment of DM2 in poor glycaemic control is to start insulin treatment, often after OAD treatment failure. Questions have been raised about the cardiovascular side effects of insulin therapy. There is some evidence, although controversial, that attainment of good glycaemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of a recent review  was to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin and basal insulin analogues (glargine, detemir, and the more recent degludec) differ essentially by various measures of pharmacokinetic and pharmacodynamic effects, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogues have a lower risk of hypoglycaemia than NPH human insulin, in both type 1 and type 2 diabetes, subsequently excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogues. However, the number of available cardiovascular events in these trials has been very small, preventing any clear-cut conclusion .
The role of incretin drugs
In the drug treatment arsenal for DM2, the incretin active drugs have rapidly developed over the last few years for clinical use, including DPP-4 inhibitors and the GLP-1 agonists, as manifested in international treatment guidelines . These drugs have been shown to reduce hyperglycaemia and to a varying degree also other cardiovascular risk factors, such as lipids and body weight. It has, however, been harder to show benefits for cardiovascular protection: so far, three large randomized studies with oral DPP-4 inhibitors have been able to show safety in general, with one exception, but no reduction of cardiovascular endpoints in comparison with placebo. These studies are the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) , EXAMINE (Study of Alogliptin in Subjects with Type 2 Diabetes and Acute Coronary Syndrome) , and TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) . Still, only two large-scale intervention studies with a GLP-1 analogue/agonist has been published, the ELIXA (Evaluation of LIXisenatide in Acute Coronary Syndrome) study, showing safety but no added cardiovascular benefits with the GLP-1 agonist lixisenatide versus placebo  and, the most recent, the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) study . The findings from these two studies support the results from a meta-analysis of data from 36 randomized controlled trials (duration ≥12 weeks) showing that GLP-1 receptor agonists did not portend any increased risk in major adverse cardiovascular events (MACE) compared with both active control and placebo combined .
The risk of congestive heart failure in DPP-4 inhibition trials
For the DPP-4 inhibitors, especially the increased risk of congestive heart failure seen in one of the trials (SAVOR-TIMI 53)  but not in the two others published so far, EXAMINE , and TECOS , as well as vascular function, hypertension and hemodynamic control, could be a contributing factor of importance. Specific data on blood pressure changes are presently lacking from these clinical endpoint trials, but it has been suggested that a small blood pressure lowering effect is associated with DPP-4 inhibitor treatment .
The first drug, saxagliptin, was tested in the SAVOR-TIMI 53 trial , a randomized, double-blind, placebo-controlled trial designed to evaluate the CV outcomes of saxagliptin during long-term treatment of patients with DM2 and high cardiovascular risk. Eligible patients were either treatment naive or on any background anti-diabetic treatment (except incretin therapy) with a history of established CV disease or multiple risk factors randomized to saxagliptin 5 mg QD (2.5 mg in subjects with moderate/severe renal impairment) or matching placebo, stratified by qualifying disease state. The primary endpoint was the composite of CV death, non-fatal myocardial infarction, or non-fatal ischemic stroke. A total of 16,496 diabetic patients either with established CV disease (78.3%) or with ≥two additional CV risk factors (21.7%) were randomized to saxagliptin or placebo. Results showed that a primary endpoint event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, p=0.99 for superiority; p<0.001 for non-inferiority). The major secondary endpoint of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1,059 patients in the saxagliptin group and in 1,034 patients in the placebo group (12.8% and 12.4%, p=0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio [HR] 1.27; 95% CI: 1.07 to 1.51; p=0.007). In a subgroup analysis, the SAVOR-TIMI 53 investigators noted that several factors were strongly associated with hospitalization for congestive heart failure in the first 12 months of therapy, but not thereafter, regardless of treatment, i.e., prior heart failure, elevated N-terminal pro-B-type natriuretic peptide, and an estimated glomerular filtration rate ≤60 mL/min/1.73 m2 . Otherwise, the safety profile was equal between the randomized groups.
