STATE-OF-THE-ART PAPER
Cardiovascular Therapies and Associated Glucose HomeostasisImplications Across the Dysglycemia Continuum
Rhonda M. Cooper-DeHoff, PharmD, MS*,*,
Michael A. Pacanowski, PharmD, MPH and
Carl J. Pepine, MD, MACC*
* Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, Florida
Department of Pharmacy Practice and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida
Manuscript received April 7, 2008;
revised manuscript received October 27, 2008,
accepted October 28, 2008.
* Reprint requests and correspondence: Dr. Rhonda M. Cooper-DeHoff, Division of Cardiovascular Medicine, University of Florida College of Medicine, P.O. Box 100277, Gainesville, Florida 32610-0277 (Email: dehofrm{at}medicine.ufl.edu).
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Abstract
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Certain cardiovascular drugs have adverse effects on glucose homeostasis, which may lead to important long-term implications for increased risks of adverse outcomes. Thiazide diuretics, niacin, and beta-adrenergic blockers impair glucose homeostasis. However, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have demonstrated beneficial metabolic effects. The newer vasodilating beta-blocking agents and calcium antagonists appear to be metabolically neutral. These considerations, in addition to meticulous attention to blood pressure control and lifestyle changes, have the potential to beneficially modify glycemia and long-term risks. These considerations have particular importance in younger patients who may also have pre-diabetes or the metabolic syndrome and who are likely to require therapy over the course of decades.
Key Words: metabolic syndrome • pre-diabetes • thiazide diuretic • dysglycemia • glucose homeostasis
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Abbreviations and Acronyms
| | ACE = angiotensin-converting enzyme | | ARB = angiotensin receptor blocker | | BP = blood pressure | | CAD = coronary artery disease | | CHD = coronary heart disease | | CV = cardiovascular | | HDL-C = high-density lipoprotein cholesterol | | IFG = impaired fasting glucose | | IGT = impaired glucose tolerance | | MetSyn = metabolic syndrome | | RAAS = renin-angiotensin-aldosterone system |
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Diabetes is a leading cause of cardiovascular (CV) morbidity and mortality worldwide, and in the U.S. it is associated with an estimated cost of $174 billion annually (1). Patients with diabetes have increased risk for coronary heart disease (CHD), CHD-related death, and stroke compared with those without diabetes (2). Among those with established CHD, the risk for adverse outcomes (e.g., death, myocardial infarction, or stroke) increases approximately 2- to 4-fold (3,4). Characteristics of patients at risk for developing diabetes include race, ethnicity, increased body mass index, left ventricular hypertrophy, stroke, and elevated blood pressure (BP) (5–7). It is now increasingly recognized that dysmetabolic states, such as metabolic syndrome (MetSyn), especially when elevated glucose is present, also increase CV risk, although as will be discussed, to a lesser extent than diabetes. These states often progress to diabetes. Indeed, hypertension, diabetes, and coronary artery disease (CAD), both diagnosed and undiagnosed, frequently coexist, particularly when the diagnoses are broadened to include pre-hypertension, atherosclerosis, and pre-diabetes (Fig. 1). Pre-diabetes was introduced not only in the hopes of making the concepts of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) more understandable to the lay audience, but also in the hope that increased attention to the consequences of diabetes could perhaps forestall its development. Ultimately, however, the concept of pre-diabetes must relate to identification and management of patients at risk for CHD.
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Figure 1 Cardiovascular Disease: Coincidence of Hypertension, Coronary Artery Disease, and Diabetes
Inner circles and outer circles represent diagnosed and undiagnosed hypertension, coronary artery disease, and diabetes, respectively. Areas and their overlaps are roughly proportional to estimated prevalence of these conditions in the U.S. population. The larger outer area represents incidence of metabolic syndrome, which includes pre-hypertension, pre-diabetes, and dyslipidemia. Data from the American Heart Association (2) and the Centers for Disease Control and Prevention (10).
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Concept of Pre-Diabetes
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Pre-diabetes is a relatively common condition characterized by either IFG (fasting plasma glucose of 100 to 125 mg/dl) or IGT (2-h plasma glucose of 140 to 199 mg/dl after a 75-g glucose load) (8). Among U.S. adults ages 40 to 74 years between 1988 and 1994, approximately 15% had IGT and approximately 34% had IFG. Projecting these rates onto the total U.S. population in 2007, an estimated 54 million adults have pre-diabetes (9), which is an approximate increase of >10 million people since 2000 (10).
