INTRODUCTION: DIABETES AND HEART FAILURE
Type 2 diabetes mellitus (T2DM) is a well-established risk factor for cardiovascular (CV) disease. It is also a growing pandemic. Although heart failure is tightly linked to T2DM, this complication is under recognized. In 1979, the Framingham Heart Study documented that men and women with prior evidence of diabetes had a 2- and 5-fold risk, respectively, of HF compared with age-matched controls.1 In 2000, the U.K. Prospective Diabetes Study reported that patients with T2DM had HF incidence rates of 2.3 to 11.9 per 1000 patient-years over 10 years of follow-up.2 Subsequent retrospective cohort studies such as the one conducted by Nichols et al. state an even higher incidence rate of HF in diabetic versus nondiabetic patients (30.9 vs 12.5).3 The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) trial reported that more than 40 of individuals hospitalized with HF have T2DM.4 Furthermore, for those without a prior diagnosis of T2DM, the presence of HF itself can cause diabetes.5 It is clear that the two are often related, and the combination complicates the management of both.
Several mechanisms have been proposed to explain the relationship between T2DM and HF. Echocardiographic evaluations of patients with T2DM reveal an increase in left ventricular (LV) hypertrophy and systolic and diastolic dysfunction.6 Studies have shown that these changes appear to occur even in the absence of coronary artery disease. Diastolic dysfunction is an important manifestation of diabetic cardiomyopathy, with a reported prevalence as high as 40 to 60.6 Indeed, systemic insulin resistance with compensatory hyperinsulinemia is a more important prognostic factor in HF incidence than hyperglycemia.7 Insulin resistance results in a predominately fatty acid substrate oxidation phenotype of the diabetic heart, which leads to the accumulation of toxic lipid compounds (Figure 1).8 Other established factors known to occur in T2DM patientssuch as accelerated atherosclerosis, hypertension, and expansion of extracellular fluid volumeare also likely to contribute to HF pathogenesis in this population.
Agents that demonstrate not only CV safety but also improved CV outcomes have emerged as effective alternatives in the management of T2DM. This paper reviews antihyperglycemic agents that have been studied in HF patients, discusses their mechanisms of action and risk/benefit profiles, and provides recommendations based on HF stage.
DIABETIC THERAPIES AND HEART FAILURE: FROM TRADITIONAL DRUGS TO NEWER AGENTS
Sulfonylureas are an older class of diabetic drugs that have been shown to increase HF risk in multiple studies. A large retrospective study in the United Kingdom looked at 91,521 patients with T2DM and found that second-generation sulfonylurea use was associated with an 18 increase in developing HF compared to patients using metformin.9 Two other studies analyzing databases from the Cleveland Clinic and Saskatchewan found a similar increase in HF admissions in patients using sulfonylurea versus metformin.10 Thus, this class of medications has fallen out of favor in HF patients and in those at risk for developing this condition.
Thiazolidinediones (TZDs) such as rosiglitazone are antihyperglycemic agents that were initially thought to be effective in patients at risk for CV disease.11 Unfortunately, safety and efficacy trials, which excluded NYHA class III and IV patients, showed a significant increase in hospital admissions for HF. The fluid retention seen with this class is thought to result from activation of sodium channels in the collecting ducts (mediated by peroxisome proliferator-activated receptor gamma) and sodium transporters in the proximal tubule.11 Additionally, factors such as higher perfusion pressure leading to increased fluid extravasation and increased vascular permeability are also thought to contribute to the edema and volume overload seen with TZDs.
A cornerstone of T2DM therapy, metformin was initially contraindicated for HF due to concerns regarding lactic acidosis. However, observational studies, including an extensive meta-analysis by Eurich et al., have shown no increases in lactic acidosis in patients treated with metformin versus other therapies; in fact, this group reported that metformin-based therapies had a 20 relative risk reduction in all-cause mortality compared to other therapies. Furthermore, in patients with reduced LV ejection fraction (LVEF) (EF < 40), metformin-based therapies did not increase mortality, and there was a trend towards improved survival. The absolute contraindication warning was removed by the U.S. Food and Drug Administration (FDA) in 2006 and by Health Canada in 2010.12 Metformin is now one of the first-line agents in patients with both T2DM and HF.