The second drug, alogliptin, was tested in a randomized, placebo-controlled clinical study (EXAMINE) in DM2 patients with acute coronary syndrome (ACS) within 15 to 90 days prior to randomization . The primary CV endpoint for this trial was a composite of CV death, non-fatal myocardial infarction, and non-fatal stroke. In total, 5,400 men and women with DM2 on standard anti-diabetic treatment and ACS (acute myocardial infarction or unstable angina) were recruited and followed up for up to 4.5 years. The dosage of alogliptin used was adjusted to the estimated glomerular filtration rate (eGFR) (25 mg once daily for normal or mildly impaired eGFR, 12.5 mg once daily for moderately impaired eGFR, and 6.25 mg once daily for severely impaired eGFR). The results from EXAMINE showed that in 5,380 patients who were followed for up to 40 months (median, 18 months) a primary endpoint event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (p<0.001 for non-inferiority). Incidences of hypoglycemia, cancer, pancreatitis, heart failure and initiation of dialysis were similar with alogliptin and placebo. A recently published post hoc analysis confirmed no increased risk of hospital admission for heart failure with alogliptin 3.1% vs. 2.9%; HR 1.07 (95% CI: 0.79 to 1.46; p=0.66).
The third drug, sitagliptin, was used when 14,671 patients with pre-existing CV disease were randomized to either sitagliptin or placebo in addition to their existing therapy in the TECOS trial . The primary cardiovascular outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina. Results showed that, after a median follow-up of 3.0 years, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was non-inferior to placebo for the primary composite cardiovascular outcome (p<0.001). Rates of hospitalization for heart failure did not differ between the two groups (p=0.98) and safety in general showed no difference between groups.
Finally, the Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial, presented but not yet reported, is an important small mechanistic trial as all patients in this study had evidence of symptomatic heart failure with a left ventricular ejection fraction (LVEF) of less than 35%. Worsening heart failure was an adjudicated endpoint in VIVIDD, showing no difference in event rates between 128 patients treated with vildagliptin, a DPP-4 inhibitor, and 125 patients treated with placebo, occurring in 18.0% of the vildagliptin group and 17.6% of the placebo group. The primary endpoint of the VIVIDD study, a change in LVEF from baseline to 52 weeks, showed no differences between groups. Plasma brain natriuretic peptide concentrations were reduced in both groups over the study period, but more so in the vildagliptin group (ratio of 0.72 vs. baseline) versus placebo (0.86 vs. baseline). Somewhat surprisingly, LV diastolic and systolic volumes were both increased with vildagliptin compared with placebo, despite the absence of change in LVEF and the greater decrease in brain natriuretic peptide concentrations with vildagliptin. No data on blood pressure changes are known.
A general view on effects and safety of the DPP-4 inhibitors
It would be unfortunate to reject the clinical significance of these non-significant findings for the primary composite CV endpoint without a critical appraisal of several aspects. First, the results should be interpreted against the background of extensive use of concomitant drug treatment, currently provided to most patients with DM2 based on guidelines. These preventive drugs include lipid-lowering (mostly statins), angiotensin-converting enzyme (ACE) inhibition and antiplatelet therapy. Particularly relevant can be the concomitant use of diuretics and calcium channel blockers, because, as recently demonstrated, their use is associated with lower and higher risk of heart failure, respectively, in patients with DM2. This means that any new add-on drug has to provide extensive CV benefits to override the effects of the concomitant medication - a challenge for the new drugs which is not always possible to overcome. Second, the design of the composite endpoints is also of great importance. If the inclusion of a variety of endpoints is used, and the study terminates when a certain number of endpoints have been accrued, sometimes the results will be neutral if some endpoints are “softer”, as was discussed after publication of the PROactive trial comparing pioglitazone vs. placebo for secondary prevention in patients with DM2 . Third, the populations included in these studies consist of high-risk DM2 patients who had already presented CV events to a large extent. Therefore, their results cannot be applicable to patients without overt CV disease who could benefit from the early CV prevention potentially afforded by incretin-based drugs. This aspect is important, bearing in mind that, besides their incretin effects and their effects on glucose control, incretin-based therapies (namely, DPP-4 inhibitors) can favourably influence some CV risk factors, which may contribute to slowing the atherogenic process in patients with DM2. Finally, although most available experimental evidence suggests that DPP-4 inhibitors can mediate some cardioprotection, the question is whether cardioprotection is really translated to clinical medicine, and who mainly receives these benefits among the patients with cardiovascular diseases and/or DM2 (i.e., personalized medicine).