Impaired fasting glucose is a component of MetSyn, which is a constellation of risk factors including abdominal adiposity, hyperglycemia, hypertension, and dyslipidemia (11). The risk of developing diabetes is increased 3- to 5-fold when MetSyn is present (12), and CV disease risk in patients with MetSyn is increased 1.5- to 3.5-fold compared with those without MetSyn (13,14). Hyperinsulinemia and insulin resistance, defined as a failure of target organs to respond normally to insulin, may be important in the pathogenesis of, and often coexist with, hypertension, obesity, and diabetes (15,16). The prevalence of MetSyn is estimated at 25% in the U.S., and prevalence increases with age. In people age 20 to 29 years, the prevalence was 6.7% compared with people age 60 to 69 years, in whom the prevalence was 43.5% (17).
At the vascular wall level, hyperglycemia decreases the bioavailability of nitric oxide and prostaglandin I2 and increases synthesis of vasoconstrictor prostanoids and endothelin via multiple mechanisms (18). The resultant vascular dysfunction has important functional and structural consequences as discussed elsewhere in this supplement. There is controversy regarding the degree to which pre-diabetes alone increases CV risk. There are data indicating no increase in CV risk associated with either IFG or IGT (19) and data that suggest the CV risk associated with pre-diabetes is lower than that associated with diabetes (20,21). However, many studies indicate that like diabetes, pre-diabetes (alone or in combination with MetSyn) is associated with a significant increase in CV morbidity and mortality (22–25). These controversial findings may relate to varying levels of risk in the cohorts followed, as well as varying follow-up durations.
Unfortunately, many drugs used in the management of CV disease or its risk conditions can affect glucose and lipid homeostasis, and insulin resistance is an important mediator of these metabolic effects. Although length of follow-up and exact metabolic outcome in many of the reports vary, the results are consistent. For instance, diuretics, beta-blockers, and niacin have adverse metabolic effects that may precipitate diabetes development in those with pre-diabetes, but the renin-angiotensin-aldosterone system (RAAS) antagonists may have beneficial effects that may delay or prevent the development of diabetes. A recent network meta-analysis of hypertension clinical trials ranked the association of antihypertensive agents with incident diabetes as lowest for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), followed by calcium antagonists, which appear neutral, and highest for beta-blockers and diuretics (26). There was no significant difference in the odds ratio for diabetes development comparing diuretics and beta-blockers (26). The presence of diabetes or pre-diabetes, especially in the presence of the risk factors associated with MetSyn, should be considered when choosing CV therapies.
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CV Agents With Unfavorable Metabolic Effects
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Thiazide diuretics.
Thiazide diuretics have been available for the treatment of hypertension since the late 1950s, and reports of thiazide-associated hyperglycemia began appearing shortly thereafter (27,28). However, benzothiadiazine derivatives (hydrochlorothiazide most commonly) continue to be recommended as first-line therapy for hypertension without regard to metabolic status (29). The American Diabetes Association, in its recently published standards, suggests treatment of hypertension and other CV disease risk factors to prevent and/or delay type 2 diabetes, but makes no mention of which antihypertensive agents should be preferentially used (8). Data from a number of large hypertensive treatment trials, as well as epidemiologic data from large cohort studies, have associated a new diagnosis of diabetes with hypertension treatment that contains a thiazide diuretic, including chlorthalidone (30,31), hydrochlorothiazide (32,33), and bendroflumethiazide (34). Although there is not uniform agreement on the long-term significance of diuretic-induced diabetes (35), the controversy seems more about the relative benefits from improved BP control offset by the consequences of worsening metabolic status related to the thiazide diuretic. Data from ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) study suggest there may be no increased risk for CV outcomes in those with chlorthalidone-induced dysglycemia or diabetes (36). However, lack of documented increased risk for adverse outcomes is not the same as proof that risk for adverse outcomes is not increased with thiazides. In many situations, their effective reduction in BP and favorable adherence profile likely obscured such adverse effects. Also, the failure of increased risk to emerge may be related to the relatively short follow-up period (37) and lack of power to detect a difference in outcomes in this subset of patients, because ALLHAT was not designed a priori to make this comparison (33,38). Indeed, less than one-quarter of the patients had a fasting glucose measured during follow-up and the patient sample used for this analysis included 3 times more patients taking chlorthalidone than the ACE inhibitor, with only about 3 years of follow-up. In patients followed for 15 years, diabetes associated with diuretic use was linked with significant CV risk (32). Recent data add to the growing evidence documenting additional adverse outcomes (e.g., heart failure and atrial fibrillation) related to incident diabetes associated with use of antihypertensive regimens containing a diuretic and/or beta-blocker (39).