The relationship between insulin and HF is complicated. Although several observational studies point to a worse prognosis in insulin-treated patients with T2DM and HF, there are no specific studies evaluating insulin treatment in HF progression.13 It is well known that insulin promotes sodium retention, likely through potentiation of sodium transporters in the kidney. While extensive edema is rare with insulin therapy, it is thought that milder volume expansion may predispose patients to develop HF.10 Additionally, several observational studies found that insulin-treated T2DM patients have worse morbidity and mortality compared to their noninsulin-treated counterparts.13,14 However, reports such as the U.K. Prospective Diabetes Study did not see such a difference in HF incidence when comparing insulin to noninsulin therapies.10 Overall, it remains unclear whether insulin therapy is more common in higher-risk HF patients or if the therapy itself is detrimental to HF patients at all stages. Insulin therapy continues to be a last resort in patients with uncontrolled T2DM, which may limit alternate therapies in this patient population.
NEWER AGENTS, MECHANISM OF ACTION, AND DIRECT EFFECTS ON THE HEART
Three new classes of antihyperglycemic drugs have received considerable attention due to their CV and HF benefits (Table 1): dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors. DPP-4 inhibitors and GLP-1 agonists achieve glycemic control by prolonging the action of the endogenous incretin hormones and by directly stimulating GLP-1 receptors, respectively. Incretin hormones, GLP-1 and gastric inhibitory polypeptide (GIP), are both decreased in T2DM but have several beneficial glucoregulatory effects; for example, they stimulate insulin release in response to glucose levels, inhibit glucagon secretion, increase beta-cell proliferation, and decrease beta-cell apoptosis.15 GLP-1 receptors are located not only on the pancreatic islet cells but are also widely distributed across several organs, such as the heart, kidneys, gastrointestinal tract, endothelium, and pituitary and nervous systems.16 In experimental models, GLP-1 has been shown to modulate heart rate, blood pressure, myocardial contractility, and vasodilation and protect against ischemia-reperfusion injury.17 Additionally, GLP-1 agonists have demonstrated favorable effects in animal models of HF, including increased myocardial glucose uptake and improved parameters of LV function.18 Small human studies have also shown compatible results, demonstrating an increase in LVEF and functional status.19
|ANTIHYPERGLYCEMIC CLASS||HBA1C LOWERING EFFECT||COMMON SIDE EFFECTS||WARNINGS/CONTRAINDICATIONS|
|DPP-4 inhibitors||0.50.8%||Headaches, upper respiratory tract infection, nasopharyngitis, joint pain, dizziness||Warnings: pancreatitis (avoid if history of chronic pancreatitis or discontinue if acute pancreatitis); heart failure (saxagliptin and alogliptin); arthalgias and bullous pemphigoid; hypersensitivity-related events; hepatotoxicity (alogliptin)
Contraindications: serious hypersensitivity reactions to agent
|GLP-1 agonists||11.5%||Nausea, vomiting, diarrhea (mostly self limited and dose related), antibody development (attenuated glycemic response), injection site reaction, headaches, sinus tachycardia, abdominal pain or distension||Warnings: pancreatitis (avoid if history of chronic pancreatitis or discontinue if acute pancreatitis); gallbladder and bile duct disease; severe gastroparesis, caution on renal impairment (risk of acute injury observed if severe GI symptoms); increased risk of complications from diabetic retinopathy (semaglutide)
Contraindications: serious hypersensitivity reactions to agent, personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (boxed warning)
|SGLT2 inhibitors||0.71.0%||Genitourinary fungal infection, urinary tract infection, increased urine output, nausea, nasopharyngitis, hypotension||Warnings: euglycemic diabetic ketoacidosis, hypotension, acute kidney injury, urosepsis and pyelonephritis, increased LDL-C, genital mycotic infections, increased risk of bone fracture (canagliflozin), increased risk of lower limb amputation (canagliflozin) (boxed warning), avoid or use caution if active or history of bladder cancer, respectively (dapagliflozin)
Contraindications: severe hypersensitivity reaction, severe renal dysfunction or end-stage kidney disease
A novel class of oral antihyperglycemic agents, DPP-4 inhibitors target the incretin system and block the degradation of endogenous GLP-1 by inhibiting the DPP-4 enzyme. This, in turn, increases the concentrations of circulating GLP-1 and improves glycemic control.20 DPP-4 inhibitors are increasingly prescribed because of their weight-neutral effects and favorable tolerability profiles.
