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Managing diabetes mellitus is an ongoing concern, especially in the presence of heart failure. Recent reports have drawn attention to adverse cardiovascular events associated with the use of thiazolidinediones, including rosiglitazone (Avandia). In 2011, the U.S. Food and Drug Administration implemented a stringent “restricted access program” for the prescription of Avandia. Other studies, which have revealed increased mortality rates in association with tight glycemic control, raise serious concerns about managing diabetes in heart-failure patients.
Herein, we provide a perspective on the management of noninsulin-dependent diabetes in patients with heart failure. We point out that thiazolidinediones exert their major effects through insulin sensitization, which potentiates the action of insulin. A defining feature of insulin resistance is excess fuel supply and restricted rates of substrate utilization by the heart. We postulate that the use of excess insulin and insulin-sensitizing agents can lead to adverse cardiovascular events and contractile dysfunction through an increase of substrate uptake to an insulin-resistant heart that is already flooded with fuel. We include a table of antidiabetic agents and nonpharmacologic interventions aimed at lowering substrate supply, and of the respective clinical trials supporting their safety and efficacy. Although previously contraindicated in patients with heart failure, metformin appears to be both safe and effective therapy for diabetes in those patients. Because metformin reduces gluconeogenesis in the liver, we propose that the management of diabetes in heart-failure patients should target the source, rather than the destination, of excess fuel.
Diabetes mellitus is a strong independent risk factor for premature death and disability from coronary artery disease. However, to what degree does glycemic control influence the survival of patients with diabetes and severe heart failure? At this time, there is no answer to this question. This review was prompted by a series of reports on cardiovascular sequelae accompanying tight glycemic control either by insulin1,2 or, more specifically, by the group of insulin-sensitizing agents known as thiazolidinediones (TZDs).3 The TZDs are modulators of peroxisome proliferator-activated receptors, which function as transcription factors that regulate the expression of multiple genes for proteins in metabolic pathways.
The TZD rosiglitazone (Avandia®, GlaxoSmithKline; Research Triangle Park, NC) has been under scrutiny since it was approved by the U.S. Food and Drug Administration (FDA) in 1999 for glycemic control and the treatment of type 2 diabetes mellitus.4 Major medical concerns, including adverse lipid effects, edema, and increased cardiovascular risk, surrounded the drug early in its history. By 2001, reports suggested that TZDs exacerbate heart failure,5 and the FDA added a precaution in 2002 regarding rosiglitazone-induced congestive heart failure. A consensus paper by the American Heart Association and the American Diabetes Association in 2004 stated, “Both patients and healthcare providers should be cognizant of the risk of heart failure when TZDs are used in patients with type 2 diabetes.”6 Despite these concerns, trials revealed the efficacy of rosiglitazone in achieving great durability in glycemic control, enabling the drug to reach peak annual sales of $3.3 billion in 2006.7 A “big upset” occurred in 2007 when a meta-analysis of 42 clinical trials by Nissen and Wolski8 drew special attention to cardiovascular sequelae in patients undergoing rosiglitazone therapy, prompting more questions about the safety of this drug. Shortly thereafter, the FDA revealed similar results in a separate meta-analysis.9
Avandia made headlines. Negative reports, skepticism within the medical community, and consumer caution prompted a joint meeting with the FDA's endocrinologic and metabolic drugs advisory committee and the drug safety and risk management advisory committee in 2010. At the meeting, Nissen presented an updated meta-analysis that again showed increased cardiovascular risk from the use of rosiglitazone.10 In addition, the associate director of the FDA's office of drug safety presented the results of a retrospective cohort study, which also suggested an adverse cardiovascular-event profile in association with TZDs.11 The FDA has since implemented a stringent “restricted access program” for the prescription of rosiglitazone, and this has reduced the use of the drug.12
Heart failure appears to be a class-specific adverse effect with respect to TZDs; studies suggest that either rosiglitazone or pioglitazone (Actos®, Takeda Pharmaceuticals North America, Inc.; Deerfield, Ill) can exacerbate heart failure.5 In 2007, a meta-analysis13 showed that pioglitazone was associated with increased heart failure without an associated increase in mortality rates. However, the two TZDs seem to have different cardiovascular-event profiles, and mechanisms to explain these drug-specific differences require further investigation.
