management of type 2 diabetes in patients with heart failure

Diabetes mellitus and heart failure (HF) are major health problems. Nearly 5 million people have HF, and more than 500,000 are newly diagnosed with HF each year in the United States [1]. Similarly, the burden of diabetes continues to increase in the United States, as the prevalence of type 2 diabetes mellitus increased from 4.9% in 1991 to 7.9% in 2001 [2]. Both diseases have a tremendous health and economic toll. For example, HF accounts for more than 12 mil-lion offi ce visits and 6.5 million hospital days yearly and is estimated to have a total (direct and indirect) cost of nearly $28 billion per year in the United States [1]. The age-adjusted risk of death among people with diabetes is approximately twice that of people without diabetes, and the estimated total (direct and indirect)

annual cost of treating diabetes in the United States is approximately $132 billion [3].

The development of cardiovascular disease accounts for a substantial portion of the increased morbidity and mortality in diabetic individuals [4], and an important manifestation of cardiovascular disease in diabetic indi-viduals is HF. Multiple studies have established diabe-tes as a major risk factor for HF development [5,6]. In addition, the presence of HF itself has been described as an insulin-resistant state and is associated with sig-nifi cant risk for the future development of diabetes [7]. Because of these common features, it is not surprising that diabetes and HF commonly coexist. The prevalence of diabetes in major HF trials is approximately 20% to 30% [8], although recent data from an acute HF registry

Management of Type 2 Diabetes in Patients With Heart FailureDavid Aguilar, MDCorresponding authorDavid Aguilar, MDCardiovascular Division, Baylor College of Medicine, 1709 Dryden Street-BCM 620, Suite 500, Box 13, Houston, TX 77030, USA.E-mail: [email protected]

Current Treatment Options in Cardiovascular Medicine 2008, 10:465–475Current Medicine Group LLC ISSN 1092-8464Copyright © 2008 by Current Medicine Group LLC

Opinion statementDiabetes mellitus and heart failure (HF) commonly coexist, and together these conditions are associated with increased morbidity and mortality compared with either condition alone. Although the optimal treatment strategy to achieve glu-cose control in HF patients with type 2 diabetes has not been well studied, given the common coexistence of these conditions and the need to adequately treat hyperglycemia to prevent microvascular complications, it is important for clini-cians to understand the potential implications of diabetic therapy in patients with established HF. Until recently, metformin was contraindicated in patients with HF because of the potential risk of lactic acidosis; however, recent retrospective studies of metformin use in HF patients have shown that this medication may be used safely and indeed may be benefi cial in patients with stable HF. The associa-tion between thiazolidinediones (TZDs) and HF remains controversial, but recent prospective randomized trials of TZD use in HF patients suggest that worsen-ing volume retention associated with these agents may lead to worsening of HF symptoms. The recently developed incretin-based therapies, such as exenatide and sitagliptin, also have not been extensively studied in HF populations; how-ever, small pilot studies of glucagon-like peptide-1 have shown potential promise in the treatment of diabetic patients with HF. Although they may be diffi cult to perform, future randomized controlled trials are needed to establish optimal treat-ment goals and strategies in this population.

Introduction

466 Valvular, Myocardial, Pericardial, and Cardiopulmonary Disease

Pharmacologic treatmentSulfonylurea secretagogues

• The fi rst-generation sulfonylurea secretagogues are chlorpropamide, tol-butamide, and tolazamide. The second-generation agents are glimepiride, glyburide, and glipizide.

• Sulfonylureas stimulate endogenous insulin production from pancreatic β cells via increased responsiveness of these cells to glucose and non-glucose secretagogues (such as amino acids). This action results in more insulin being released at all blood glucose concentrations. Sulfonylureas may be effective when used as monotherapy or in combination with other oral hypoglycemic drugs or with insulin.

• Despite limited data, sulfonylureas are commonly used in patients with HF. In a study with more than 16,000 Medicare recipients who had recently been discharged with a diagnosis of HF, approximately half of the patients were treated with sulfonylureas [25••]. In this study, sulfonylurea use was not associated with increased mortality (hazard ratio [HR], 0.99;

suggest that the prevalence may be as high as 45% [9]. In addition, a recent study has shown that the preva-lence of diabetes in HF patients has increased markedly over time (3.8% per year) [10].