GLP-1 Receptor Agonists
GLP-1 agonists are a class of injectable drugs resistant to DPP-4 enzymatic degradation.21 As with DPP-4 inhibitors, GLP-1 agonists target the incretin system and exert enhanced pancreatic and extra-pancreatic effects. For example, exocrine pancreatic changes noted in rodents include stimulation of beta cell neogenesis, replication, and acinar cell inflammation and are likely associated with the clinically significant finding of increased risk of pancreatitis found with this class.22 In addition, the agents within this drug class have significant physiological and clinical differences with regard to efficacy and side effects (Table 2). DPP-4 inhibitors increase endogenous GLP-1 to physiological levels (1025 pmol/L) while GLP-1 agonists reach significantly higher concentrations (6090 pmol/L), which may account for their stronger glucose-lowering effect. These agonists delay gastric emptying and often result in nausea and decreased appetite, both of which contribute to the clinically significant weight loss distinctive of this class.23
|FEATURES||DPP-4 INHIBITORS||GLP-1 AGONISTS|
|Biological effect||Both GLP-1 and GIP enhanced
Increased to physiological endogenous levels (1025 pmol/L)
|Pure GLP-1 effect
Increased to supraphysiological levels (6090 pmol/L)
|Route of administration||Oral||Subcutaneous|
|Efficacy||Moderate efficacy||Enhanced efficacy|
|Impact on HBA1c||0.51%||11.5%|
|Tolerance||Usually well tolerated||Common tolerance issues at initiation (nausea, gastrointestinal upset)|
|Cardiovascular risk||Noninferior to traditional therapies||Decreased compared to traditional therapies|
|Cost||Less expensive (approximately 150450)||More expensive (approximately 600850)|
|Effect on weight||Neutral||Promotes weight loss|
This new class of antihyperglycemic drugs has a unique mechanism of action that improves glycemic control. By inhibiting the SGLT2 cotransporters on renal tubules, these drugs effectively decrease the threshold for renal reabsorption of glucose and sodium, thereby increasing urinary glucose and sodium excretion.24 SGLT is a sodium glucose cotransporter present in two major isoforms, SGLT1 and SGLT2. SGLT2 is mainly found in the lumen of the small intestine and kidneys and regulates the absorption and reabsorption of glucose. SGLT1 is primarily present in the cardiac capillaries and cardiomyocytes and has an important role in glucose uptake into the myocardium.25
Despite the relative absence of SGLT2 cotransporters in the heart, SGLT2 inhibitors have been shown to have a positive impact on blood pressure control, arterial stiffness, vascular resistance, and microvascular remodeling.26 A number of mechanisms have been proposed, including beneficial effects on ion hemostasis, calcium handling, reduction of cardiac oxidative stress, and vascular inflammation.27 SGLT2 cotransporters also modulate myocardial metabolism by shifting away from glucose and lipid oxidation and instead utilizing ketone bodies, which is more energy efficient and ultimately improves cardiac contractility.28 This leads to beneficial changes in weight, blood pressure, diuresis, and natriuresis with a decrease in glomerular hyperfiltration. The net effects of SGLT2 inhibition likely confer CV protection.29,30
STAGE-BASED RECOMMENDATIONS FOR ANTIHYPERGLYCEMIC THERAPY