Insulin resistance is defined as the diminished ability of cells to respond to the action of insulin in transporting glucose from the bloodstream into muscle.14 In reality, insulin resistance is a metabolic disorder of extraordinary complexity.15,16 With respect to the heart, a major effect of insulin resistance is the imbalance in the supply of energy-providing substrates on the one hand and reduced substrate oxidation on the other. For example, insulin resistance results from increased lipolysis, an upregulation in hepatic lipogenesis, and increased hepatic gluconeogenesis. Excess fuel supply and decreased oxidation are chief features of insulin resistance in muscle, and this includes heart muscle.
It has been suggested that insulin resistance predicts the incidence of heart failure independent of established risk factors, including diabetes.17 In addition, therapeutically targeting impaired insulin sensitivity potentially benefits patients with heart failure.18 In short, the medical literature supports a causal relationship between insulin resistance and heart failure. It has been shown that the failing human heart will exhibit features of insulin resistance and lipid overload.19 Possible mechanisms include the generation of reactive oxygen species, diacylglycerol formation, and protein kinase C activation. The question arises: Why would a failing heart become insulin-resistant? Fuel metabolism of the heart and the role of insulin resistance merit consideration.
From a biochemical perspective, fatty acids and glucose intracellularly inhibit each other as they enter their pathways of oxidation.20 We propose that the heart already has an innate intracellular mechanism to protect it from substrate overload. An increasing number of reports show higher mortality rates in association with tight glycemic control, mainly through the use of insulin, in patients with diabetes and heart failure.21,22 We suggest that insulin and insulin-sensitizing agents augment substrate uptake by a heart already flooded with energy-providing substrates, including fats and sugars. In other words, the heart is overwhelmed with oxidizable fuel. If our hypothesis is correct, the treatment of type 2 diabetes mellitus should focus on lowering substrate supply, rather than on promoting substrate uptake.
Not only is the insulin receptor signaling and intermediary pathway extremely complex, but it is mediated at the level of individual organs through distinct mechanisms.23 Therefore, all cell types and organs—especially the heart—should be carefully observed with regard to medications that alter the mechanism by which insulin exerts its actions within the human body. Fortunately, agents are available to decrease the substrate supply.
We propose that targeting the source of excess fuel rather than the destination of the fuel is the appropriate way to treat hyperglycemia in patients with diabetes and heart failure. Therapeutic approaches to lowering the substrate supply are especially important in the presence of heart failure, given the alterations in cardiac metabolism.
Diet and exercise improve glycemic control in patients with type 2 diabetes, as illustrated by the findings of several meta-analyses.24 Exercise can benefit patients who already have diabetes and help to prevent type 2 diabetes in those who are at high risk. This is another example of lowering substrate supply. Given the epidemic of obesity in the United States, bariatric surgery has also had beneficial effects on glycemic control, as well as on cardiac function and metabolism. In participants in a study designed to define muscle metabolic and cardiovascular changes after bariatric surgery,25 weight loss resulted in lower fasting glucose levels and in an early reversal of maladaptive processes, through a decrease in metabolic gene expression in the patients' systemic metabolism and skeletal muscle. This suggested a reversal of insulin resistance. Furthermore, left ventricular relaxation impairment, evaluated by means of tissue Doppler imaging, became normal 9 months after bariatric surgery.25