HF development in patients with diabetes likely is multifactorial. Coronary heart disease, including myocardial infarction, is a major risk factor for HF development [6,11,12]. Other clinical factors that have been associated with increased risk of diabetic patients developing HF are increased age [6,11,12], hypertension [11,13], increased body mass index [13], poor glycemic control [6,12,14,15], proteinuria [6,12], end-stage renal disease [11,13], retinopathy [11,16], duration of diabetes [13], tobacco use [12], peripheral vascular disease [11], and insulin use [13]. In addition to these clinical factors, data have suggested that dia-betes may have an independent effect on cardiac struc-ture (ie, the diabetic cardiomyopathy) [17].

Importantly, the coexistence of diabetes and HF portends a poor prognosis. Several studies have demonstrated that mortality is increased in diabetic patients who develop HF compared with those who do not [11,12]. For example, in a national sample of Medicare patients with diabetes, mortality rates were nearly 10-fold greater in those who developed inci-dent HF compared with those who remained HF-free [11]. Similarly, in cohorts of patients with established HF, diabetes has also been associated with increased mortality and increased rates of hospitalization for worsening HF [18•,19]. Therefore, efforts to reduce morbidity and mortality in diabetic patients are increasingly important.

Although studies have shown that drugs known to be effective in treating HF are effective in diabetic patients [20], the optimal treatment of hyperglycemia in diabetic patients with established HF has not been well studied. Studies have established that elevated glycosyl-

ated hemoglobin (HbA1c) is a marker of increased risk of developing HF in diabetic patients [6,14,15]; how-ever, studies examining treatment strategies of intensive glucose control, such as the UKPDS (UK Prospective Diabetes Study) [21] and the more recently completed ACCORD (Action to Control Cardiovascular Risk in Diabetes) [22••] and ADVANCE (Action in Diabetes and Vascular Disease) [23] studies, have not shown statistically signifi cant reductions in HF incidence rates in patients assigned to more intensive glucose control strategies when compared with those assigned to stan-dard therapy. Similarly, in diabetic patients hospitalized with HF, elevated admission blood glucose levels have been correlated with duration of hospitalization [24], but the optimal level of glucose control and the opti-mal treatment strategy in these patients with established HF have not been well studied. Nonetheless, given the common coexistence of HF and diabetes, the increased morbidity and mortality associated with these diseases, and the need to adequately treat hyperglycemia to pre-vent microvascular complications, it is important for clinicians to understand the potential implications of diabetic therapy in patients with established HF.

Currently, the lack of prospective data and poten-tial problems associated with certain diabetic treat-ment strategies represent dilemmas faced by clinicians who commonly encounter HF patients with diabetes in their daily practice. For example, the use of commonly prescribed medications for diabetes treatment, such as metformin and thiazolidinediones (TZDs), have been “relatively contraindicated” in patients with HF. This article reviews common pharmacologic therapies for type 2 diabetes (sulfonylureas, metformin, TZDs, and insulin) and the potential implications of these thera-pies in patients with diabetes and established HF. It also presents recent data on the emerging incretin-based therapies.

Management of Type 2 Diabetes in Patients With Heart Failure Aguilar 467

95% CI, 0.91–1.08). In another study of diabetic patients who received a new HF diagnosis and were being started on oral hypoglycemic therapy, metformin (either as monotherapy or in combination with sulfonylurea) was associated with reduced mortality when compared with sulfonylurea monotherapy [26••]. Prospective studies testing the safety and effi cacy of sulfonylurea-based strategies in HF patients are necessary.

• Major adverse risks include hypoglycemia and weight gain. In addition, there has been concern that therapy with older-generation sulfonylureas may interfere with ischemic preconditioning [27], but the clinical results of this possible effect have not been clearly established [28] and most re-cent trials have not demonstrated increased cardiovascular risk associated with sulfonylurea therapy [21].

Standard dosage• A typical initial sulfonylurea regimen consists of 2.5 mg of glipizide or

glyburide. The maximum dosage of glyburide is 20 mg/d; the maximum dosage of glipizide may be up to 40 mg/d.