Although the mechanism of thiazide-induced glucose elevation may not have been well understood in the late 1950s, a significant inverse relationship between potassium and glucose levels in which lower blood potassium levels are associated with higher glucose values has been documented (40). There is an association between hypokalemia and impaired insulin secretion that may partially explain this inverse relation (41), but this is unlikely to be the only mechanism. Although it has been suggested (40,42) that maintenance of potassium homeostasis by supplementation or concomitant use of an ACE inhibitor or ARB may reduce or prevent the glucose increases associated with thiazide diuretics, this has not been prospectively evaluated in patients with pre-diabetes or MetSyn. We have observed that an ACE inhibitor is protective in hypertensive CAD patients taking a calcium antagonist but not a beta-blocker plus diuretic at low or moderate doses (Fig. 2) (6). Importantly, it is not known if potassium supplementation modifies the increased risk for diabetes associated with thiazide diuretics. To this end, the National Heart, Lung, and Blood Institute has constituted a working group to develop a clinical trial initiative to better elucidate the relationship between glucose, potassium, and thiazide-induced diabetes (41).
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Figure 2 Risk of Diabetes by Base- and Added-Strategy Drug Dose in Hypertensive Coronary Artery Disease Patients
Reference (hazard ratio [HR]: 1.0) = atenolol 50-mg/day monotherapy. Data from the INVEST (International Verapamil SR-Trandolapril Study) trial (6). CI = confidence interval; HCTZ = hydrochlorothiazide; SR = sustained release.
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A main concern of CV specialists is the use of agents that have a negative impact on glucose homeostasis in hypertensive and/or other vascular disease patients, who may also have pre-diabetes or MetSyn. This concern is most relevant when these patients are relatively young, have a lengthy life expectancy, and perhaps may be most susceptible to worsening glucose tolerance secondary to diuretics. These patients are likely to receive thiazide diuretics for decades, and the implications of diuretic-induced diabetes may not be fully understood in the relatively short-term clinical trial data available to date (43). When a thiazide diuretic is required for BP reduction, close attention should be paid to glucose homeostasis, with recognition that pharmacologic management of glucose may be required (44).
Beta-blockers.
Beta-adrenergic blockers have also long been recommended as first-line therapy for the treatment of hypertension (29) and CAD. However, like thiazide diuretics, beta-blockers have been implicated in altering glucose homeostasis, primarily through inhibition of pancreatic insulin secretion and promoting insulin resistance (45,46). Beta-receptor selectivity appears to play a role in the degree of downstream metabolic effects, which include not only glucose increases but also weight gain and dyslipidemia. Although nonselective and higher-dose selective agents result in the largest adverse metabolic changes (47), vasodilating beta-blockers (e.g., nebivolol and carvedilol) appear to minimally affect glucose homeostasis and improve insulin sensitivity (47–49). These adverse metabolic effects, in combination with limited data supporting beneficial antihypertensive effects of beta-blockers as first-line or monotherapy for uncomplicated hypertension, have led to the suggestion that beta-blockers be reserved for the treatment of complicated hypertension, heart failure, arrhythmia, and post-myocardial infarction patients (50).
A recent meta-analysis of beta-blockers and new-onset diabetes in almost 95,000 patients (51) and a network meta-analysis in over 143,000 patients (26) from hypertension trials document the relative diabetogenic effect of beta-blockers when given alone or with other agents, which is often the case among patients with CV disease. In both analyses, beta-blockers were similarly diabetogenic compared with thiazide diuretics and much more so compared with ACE inhibitors, ARBs, which were beneficial in this regard, and calcium antagonists, which were neutral.
Niacin.
