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Cardiovascular risks and benefits with oral drugs for Type 2 diabetes mellitus Expert Rev. Clin. Pharmacol. 7(2), 225–233 (2014)
Emily Weidman-Evans*1,2, Steven M Metz3, Jeffery D Evans1,2 1 Department of Clinical and Administrative Sciences, University of Louisiana at Monroe College of Pharmacy, Louisiana 71201, LA, USA 2 Department of Family Medicine and Comprehensive Care, Louisiana State University Health-Shreveport, 1725 Claiborne Avenue, Shreveport, Louisiana 71103, LA, USA 3 University of Louisiana at Monroe College of Pharmacy, Louisiana 71201, LA, USA *Author for correspondence: Tel.: +1 318 632 2007 (Extn. 231) [email protected]
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Type 2 diabetes mellitus affects approximately 321 million people worldwide. It is estimated that about half of these patients will die from cardiovascular complications. In spite of these statistics, medications for diabetes are approved based not on outcomes, but on surrogate markers such as blood glucose or glycosylated hemoglobin. In recent years, however, the safety of diabetes medications has come under scrutiny, and more studies are being undertaken to determine the effect(s) of the medications on actual outcomes. In this review the authors review available study results for all of the currently approved classes of oral medications for Type 2 diabetes, and discuss the possible mechanisms for the findings. More studies are necessary for many of these classes, however, to make definitive recommendations regarding their cardiovascular effects. KEYWORDS: cardiovascular risk • diabetes • drugs • rosiglitazone • Type 2
Diabetes mellitus (DM) is a common and complicated condition that affects an estimated 347 million people worldwide [1]. About 90% of these have Type 2 DM. The WHO anticipates that DM will be the seventh leading cause of death by the year 2030, with about half of those diagnosed with the condition dying from cardiovascular complications such as myocardial infarction (MI) or stroke. There is strong evidence that aggressively lowering blood glucose into the target range will decrease the incidence of the microvascular complications of DM – nephropathy, retinopathy and neuropathy [2,3]. However, the data supporting a link between blood glucose control and cardiovascular or macrovascular disease are much more tenuous. After at least 10 years of follow-up, the UK Prospective Diabetes Study showed a reduction in MI related to glucose lowering [4]. However, other large trials have suggested that lowering blood glucose to near-normal or even optimal levels do not reduce cardiovascular events. The Veterans Affairs Diabetes Trial showed no difference in time to major cardiovascular event when A1c was lowered by 1.5% [5]. The Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Trial demonstrated a
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significant reduction in the combined end point of microvascular and macrovascular outcomes, but, when analyzed separately, this difference stemmed almost entirely from a reduction in nephropathy [3]. There was no difference in cardiovascular events. The Action to Control Cardiovascular Risk in Diabetes study was discontinued after 3.5 years due to a higher rate of death, from both any cause and cardiovascular causes, in those patients whose blood glucose was intensively managed, although no difference in the primary end point of major cardiovascular events was seen prior to study discontinuation [6]. (It is interesting to note that there was a statistically significant decrease in nonfatal MI in the intensively managed group in this study). In spite of this apparent lack of relationship between glucose lowering and cardiovascular outcomes, the majority of Phase III drug trials involve only the degree of glycated hemoglobin (HbA1c) lowering and are of much too short a duration (~12 months) to determine if the drug improves cardiovascular outcomes. In response to potential adverse effects seen with rosiglitazone (which will be discussed later), in 2008, the US FDA released its recommendations that manufacturers of new therapies for Type 2 DM provide evidence that their
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therapy will, at best, improve glucose control without increasing cardiovascular risk [7]. Ideally, though, blood glucose and cardiovascular complications will both be reduced as new therapies are developed. There are many measurable risk factors of cardiovascular disease associated with the insulin resistance of Type 2 DM, including endothelial function/hemostasis, dyslipidemia, hypertension and inflammation [8]. The goal of this review is to evaluate the currently available antihyperglycemic agents, their effect on actual cardiovascular outcomes and the potential mechanisms of these outcomes outside of their effects on blood glucose control. Metformin
Metformin is generally considered the preferred first-line treatment option for Type 2 diabetes, provided that no contraindications to therapy are present [9,10]. Metformin’s primary mechanism is via a decrease in hepatic glucose production, through hepatic insulin sensitization and/or inhibiting key enzymes in the gluconeogenesis pathway. It improves glucose tolerance by decreasing the absorption of glucose in the intestines and production in the liver. Improved insulin sensitivity also results in increased uptake and utilization of glucose in the periphery [11]. In 2008, the UK Prospective Diabetes Study long-term follow-up study found that metformin caused significant reductions in several outcomes compared with lifestyle intervention alone. It found that 122 patients must be treated for a year to prevent one diabetes-related event; 257 to prevent one MI; and 139 patients to prevent one death from any cause. This