Contraindications• Hypersensitivity to any component of the sulfonylurea formulation

or to other sulfonamides; type 1 diabetes mellitus (insulin dependent, IDDM); and diabetic ketoacidosis. Glyburide is contraindicated in patients receiving bosentan.

Main drug interactions• Some sulfonylureas have signifi cant interactions with alcohol as well

as medications including warfarin, high doses of salicylates, keto-conazole, α-glucosidase inhibitors, and fl uconazole. Glyburide may enhance the hepatotoxic effect of bosentan, and the concomitant use of bosentan is contraindicated.

Main side effects• Hypoglycemia is the most common side effect and is more common with

long-acting sulfonylureas, such as glyburide. Hypoglycemia may be of particular concern in the elderly. Most sulfonylureas are metabolized in the liver to compounds that are cleared in the kidney. Thus, their use in individuals with signifi cant hepatic or renal dysfunction is cautioned. Weight gain also may occur.

Cost/cost-effectiveness• Generic forms of glyburide and glipizide make this class of medications

relatively inexpensive.

Metformin• Metformin is a biguanide that decreases hepatic glucose production,

improves glucose uptake and utilization, and improves insulin sensitivity. Metformin has a neutral effect on weight. It is used in type 2 diabetes management as monotherapy or concomitantly with other oral medica-tions or insulin to improve glycemic control.

• Until recently, metformin use was contraindicated in patients with HF because of concerns regarding the risk of lactic acidosis. These concerns


stemmed from previous reports of an association between phenformin, another biguanide, and cases of lactic acidosis [29]. In addition, in the fi rst year of postmarketing surveillance after metformin was introduced in the United States, lactic acidosis was reported in 47 patients, 18 of whom had a history of HF [30]. On the basis of these reports received by the US Food and Drug Administration (FDA), congestive HF was added as a contraindi-cation to metformin therapy in 1998. Despite these initial reports, subse-quent analyses revealed that the risk of lactic acidosis was very low [31].

• In addition, two recent retrospective, nonrandomized studies of diabetic pa-tients with HF [25••,26••] suggested that metformin was commonly used in patients with HF and appeared safe and potentially benefi cial in those patients. In a retrospective cohort of 16,417 Medicare patients recently discharged from the hospital with a primary diagnosis of HF, 13% were discharged on metformin. When compared with individuals discharged on noninsulin-sensitizing drugs (insulin and/or sulfonylurea), metformin use was associated with a 13% lower risk of death at 1 year and an 8% reduced risk of HF hospitalization [25••]. In this study by Masoudi et al. [25••], readmissions for lactic acidosis were similar in patients not treated with an insulin sensitizer (2.6%) and in those discharged with a prescrip-tion for metformin (2.3%, P = 0.40). Similarly, in a retrospective analysis of 1833 HF patients in whom oral antidiabetic therapy had been recently initiated, fewer deaths occurred in those receiving metformin monotherapy (HR, 0.70; 95% CI, 0.54–0.91) or metformin/sulfonylurea combination therapy (HR, 0.61; 95% CI, 0.52–0.72) compared with those receiving sulfonylurea therapy alone [26••]). With this information, the FDA alerted metformin manufacturers that a label change was appropriate, and the con-traindication to metformin use in diabetic patients with HF was removed [32]. Renal dysfunction and metabolic acidosis remain contraindications, and metformin use in HF patients still carries an FDA warning.

Standard dosage• The initial dosage of metformin is 500 mg once or twice a day, and it

may be increased to 1000 mg twice a day. An extended-release form and combination forms with rosiglitazone, pioglitazone, glimepiride, glipizide, or sitagliptin are available.

Contraindications• Hypersensitivity to metformin or any component of the formulation;

renal disease or renal dysfunction (serum creatinine ≥ 1.5 mg/dL in males or ≥ 1.4 mg/dL in females or abnormal creatinine clearance from any cause, including shock, acute myocardial infarction, or septicemia); and acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis). Metformin therapy should be used with caution in elderly people with reduced body mass because their glomerular fi ltra-tion rate may be signifi cantly decreased despite small changes in serum creatinine levels. In addition, metformin should be avoided in patients with impaired liver function because of the potential for lactic acidosis. Metformin should also be discontinued in patients who are severely ill.