Perhaps the best results in diabetic patients with heart failure have been obtained with metformin (1–2 g/d in divided doses) for glycemic control. Metformin decreases hepatic glucose production and decreases intestinal absorption of glucose.26 In a systematic review and meta-analysis of controlled studies evaluating antidiabetic agents and outcomes in patients with heart failure and diabetes,27 metformin was the only antidiabetic agent not associated with harm. Metformin was associated with reduced all-cause death, whereas TZDs were associated with an increased risk of hospital admission for heart failure. Results from another case-control study, nested within the General Practice Research Database cohort (United Kingdom), confirmed the benefits of trial-proven antifailure therapies in diabetic patients and supported the use of metformin-based treatments to lower glucose levels in heart-failure patients.28 Compared with patients who were not given antidiabetic drugs, the current use of metformin monotherapy or metformin with other agents was associated with lower mortality rates. Those studies suggested that the use of metformin in patients with diabetes and heart failure is both safe and effective. However, metformin was previously considered to be contraindicated in patients with heart failure, because of the potential production of lactic acidosis. In 2006, the FDA removed the heart-failure contraindication from the use of metformin, although a caution still exists.29
A retrospective cohort analysis of patients with diabetes and advanced systolic heart failure30 revealed that patients who took metformin had a trend toward improved survival, compared with those who did not take metformin. One-year survival in metformin-treated and non-metformin-treated patients was 91% and 76%, respectively (relative risk, 0.37; 95% confidence interval [CI], 0.18–0.76; P=0.007). Another study, of a national cohort of 6,185 patients with diabetes and heart failure who were being treated at Veterans Affairs Medical Centers, revealed that metformin therapy was associated with fewer deaths. The mortality rate in 232 patients who were given metformin was 16.1%, compared with 19.8% in 285 patients who were not given metformin (hazard ratio, 0.76; 95% CI, 0.63–0.92; P <0.01).31 Metformin is first-line therapy for noninsulin-dependent diabetes, but its use in patients with heart failure has been limited. Although an added benefit clearly appears to exist, there is still a need for prospective trials that involve the use of metformin in patients with heart failure.
Glucagon-like peptide (GLP-1) analogs such as exenatide (Byetta®, Amylin Pharmaceuticals, Inc.; San Diego, Calif) (FDA-approved in 2005) and dipeptidyl peptidase 4 (DPP-4) inhibitors such as sitagliptin (Januvia®, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Whitehouse Station, NJ) (FDA-approved in 2006) appear promising in that they augment the pancreatic response to meals, decrease gastric emptying, and reduce glucose levels without cardiovascular risk.32–34 Alpha-glucosidase inhibitors such as acarbose inhibit the upper-gastrointestinal enzymes that convert complex polysaccharide carbohydrates into monosaccharides. This slows the absorption of glucose and results in a slower rise in postprandial glucose levels.35 Sodium-glucose cotransporter 2 (SGLT-2) is the major cotransporter involved in glucose reabsorption in the kidney. Clinical trials are currently under way to investigate the safety and efficacy of SGLT-2 inhibitors such as dapagliflozin.36,37 Finally, centrally acting drugs may be effective. Although traditionally used to treat Parkinson's disease and pituitary tumors, bromocriptine is a dopamine agonist approved by the FDA in 2009 as therapy for type 2 diabetes under the trade name Cycloset® (VeroScience LLC; Tiverton, RI).38,39 The aforementioned therapies all have one thing in common: they lower the substrate supply without promoting substrate uptake. Table I shows these therapeutic approaches.
Insulin resistance, type 2 diabetes mellitus, and heart failure are the result of complex pathophysiologic derangements. As insulin-sensitizing agents, TZDs have many effects on metabolic homeostasis. We suggest that the consequence of fuel overload in the heart-muscle cell is an imbalance of increased substrate uptake and decreased substrate oxidation. In this context, it is also reasonable to assume that the end consequence is worsening heart failure. We propose, therefore, that glucose-lowering therapies target the source, rather than the disposal, of excess fuel in heart-failure patients who have diabetes mellitus.
We thank Roxy Ann Tate for expert editorial assistance.
Address for reprints: Heinrich Taegtmeyer, MD, DPhil, Department of Internal Medicine, Division of Cardiology, UT Medical School at Houston, 6431 Fannin St., MSB 1.246, Houston, TX 77030
Work in the laboratory of Dr. Taegtmeyer is supported in part by grants from the National Heart, Lung, and Blood Institute (HL061483 and HL073162) and the American Heart Association (09POST2060155).