helped to solidify metformin’s place as first-line therapy [4]. There are several proposed mechanisms for this improvement in cardiovascular outcomes, based upon known risk markers. None of these hypotheses has been definitively proven, but all may contribute to the apparent cardiovascular benefits of metformin. It is generally thought that metformin has its beneficial effects via improvement of endothelial function and inflammation. This is supported by a study by de Jager et al., which found that metformin use significantly reduced the concentrations of von Willebrands factor, soluble cellular adhesion molecules (sVCAM-1 and sICAM-1), tissue plasminogen activator and plasminogen activator inhibitor-1 [12]. Metformin has also been shown to have beneficial effects on the lipid profile of patients with insulin resistance, reducing LDL by about 10% and increasing HDL by about 20% [8]. The magnitude of the change is dependent upon baseline values, so those patients with higher baseline values have a greater improvement. Metformin may also have direct cardiac effects. Animal studies have shown that metformin improves chronic AMPactivated protein kinase activation and cardiac autophagy, both of which help to preserve cardiac function in diabetic mice [13]. It is also through this AMP-activated protein kinase activation that metformin is thought to confer its anti-inflammatory effects, independent of blood glucose-lowering effects. Another study utilized tissue Doppler imaging in patients with diabetes 226
to assess improvement in left ventricular diastolic function while on metformin [14]. The study found that patients on metformin had a lower isovolumic relaxation time and slightly higher early diastolic longitudinal tissue velocity. Both of these factors come into play during the early part of diastole, where myocardial relaxation occurs (a very high energy process), and reflect the left ventricular relaxation rate. In spite of its established role in therapy and these positive effects on markers for cardiovascular risk, some questions have begun to emerge regarding metformin’s effect on actual cardiovascular outcomes. A large meta-analysis from 2009 that included only studies of 1 year or more duration found that metformin therapy did significantly reduce cardiovascular mortality compared with placebo or no therapy (MH-OR: 0.79 [95% CI: 0.64–0.98], p = 0.031), but not when compared with another active drug [15]. The authors concluded that these results show that it is the glucose-lowering ability of metformin that had positive effects on cardiovascular outcomes and not other mechanisms. Two other meta-analyses showed no effect of metformin therapy on cardiovascular morbidity or mortality [16,17]. At this time, however, it is still generally accepted that metformin has beneficial cardiovascular effects. Sulfonylureas
Sulfonylureas are one of the oldest and most well-established classes in the treatment of Type 2 DM. They are generally considered one of the ‘second-line’ agents from which to choose after metformin [9]. They work by blocking ATP-dependent K+ channels, leading to induce insulin secretion from the b-cells in the pancreas, and can result in hypoglycemia and weight gain, both of which are risk factors for cardiovascular events or disease, independent of DM [10,18,19]. In 1970, it was found that tolbutamide increased the incidence of cardiovascular mortality [20]. Since that time, tolbutamide and all subsequent drugs in this class have carried a black box warning on their official FDA labeling that warns of the potential risk for increased cardiovascular mortality. However, there is much controversy as to whether the effect is a classwide effect or specific to tolbutamide itself. A well-designed meta-analysis from 2013 showed no difference in cardiovascular death or MI even when compared with metformin. There was, however, an increase in overall all-cause mortality (MH-OR: 1.22 [95% CI: 1.01–1.49]; p = 0.047) and stroke (MH-OR: 1.28 [95% CI: 1.03–1.60]; p = 0.026) [18]. The individual trial designs and results vary greatly, though, and many do report negative cardiovascular outcomes. The authors point out that most included trial only reported the overall mortality and not the cause (cardiovascular or otherwise). The hypothesis as to why potential increases in negative cardiovascular outcomes occur with sulfonylureas involves the protective process of ischemic preconditioning, which is a cycle of sublethal myocardial ischemia and brief periods of reperfusion. When this occurs prior to a prolonged period of ischemia, infarct size is reduced and tissue damage minimized [21]. Older, nonspecific sulfonylureas such as tolbutamide and glyburide Expert Rev. Clin. Pharmacol. 7(2), (2014)
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Cardiovascular risks & benefits with oral drugs for Type 2 DM
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June – Rosiglitazone (Avandia™) approved by the US FDA
1999
May – Nissen et al. meta-analysis. Increased incidence of MI, but not CV mortality [35]
2007
2008
June – RECORD trial published. No increase in CV death. Could not rule out link to MI [36]
2009
June – FDA black box warning re: CV events
June – FDA REMS program, limiting use to those already taking rosiglitazone or those for whom other drugs were not effective [37]
2010
2011
July – Nissen & Wolski metaanalysis, including RECORD data. Same results as 2007 metaanalysis [38]
June – RECORD reanalysis. Same results as original [39]
2012
November – FDA removes restrictions to access [42]
2013
June – FDA subcommittees† meet and vote to relax the restrictions of the REMS program [40]
Figure 1. Rosiglitazone: research and policy. † Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. CV: Cardiovascular; MI: Myocardial infarction; REMS: Risk Evaluation and Mitigation Strategy.