Main drug interactions• Contrast agents may increase the risk of metformin-induced lactic

acidosis (because of the potential for acute alteration in renal func-tion); therefore, metformin should be discontinued 48 hours before


radiologic studies involving the intravascular administration of iodin-ated contrast materials.

Main side effects• The most common side effects include gastrointestinal effects (diarrhea,

anorexia, nausea, vomiting, and metallic taste). These effects can be minimized with gradual dose escalation.

Cost/cost-effectiveness• Metformin is available in a generic formulation, making this medication

relatively inexpensive.

Thiazolidinediones• TZDs target insulin resistance by acting as agonists for the nuclear tran-

scription factor peroxisome proliferator–activated receptor-γ (PPARγ) [33]. TZDs increase insulin sensitivity by acting on adipose tissue, muscle, and liver to increase glucose utilization and decrease glucose production [34]. The two currently available TZDs, pioglitazone and rosiglitazone, are used as monotherapy or in combination with other medications for treating hyperglycemia.

• There is signifi cant controversy regarding TZD use and the risk of wors-ening HF. In addition to its benefi cial effects on insulin sensitivity and glucose homeostasis, activation of the PPARγ system results in a myriad of potentially benefi cial metabolic [34], vascular [35], and neurohor-monal effects [36] that may be advantageous in preventing HF and/or treating diabetes in those with established HF. Despite these potential benefi ts, there is evidence that TZDs contribute to fl uid retention and increase the risk of HF. A recent meta-analysis of 20,191 patients with prediabetes or diabetes who were enrolled in randomized controlled tri-als of TZD treatment examined the associated risk of HF events [37••]. In this meta-analysis, 214 patients in the TZD group and 146 in the comparator arm developed HF (RR, 1.72; 95% CI, 1.21–2.42) [37••]. The authors noted that despite the increased risk for HF development, the risk of cardiovascular death did not increase with either of the two TZDs (RR 0.93; 95% CI, 0.67–1.29) [37••].

• Studies of the risk of TZD use in patients with established HF have been limited. In the study by Masoudi et al. [25••] described earlier, TZDs were associated with a 13% decreased risk of death (HR, 0.87; 95% CI, 0.80–0.94) when compared with non–insulin-sensitizing medications; however, TZDs were also associated with an increased risk of readmission for HF (HR, 1.06; 95% CI, 1.00–1.09). In another retrospective study of ambulatory patients with HF treated in the Veterans Affairs system, TZD use was not associated with changes in mortality or rates of HF hospital-ization compared with insulin-sensitizing medication use [38].

• Two prospective randomized controlled studies examined the use of TZDs in individuals with established HF [39,40]. In a 52-week study by Dargie et al. [39], 224 type 2 diabetic patients with New York Heart Association (NYHA) class I/II HF and a left ventricular ejection fraction (LVEF) less than 45% were randomly assigned to rosiglitazone or place-bo. The results demonstrated that rosiglitazone did not adversely affect LVEF as assessed by echocardiography, but rosiglitazone was associated with an increased occurrence of edema (25.5% vs 8.8%) and the need for increased HF medication (32.7% vs 17.5%) when compared with


placebo [39]. In a prospective, 6-month, double-blind, controlled trial evaluating HF progression in 518 patients with type 2 diabetes, NYHA class II/III HF, and an LVEF less than 40%, a diabetic treatment strategy based on pioglitazone was compared with a glyburide-based strategy [40]. In this study enrolling patients with more severe HF, pioglitazone was not associated with echocardiographic indices of worsening cardiac structure and function, but the composite outcome of cardiovascular mortality and hospitalization or an emergency department visit for HF was greater in the pioglitazone group than the glyburide group (13.4% vs 8.2%; P = 0.024). This hazard was predominantly the result of the need for overnight hospitalization for worsening HF (9.9% in the pio-glitazone group and 4.7% in the glyburide group; P = 0.024), with no statistical difference in the incidence of cardiovascular death (1.9% in the pioglitazone group and 2.3% in the glyburide group).