A more worrying fact is that the receptor of the glucose-dependent insulinotropic polypeptide (GIPR), a receptor for one of the incretin hormones, has been associated with increased cardiovascular risk in experimental and genetic studies. While GIPR expression is predominantly endothelial in healthy arteries from human, mouse, rat and pig, remarkable up-regulation is observed in endothelial and smooth muscle cells upon culture conditions yielding a "vascular disease-like" phenotype. Moreover, a common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in DM2 patients . What these findings mean in a human setting has to be evaluated further in clinical studies.
In summary, the limited blood pressure reduction following treatment with a DPP-4 inhibitor is of interest but not different from that found by the use of other anti-hypertensive drugs and even less than found with an SGLT2 inhibitor . Still, there is a need for more extensive evaluations of diurnal blood pressure control by use of 24-hr ABPM as well as a deeper understanding of vascular effects in general following treatment with incretin active drugs. Genetic arguments even open up for critical analyses on the role of incretins and GIPR for influencing detrimental vascular effects , but this still has to be proven. Two out of three new intervention trials with a DPP-4 inhibitor versus placebo could not show any increased risk of congestive heart failure [3,16], but it was found in the third one, SAVOR-TIMI 53 . This consequence has to be further elucidated in other studies using DPP-4 inhibitors, for example the CAROLINA (Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes) trial (NCT01897532), or in trials involving GLP-1 agonists. Is it real or a chance finding in only one study so far? Could differences in diurnal blood pressure control via 24-hr ABPM show differences between the available DPP-4 inhibitors and, if so, could this impact on the risk of congestive heart failure?
The mechanisms underlying the potential increased risk of heart failure upon DPP-4 inhibitor use remain largely unclear. This result may be a chance, false positive resulting from multiple testing, a class effect, or differences between the enrolled populations. Because the risk of hospitalization for HF was highest in patients with the highest BNP quartile at baseline, these data raise the possibility that the heart failure proportion was underestimated in both studies. Another plausible explanation is that the increase in substance P, a DPP-4 substrate, could have stimulated sympathetic tone and heart rate during the combined ACE and DPP-4 inhibitor treatment . In addition, inactivated GLP-1(9-36) amide had the potential to exert cardioprotective action in an experimental model. Thus, some researchers have speculated that a reduction in the GLP-1(9-36) amide could enhance the negative effects on CV pathophysiology in the presence of DPP-4 inhibitor treatment.
The role of GLP-1 analogue treatment in the LEADER study
The presentation of the LEADER study at the American Diabetes Association (ADA) Meeting in June 2016 attracted considerable interest due to its impressive findings. In LEADER, the cardiovascular effect of liraglutide, a GLP-1 analogue versus placebo, was added to standard care in patients with DM2 . The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. In total, 9,340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (13.0%) than in the placebo group (14.9%), hazard ratio, HR 0.87 (95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (4.7%) than in the placebo group (6.0%), HR 0.78 (95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was also lower in the liraglutide group (8.2%) than in the placebo group (9.6%), HR 0.85 (95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure did not differ between the groups. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The authors concluded that the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. This shows the safety and effectiveness of this injectable drug in DM2 patients at high risk, many with a previous history of CVD.
The EMPA-REG Study and cardiac effects
The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2 promoting glucosuria, in addition to standard care, on cardiovascular morbidity and mortality in patients with DM2 at high cardiovascular risk were evaluated in the EMPA-REG Outcome Study . Patients were randomly assigned to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. A total of 7,020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4,687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2,333 patients (12.1%) in the placebo group (HR 0.86, 95% CI: 0.74 to 0.99; p=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7% vs. 5.9% in the placebo group; 38% relative risk reduction [RRR]), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% RRR), and death from any cause (5.7% and 8.3%, respectively; 32% RRR). There was no significant between-group difference in the key secondary outcome (p=0.08 for superiority). It was concluded that patients with DM2 at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.