Hypertensive, MetSyn, and CAD patients often have reduced high-density lipoprotein cholesterol (HDL-C), and former guidelines for the care of these patients included niacin (nicotinic acid) in the hope that it may reduce morbidity and mortality by raising HDL-C (22). However, in current guidelines, niacin is only recommended for reduction of triglycerides >500 mg/dl or as a last resort for reducing non–HDL-C (52). Niacin's action on insulin resistance, dysglycemia, and diabetes control is very potent and well recognized (53). Although beneficial effects of niacin on lipids have been shown in populations with MetSyn, diabetes, and atherosclerosis (54,55), worsening glycemic control remains a concern over the long term and modifications in antidiabetic medications will likely be necessary to maintain adequate glucose control. Among participants in the HATS (HDL-Atherosclerosis Treatment Study) trial without diabetes or IFG at baseline, 2.4% and 9.7% developed diabetes and IFG, respectively, during the study, although this was not statistically significant (56). Although niacin has been shown to be beneficial in post-myocardial infarction patients (57), in the absence of atherosclerotic CV disease, documented benefits of HDL-C raising with niacin are lacking; thus niacin should not be used in patients with MetSyn but without atherosclerosis.
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CV Agents With Favorable Metabolic Effects
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RAAS antagonists.
The RAAS has been implicated in glucose and insulin regulatory pathways (25,58), and inhibition of the RAAS by ACE inhibitors and ARBs has been associated with prevention of diabetes in many randomized trials of hypertensive, heart failure, and high-risk patients (33,59,60). These data prompted the DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) study, a clinical trial of diabetes prevention with ramipril. In >5,000 MetSyn patients followed for 3 years, almost three-quarters of whom had pre-diabetes at baseline (either IFG [28%], IGT [57%], or both [28%]), treatment with ramipril was associated with a significant increase in regression to normoglycemia, although ramipril did not significantly reduce the incidence of new diabetes (61). Because the DREAM study was stopped early, the 3-year follow-up period may have been insufficient time to detect a significant difference in the already developing trend of new-onset diabetes reduction observed.
Direct renin inhibitors, the newest agents in the RAAS antagonist class of medications, are effective alone and in combination with either ACE inhibitors or ARBs for BP lowering in those with and without diabetes. However, there are no published data at this time indicating their effects on glucose and insulin regulatory pathways, or on diabetes prevention.
Recently, aldosterone has been implicated in the insulin regulatory pathway, impairing insulin signaling by down-regulating insulin receptor substrate-1 in vascular smooth muscle cells (62). Local aldosterone has also been implicated in worsening vascular disease. Whether there is a causal relationship between aldosterone and insulin resistance and/or hyperinsulinemia is unclear, but there is evidence that aldosterone may worsen pre-existing alterations in glucose homeostasis, as in those with MetSyn (63). Although there are currently limited data evaluating the effects of aldosterone blockade on glucose or insulin homeostasis, use of aldosterone antagonists for the treatment of resistant hypertension in patients with pre-diabetes or MetSyn may be beneficial. The mild diuretic effect of spironolactone may be useful to avoid the need for hydrochlorothiazide or to help reduce the dose of hydrochlorothiazide. More research is needed to better understand the role of these agents in improving glucose homeostasis.
Antianginal agents.
Diabetes is a frequent comorbidity in patients with CAD, many of whom also have chronic stable angina and at least one-half of these angina patients have less than optimal BP control. In a cohort of 22,000 CAD patients followed for about 3 years, presence of diabetes independently predicted an almost doubling (14.3% vs. 8.4%) in the rate of death, nonfatal myocardial infarction, or nonfatal stroke (3). Although use of multiple antidiabetic agents is common in diabetes patients with CAD and chronic angina, diabetes control is often lacking.