• One of the most likely mechanisms contributing to TZD-associated volume retention and edema is increased renal sodium reabsorption and excre-tion [41,42]. In animal studies, amiloride treatment eliminated the plasma volume expansion observed with pioglitazone alone [42]. Limited human studies also have suggested that spironolactone may be useful in treating the plasma expansion that may occur in the setting of TZD use [43•].

• Overall, given the potential effects of worsening edema and potential worsening of HF, TZDs should be used cautiously in stable patients with established HF and should be avoided in patients with NYHA class III or IV symptoms [44].

• The rosiglitazone labeling has recently been changed to include a warn-ing that a recent meta-analysis of 42 clinical studies (most of which compared rosiglitazone with placebo) showed rosiglitazone to be associ-ated with an increased risk of myocardial ischemic events such as angina and myocardial infarction [45]. Similar fi ndings have not been seen with pioglitazone [46]. Although these fi ndings remain controversial, future studies are needed to study the implications of this potential risk in patients with diabetes, ischemic heart disease, and HF.

Standard dosage• The therapeutic range for pioglitazone is 15 to 45 mg/d in a single daily

dose. The therapeutic range for rosiglitazone is 2 to 8 mg/d administered once or twice daily in divided doses. Pioglitazone and rosiglitazone are both available in combination with metformin or glimepiride.

Contraindications• Rosiglitazone and pioglitazone are contraindicated in patients with

established NYHA class III or IV HF or known hypersensitivity to this product or any of its components. The drugs should not be used in indi-viduals with active liver disease, diabetic ketoacidosis, or type 1 diabetes.

Main drug interactions• May increase the risk of hypoglycemia when combined with insulin or

oral sulfonylureas.

Main side effects• The most common side effects are edema (particularly with concomitant

use of insulin) and weight gain. Although rosiglitazone and pioglitazone do


not appear to induce the liver abnormalities seen with troglitazone (a TZD withdrawn because of hepatotoxicity), the FDA recommends liver function testing before initiating a TZD and at regular intervals thereafter.

• Warnings for both drugs include possible increased risk of fracture. An ad-ditional warning, as described earlier, was recently added to rosiglitazone regarding the potential increased risk of myocardial ischemic events [45].

Cost/cost-effectiveness• The medications are not available in a generic formulation. A 30-day

supply of 30-mg pioglitazone is estimated at $181, and a 30-day supply of 4-mg rosiglitazone is estimated at $115.

Insulin• Several insulin preparations are available for treating type 2 diabetes,

including intermediate to long-acting preparations (NPH [neutral prot-amine Hagedorn], detemir, and glargine) and short-acting (regular) and rapid-acting insulins (lispro, aspart, and glulisine).

• Although insulin is required to treat type 1 diabetes mellitus and of-ten is needed to treat type 2 diabetes, some concerns have been raised over whether insulin has the potential to worsen outcomes in diabetic patients with established HF. For example, in diabetic patients with HF treated in the clinical trials CHARM (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) [47] and SAVE (Survival and Ventricular Enlargement) [19], insulin treatment was associated with increased mortality. This association of insulin with in-creased mortality in diabetic patients with HF was not seen in the study of more than 16,000 elderly diabetic patients discharged with HF (HR for mortality associated with insulin, 0.96; 95% CI, 0.88–1.05) [25••]. The increased hazard associated with insulin seen in some of these stud-ies may refl ect confounding due to underlying disease severity in diabetic patients with HF who require insulin; that is, insulin use may simply be a marker for patients with a longer duration of diabetes or more severe disease rather than a direct contributor to adverse outcomes in diabetic patients with HF. Future prospective studies are needed to determine the impact of early insulin use in patients with established HF.

Main side effects• The main adverse effects of insulin are associated with the risk of hypo-

glycemia and weight gain. Fluid retention may occur at higher dosages.