Two more clinical trials with an SGLT2 inhibitor are currently ongoing, evaluating the CV safety and efficacy of dapagliflozin (DECLARE-TIMI 58 [NCT01730534]) and canagliflozin (CANVAS [NCT01032629]) in DM2 patients.
Potential mechanisms behind the cardiovascular protection of empagliflozin
As mentioned, earlier studies on the effects of drugs lowering blood glucose with the aim of reducing CVD morbidity and mortality have been disappointing. One potential explanation for this is that the CVD risk associated with diabetes is not causally related to high blood glucose but instead to some other factor which is increased in parallel to blood glucose.
In the light of this, it is notable that, in the EMPA-REG Outcome Study , the effects on HbA1c levels were only marginal (0.4-0.5 percent decrease). However, over the course of the study, empagliflozin, as compared with placebo, was associated with small reductions in weight, waist circumference, uric acid level, and systolic and diastolic blood pressure with no increase in heart rate and even small increases in both LDL and HDL cholesterol. What then could play a role for the beneficial effects? As the reduction of cardiovascular mortality was largely driven by a reduction of congestive heart failure, this could imply that beneficial effects on the myocardial cells or cardiac function played a role for empagliflozin-treated patients. Furthermore, there is also an indication that markers of arterial stiffness could be reduced following treatment by empagliflozin, as shown both in patients with type 1 and in those with type 2 diabetes. As hyperglycaemia is supposed to be a detrimental factor for arterial stiffness, by glycation of vessel wall proteins, there could be a beneficial effect by empagliflozin directly on the vessel wall. Finally, a number of other protective effects could also have played a role, for example the diuretic effects by promoting glucosuria. This is, however, contradicted by the fact that office blood pressure was only marginally reduced. On the other hand, as no use of 24-hr ABPM was included in the study, this means that the full haemodynamic effect of empagliflozin could not be properly evaluated, which indeed could have “unmasked” more substantial blood pressure beneficial effects of empagliflozin treatment compared to the more modest effects seen on office blood pressure. Further studies are needed to understand better the hidden effects of empagliflozin on reduced risk of congestive heart failure, including molecular studies as well as physiological studies on cardiac function and arterial stiffness of the aorta. If a reduced aortic stiffness could lead to a reduction of the load on the left ventricle by delaying the reflex wave of pulsatile energy, this could be expected to contribute to the relatively early reduction of heart failure risk, as was encountered in the EMPA-REG Outcome Study . Further studies including SGLT2 inhibitors are eagerly awaited for a better understanding of cardiovascular effects, and whether these are seen in a broader range of patients with type 2 diabetes, not only with a heavy burden of previous cardiovascular disease manifestations.
Based on this review we may conclude that: (a) traditional anti-diabetes drugs do not differ very much in their cardiovascular effects, including also the clinical effects of metformin and insulin; (b) incretin active drugs are in general safe and without severe adverse effects, but added cardiovascular protection has (so far shown only for liraglutide in the LEADER study); and (c) the positive effects by use of an SGLT2 antagonist (so far shown only for empagliflozin in the EMPA-REG OUTCOME Study) are pronounced in secondary prevention but should be further tested in a broader range of patients with diabetes. The benefits for prevention of congestive heart failure are still enigmatic, but could be influenced by the diuretic effect as well as still poorly characterized effects on cardiac function, blood pressure and reduction of aortic stiffness.
A comprehensive risk factor control strategy should be offered to all patients with diabetes, taking into account personal characteristics (such as age), tolerability, comorbidity, cost-effectiveness and the evidence base. In the modern management of patients with DM2, metformin has been proposed as first-line drug of choice. Current evidence has questioned the evidence base for this, and new data from SGLT2 inhibition have sparked interest in this new class of drugs [4,21]. We must wait for further evidence before guidelines can be reviewed and revised in a more informed way.
The exclusion of admission to hospital for heart failure from the definition of MACE relegates it to, at best, a single component in a composite secondary outcome. Indeed, the time may have come to design and execute appropriately powered clinical trials which specifically address the safety and possible benefit of anti-diabetic drugs on the development and progression of heart failure in patients with diabetes.