The short- and long-term metabolic effects of ranolazine, a late sodium current blocker antianginal agent, have recently been explored. After 12 weeks of ranolazine (750 or 1,000 mg) daily in patients with diabetes and chronic angina, glycated hemoglobin levels were significantly reduced while fasting glucose and lipids remained unchanged from baseline (64). In the diabetic cohort of another ranolazine study in patients with acute coronary syndromes with average follow-up of 1 year (65), treatment with ranolazine was again associated with significant improvement in glycated hemoglobin. In the nondiabetic cohort, the incidence of an increased fasting glucose value was reduced (66). The beneficial antianginal and metabolic effects, in patients with and without diabetes, achieved with ranolazine suggest that this agent is a good choice for CAD patients with diabetes or at risk for diabetes (67). These data resulted in a recent change in FDA-approved labeling for ranolazine, with the inclusion of the statement ". . . produces small reductions in HbA1c in patients with diabetes, the clinical significance of which is unknown, . . . should not be considered a treatment for diabetes." The mechanism of this benefit is also unclear, but in vitro and animal studies suggest ranolazine may increase glucose-stimulated insulin secretion and this may be responsible for the improved glucose homeostasis observed (68).
Other agents.
Moxonidine is a selective imidazole II-receptor agonist that lowers BP by a central mechanism but also has been shown to have dose-dependent metabolic effects including reduction in glucose, insulin, and glycated hemoglobin in those with diabetes and MetSyn (69,70).
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Conclusions
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The prevalence of pre-diabetes and diabetes continues to increase, driven largely by obesity and physical inactivity. Because of the CV consequences of these conditions, attention to drugs that may worsen dysglycemia is important. The European Society for Hypertension/European Society of Cardiology are no longer endorsing thiazide diuretics or beta-blockers in hypertensive patients with diabetes (71) and the American Association of Clinical Endocrinologists recommends thiazide diuretic use only at low dosage and only with adequate potassium replacement and beta-blocker use only as second- or third-line agents in patients with diabetes (72). The National Institute for Health and Clinical Excellence, together with the British Hypertension Society, recently published guidelines that indicate beta-blockers are no longer a suitable first-line treatment option in uncomplicated hypertensive patients largely due to increased incident diabetes (73). They also recommend use of RAAS inhibitors as first-line therapy in younger patients, with diuretics reserved for the elderly or black patients of any age (73). While thiazide diuretics remain an inexpensive antihypertensive choice, the long-term costs of diabetes that may result far outweigh the short-term medication cost savings.
While BP control in patients with diabetes is important for prevention of CV outcomes (74), BP control is also important for lowering risk of diabetes development. Observational data indicate that on-treatment systolic BP is an important independent predictor of incident diabetes (32), and we confirmed this in a randomized clinical trial (Fig. 3) (6). For patients in whom BP control is difficult, especially diabetics, thiazide diuretics and beta-blockers remain a necessary antihypertensive option; however, they should be used at as low a dose as possible and in combination with other antihypertensives. For patients with a recent myocardial infarction, heart failure, or refractory angina, beta-blockers remain a treatment of first choice; however, metabolic status should be monitored closely in patients with diabetes and at risk for diabetes.
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Figure 3 Relationship Between Follow-Up Systolic BP and Development of Diabetes
Unadjusted relative hazard is shown (triangles) for follow-up systolic blood pressure (BP) (mean of measurements before diabetes development or censoring) with reference (hazard ratio: 1.0) of 130 mm Hg, the cut-off for metabolic syndrome. With multivariable adjustment, this relationship persists. Data from the INVEST (International Verapamil SR-Trandolapril Study) trial (6).
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With the exception of perindopril, all of the ACE inhibitors approved for use in the U.S. are now available in a generic formulation, making them both cost-effective and metabolically beneficial alternative antihypertensive agents. While generic lisinopril ranked number 2 with 62 million prescriptions, generic hydrochlorothiazide and atenolol ranked 5 and 7 in the list of the top 200 generic drugs prescribed in the U.S. for 2007, totaling 46 million and 42 million prescriptions, respectively (75).
Those with dysglycemia are likely destined to head down the path of diabetes development. Early identification of coincident hypertension and dyslipidemia is imperative. Treatment consideration should be given not only to the immediate effects of BP or angina reduction, but also to the longer term implications the medications have on the tenuous metabolic pathways across the dysglycemia continuum.
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Footnotes
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This work supported in part by National Institutes of Health grant (5K23HL086558). Drs. Cooper-DeHoff and Pacanowski have no conflicts of interest to report. Dr. Pepine has received grant/research support from or has consultant agreements with AstraZeneca, Boehringer Ingelheim, CV Therapeutics Inc, Pfizer Inc, sanofi-aventis, Schering-Plough, Daiichi Sankyo Inc, Eli Lilly and Company, and Merck & Co. Inc.
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