Emerging therapiesIncretin mimetics (exenatide and sitagliptin)

• Incretins are gut-derived peptides secreted from enteroendocrine cells of the intestinal tract. The major incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide. GLP-1 has been studied extensively in type 2 diabetes. Through actions on pancreatic cells, GLP-1 has signifi cant insulinotropic effects. These insulinotropic effects are glucose dependent and thus mitigate the risk of hypoglycemia in individuals with normal glucose. In addition, GLP-1 has been shown to reduce insulin resistance and improve glucose uptake in skeletal muscle and adipose tissue [48,49]. Furthermore, GLP-1 suppresses


postprandial glucagon secretion, promotes satiety, and is associated with modest weight loss.

• Exenatide was the fi rst incretin mimetic FDA approved for clinical use as adjunctive therapy to improve glycemic control in patients with type 2 dia-betes receiving metformin, a sulfonylurea, or a combination of these agents. Exenatide, a 39–amino acid peptide, has 58% sequence homology to native GLP-1 and activates the GLP-1 receptor [50]. Unlike native GLP-1, exena-tide is resistant to degradation by dipeptidyl peptidase-4 (DPP-4) and has an elimination half-life of 3.3 to 4 hours [50]. Sitagliptin is an oral inhibi-tor of DPP-4 and thus increases the plasma concentration of endogenously secreted incretins. Several other DPP-4 inhibitors are being developed.

• The role of incretin mimetics in treating diabetes in HF has been limited, but preliminary data suggest a potential benefi t associated with incre-tin-based therapy in patients with HF. In animal experiments, GLP-1 infusion has been associated with improvements in myocardial glucose uptake and in left ventricular and systemic hemodynamics in conscious dogs with dilated cardiomyopathy [51]. In a study of 12 patients with NYHA class III/IV HF, a continuous infusion of GLP-1 for 12 weeks im-proved LVEF (from 21% to 27%) and functional status [52•]. Similarly, in a study of 10 patients with acute myocardial infarction and severe left ventricular systolic dysfunction (LVEF < 40%), a 72-hour continuous in-fusion of GLP-1 was associated with signifi cant improvements in LVEF (from 29% to 39%) and global and regional wall motion [53].

• The commercially available incretin-based agents, exenatide and sita-gliptin, have not been studied in HF patients. In the studies that led to FDA approval of these compounds, there were no reported problems of worsening HF or volume retention.

Standard dosage• Exenatide is administered subcutaneously and is started at 5 μg twice

daily. After 4 weeks, the dosage may be increased to 10 μg twice daily (based on response).

• The recommended dosage for sitagliptin is 100 mg/d. Dosage adjustment is recommended for patients with moderate or severe renal insuffi ciency or end-stage renal disease.

Contraindications• Contraindications to exenatide and sitagliptin include hypersensitiv-

ity to any component of the formulation, type 1 diabetes, and diabetic ketoacidosis.

Main drug interactions• Because of its effects on gastric emptying, exenatide may reduce the rate

and extent of absorption of orally administered drugs. Therefore, exena-tide should be used with caution in patients receiving medications that require rapid absorption from the gastrointestinal tract. Administration of medications 1 hour before the use of exenatide has been recommend-ed by the manufacturer when optimal drug absorption and peak levels are important to the overall therapeutic effect (such as with antibiotics and/or oral contraceptives).

• Sitagliptin may increase the serum concentration of digoxin.• Concomitant use of exenatide or sitagliptin with sulfonylureas increases

the risk of hypoglycemia.


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Main side effects• The most frequently reported adverse effect of exenatide is nausea.

Modest weight loss may occur with exenatide as the result of delayed gastric emptying and early satiety. Rare cases of pancreatitis have been reported recently for exenatide.

• The most commonly reported side effects for sitagliptin are headache (5%), upper respiratory infection (6%), and nasopharyngitis (5%). There have also been postmarketing reports of rare hypersensitivity reactions, including anaphylaxis and/or severe dermatologic reactions, such as Stevens-Johnson syndrome.

Cost/cost-effectiveness• Neither exenatide nor sitagliptin is available in a generic formulation,

so these agents are expensive. A 30-day supply of 100-mg sitagliptin is $180, and a 30-day supply of exenatide (10 μg twice daily) is $230.

DisclosureNo potential confl ict of interest relevant to this article was reported.

References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:• Of importance•• Of major importance


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management of type 2 diabetes in patients with heart failure

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