(glibenclamide) seem to negate this protective effect by blocking the K+ channel in the myocardium [19,22]. Based upon animal models, the benefits of ischemic preconditioning seem to be maintained with newer, pancreatic-specific sulfonylureas, such as glimepiride and gliclazide (not available in the USA) [23,24]. This is supported by some retrospective studies comparing these newer agents to glyburide, which show that glimepiride or gliclazide has lower rates of cardiovascularrelated outcomes [25,26]. On the other hand, another cohort study matched patients treated with glyburide at the time of their hospitalization for MI or percutaneous coronary intervention to patients treated with gliclazide and found no difference in their composite endpoint of death or hospitalization for MI or heart failure [27]. Of note, there is some controversy regarding combining a sulfonylurea with metformin. The results of two meta-analyses show that the combination may actually increase cardiovascular mortality [15,28], while other observational studies designed specifically for this aim show no increased risk [29,30]. One case–control study even suggests that the combination lowers the risk of cardiovascular mortality compared with sulfonylurea therapy alone [31]. Overall, sulfonylureas are likely a safe option for most patients with Type 2 DM (alone or in combination with other drugs), except for those with unstable angina pectoris, acute MI or undergoing elective angioplasty [32]. Using the newer, more selective drugs in the class, such as glimepiride, should be recommended. Thiazolidinediones
The two currently available thiazolidinediones (TZDs), pioglitazone and rosiglitazone, vary greatly in their apparent cardiovascular informahealthcare.com
safety profiles. They are both selective PPARg agonists that rely on the presence of insulin in order to work [33]. By decreasing insulin resistance in the liver and periphery, pioglitazone decreases hepatic glucose output and increases insulin-dependent glucose disposal. In recent years, studies have suggested that rosiglitazone has an increased risk of negative cardiovascular effects, specifically an increased risk of MI, and raised concerns about the TZDs as a class [34]. Controversy has surrounded this alleged link between rosiglitazone and MI. In an attempt to resolve the conflict that existed between individual studies, Nissen et al. published a meta-analysis in 2007 that included 42 [35]. It showed a statistically significant increase in the incidence of MI with rosiglitazone, with a number needed to harm of about 50. There was no significant increase in cardiovascular mortality. FIGURE 1 shows the research and policy changes that followed [35–40]. The debate continued into 2013, when, at the June Joint Meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, it was voted to recommend to the FDA to relax the requirements of the REMS program for rosiglitazone [40,41]. In November 2013, the FDA lifted the restrictions for access to rosiglitazone [42]. Conversely, some studies have shown that pioglitazone actually has several positive cardiovascular effects. In the PROACTIVE study, it was found that while pioglitazone did not reduce the risk for coronary and peripheral vascular events, it did significantly reduce the risk of the composite endpoint of MI, stroke and death by 2.5% (18.4% relative; hazard ratio [HR]: 0.84 [95% CI: 0.72–0.98]; p = 0.027) [43]. These results are supported by a large meta-analysis that showed 227
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that pioglitazone is associated with a significantly lower risk of the same composite endpoint by 1.36% (24% relative; [HR]: 0.82 [95% CI: 0.72–0.94]; p = 0.005) [44]. In contrast, the PROACTIVE study and the Lincoff meta-analysis found that pioglitazone increased the incidence of hospitalization for HF (by 22 and 33%, respectively). Both rosiglitazone and pioglitazone have a black box warning for this serious problem [43,45]. Several potential causes of the cardiovascular differences between the two TZDs have been proposed. One theory addresses the selectivity of rosiglitazone for PPARg compared with PPARa. Rosiglitazone binds 200-times more to PPARg than PPARa [46]. Pioglitazone only binds between two and six-times more to PPARg than PPARa. This selectivity is apparently important, as other