Based on preclinical data, biological effects, and recent beneficial CV outcomes of large randomized clinical trials (RCT),10 we propose a stepwise approach to incorporating novel T2DM therapies in the care of patients with HF (Table 3). Information regarding glucose-lowering efficacy, safety profile, dosing, and renal adjustments for commonly used agents is also provided (Tables 1, 4). These general recommendations should be used in conjunction with evidence-based guidelines and the physician's own clinical judgment based on the patient's glycemic control.31
|HEART FAILURE STAGE||RECOMMENDATIONS|
|Stage A||Lifestyle interventions and metformin
Consider incretin-based therapy or SGLT2 inhibitor for overweight or obesity
|Stage B||Lifestyle interventions and metformin
Consider incretin-based therapy with DPP-4 inhibitors
Consider SGLT2 inhibitors
|Stage C||Lifestyle changes and metformin
Switch from DPP-4 inhibitors to GLP-1 agonists
|Stage D||Lifestyle changes
Insulin as mainstay of therapy
SGLT2 inhibitors and GLP-1 agonists, if tolerated
|MEDICATION||BRAND NAME||DOSING||RENAL ADJUSTMENT|
|Sitagliptin||Januvia||100 mg daily||eGFR (mL/min/1.73 m2)
3045: 50 mg daily
< 30: 25 mg daily
ESRD on HD or PD: 25 mg daily
|Alogliptin||Nesina||25 mg daily||CrCl (mL/min)
3060: 12.5 mg daily
< 30: 6.25 mg daily
ESRD on HD: 6.25 mg daily
|Saxagliptin||Onglyza||5 mg daily||eGFR (mL/min/1.73 m2)
< 45: 2.5 mg daily
ESRD: 2.5 mg daily (post-dialysis)
|Linagliptin||Tradjenta||5 mg daily||Not necessary|
|GLP-1 agonists short acting|
|Lixisenatide||Lyxumia, Adlyxin||Starting dose of 10 mg every day, titrate up to 20 mg daily||eGFR (mL/min/1.73 m2)
< 30: cautious use
< 15: not recommended
|Exenatide||Byetta||510 mg BID||CrCl (mL/min)
< 30 or ESRD: not recommended
|GLP-1 agonists long acting|
|Albiglutide||Tanzeum||3050 mg every week||Not necessary|
|Dulaglutide||Trulicity||0.751.5 mg every week||Not necessary|
|Liraglutide||Victoza||Initial dose of 0.6 mg for 1 week, titrate up to 1.2 mg daily
Increase to 1.8 mg daily if inadequate glycemic control
|Exenatide||Bydureon||2 mg every week||CrCl (mL/min)
< 30: not recommended
|Semaglutide||Ozempic||Initial dose of 0.25 mg once a week for 4 weeks, increase to 0.5 mg every week. Increase to 1 mg every week if inadequate glycemic response.||Not necessary|
|Empagliflozin||Jardiance||1025 mg daily||eGFR (mL/min/1.73 m2)
3045: not recommended
< 30: contraindicated
|Canagliflozin||Invokana||100300 mg daily||eGFR (mL/min/1.73 m2)
4560: max 100 mg daily
3045: not recommended
< 30: contraindicated
|Dapagliflozin||Farxiga||510 mg daily||eGFR (mL/min/1.73 m2)
3060: not recommended
< 30: contraindicated
STAGE A HEART FAILURE
For patients with diabetes and stage A HF, the cornerstone of therapy is dietary modification and weight reduction. Metformin is also recommended as monotherapy or in conjunction with other agents. DPP-4 inhibitors, GLP-1 agonists, or SGLT2 inhibitors would be reasonable agents to use either as add-ons or as monotherapy, with the latter two especially beneficial in overweight individuals. Insulin therapy can be considered if glycemic control is not achieved with the above therapies. If possible, sulfonylureas and thiazolidinediones (TZDs) should be avoided. Consensus guidelines from the American Diabetes Association and American Heart Association do mention cautious low-dose use of TZDs in patients without symptomatic heart disease but with one or more risk factors for congestive heart failure.11 If TZDs are used at this stage, patients should be carefully monitored for worsening signs/symptoms of HF.
STAGE B HEART FAILURE
In patients with stage B HF and T2DM, we recommend initiating early therapy with newer agents, beginning with DPP-4 inhibitors. Most of these agents have demonstrated an improved safety profile, including low risk of hypoglycemia and neutral weight effect when compared with traditional diabetic therapy.
An important caution was displayed in one of the earliest large CV trials studying the safety of these agents. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes MellitusThrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, saxagliptin showed noninferiority regarding a composite of CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke, but it also showed an unexpected early increase of 27 in HF hospitalization.32
In the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial, alogliptin demonstrated noninferiority regarding CV safety in a high-risk patient population but also displayed a nonstatistically significant 19 increase in hospitalization for HF.33 Both studies found a higher proportion of hospitalization for HF events in the top baseline quartile with B-type natriuretic peptide, suggesting a higher susceptibility of patients with underlying significant hemodynamic disturbances. Conversely, another RCT involving DPP-4 inhibitors did not show statistical difference regarding risk of HF hospitalization, which suggests that this is not a class effect.34 Their ease of use and simple dosing regimens make DPP-4 inhibitors an attractive option in the early stages of HF management, with the cautions mentioned above. Early use of SGLT2 inhibitors should also be considered based on robust clinical data (as discussed below).
STAGE C HEART FAILURE
At this stage, we recommend intensifying therapy by switching from DPP-4 inhibitors to GLP-1 agonists and avoiding the simultaneous use of two incretin-based agents. The injectable drugs have greater potency and have not been associated with adverse HF outcomes.
GLP-1 agonists have become increasingly recognized for their weight loss effect and improvement in glycemic and metabolic profiles, especially in overweight and obese patients. Although initial outcomes comparing lixisenatide and placebo in acute coronary syndrome were no different,35 more recent studies have demonstrated cardioprotective effects. For example, liraglutide showed a decrease in composite death from CV causes, nonfatal myocardial infarction, nonfatal stroke and a nonstatistically decreased rate of hospitalization for HF.36 Also, a recent RCT studying CV outcomes with the newest agent on this class, semaglutide, demonstrated significant decreased rates of CV death, nonfatal myocardial infarction, or nonfatal stroke.37 It is important to consider cost and patient preference, as these agents are injectable with variable dosing frequency (Table 4).
SGLT2 inhibitors are a promising class of antihyperglycemic agents based on their robust beneficial effect on CV risk, including HF. The landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial was the first to show a statistically significant decrease in composite risk of death from CV causes, nonfatal myocardial infarction, and risk of HF hospitalization.38 This has created a significant impact on current clinical practices as reflected in the recent clinical guidelines regarding management of T2DM.31
STAGE D HEART FAILURE
Management of diabetes in advanced HF raises significant challenges. Common antihyperglycemic agents are restricted at this stage due to significant accompanying comorbidities, including renal dysfunction, systemic hypoperfusion, lactic acidosis risk, and other hemodynamic abnormalities. This frequently leaves insulin as the primary therapy,39 despite concerns regarding its impact on HF, as explained above. The judicious use of insulin is advised, and less-strict glycemic goals should be considered, especially in elderly patients.40 Use of SGLT2 inhibitors and GLP-1 agonists could be considered as combined or monotherapy if tolerated, but more studies evaluating their safety in this population are ongoing.
Heart failure is an important and under-recognized complication of T2DM. Multiple studies have shown that patients with T2DM and congestive heart failure have poor outcomes, and basic science studies have revealed pathophysiologic mechanisms that may underlie this relationship. Therefore, it is important to understand and use appropriate T2DM therapies in this population. If appropriate, agents such as metformin, GLP-1 agonists, and SGLT2 inhibitors should be considered in HF patients. Conversely, agents such as TZDs and sulfonylureas should be avoided, if possible. Close monitoring and judicious use of diabetic therapies should be constantly reviewed in HF patients at various stages of their disease. Ultimately, further studies are needed to better guide hyperglycemia management in this population.