PPARg selective medications, such as the glitazars, have also been linked to poor cardiovascular outcomes [46], while PPARa agonists, such as fenofibrate, actually have been shown to decrease cardiovascular complications [47]. Another potential cause is the difference in lipid profiles in patients treated with rosiglitazone versus pioglitazone. One small study showed that pioglitazone decreased LDL by nearly 13.6 mg/dl (9.5%), while rosiglitazone increased it by 5.39 mg/dl (4%). Both drugs decreased the highly atherogenic VLDL, but the decrease seen with pioglitazone was much larger (33.3 vs 6.6%) [48]. Another larger and longer term study showed an increase in LDL in subjects taking both drugs, but the increase in those taking pioglitazone was significantly less than in those taking rosiglitazone (12.5 vs 21.4 mg/dl; p < 0.001) [49]. Lastly, while both of the TZDs are potent insulin sensitizers, it is possible that pioglitazone possesses stronger anti-inflammatory effects than rosiglitazone. The study by Vijay et al. showed much more pronounced decreases in both C-reactive protein (42.7 vs 27.2%) and TNFa (65.9 vs 35.4%) in those subjects taking pioglitazone [48]. As of now, the only recommendation that can be made for patients not already on rosiglitazone, but needing a potent insulin sensitizer is to start pioglitazone. Rosiglitazone is still not available in the USA except to patients who were previously on it and do not have a clear reason not to use other agents. Even though the FDA has reversed its two previous decisions about concerns over cardiovascular risk and rosiglitazone, pioglitazone is still probably a better option for most patients (without HF), as it appears to reduce cardiovascular risk as opposed to possibly increasing it. Dipeptidyl peptidase-4 inhibitors
The dipeptidyl peptidase-4 (DPP-4) inhibitors involve the first ‘new’ oral medications to be approved by the FDA for Type 2 DM since the FDA’s guidance document urging manufacturers of medications for diabetes to evaluate cardiovascular risk was released in 2008 [7]. The document also states that ‘sponsors should demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk’. 228
With a new mechanism of action, they work by increasing circulating concentrations of glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide [50]. These hormones increase glucose-dependent insulin synthesis and secretion, suppress glucagon secretion and slow gastric emptying. After gaining FDA approval based upon their glucoselowering effects, the manufacturers of the drugs within this class undertook Phase IV trials to demonstrate their cardiovascular safety. The DPP-4 inhibitors were actually expected to show positive cardiovascular outcomes in their follow-up study results. This conjecture was based upon preliminary data which showed improvement in several known cardiovascular risk factors, such as improved endothelial function, diminished oxidative stress and reduced platelet aggregation [51]. In early September 2013, the results of two of these major studies were simultaneously released. In SAVOR-TIMI 53, saxagliptin was shown to have no impact on the rate of cardiovascular death and ischemic events compared with placebo when administered with metformin [52]. However, the rate of hospitalization for HF was increased with saxagliptin from 2.8 to 3.5% (p = 0.007). In the EXAMINE study, which involved high-risk patients with a recent diagnosis of acute coronary syndrome, similar rates of cardiovascular death and ischemic events between alogliptin and placebo were shown [53]. A later post hoc analysis did show a small, nonsignificant increase in HF hospitalization in the EXAMINE study, as well. Currently, the DPP-4 inhibitors continue to have an established place as a second-line option for Type 2 DM [9,10]. While it is encouraging that the drugs in this new class did not have negative impact on their primary cardiovascular outcomes (the composite rates of ischemic events and/or cardiovascular death), it is disappointing that they did not show any improvement, either. In addition, it is unclear why hospitalizations for HF might have increased in SAVOR-TIMI 53 and EXAMINE. It is known that DPP-4 is responsible, in part, for the enzymatic inactivation of b-natriuretic peptide and also that increases in glucagon-like peptide-1 can decrease b-natriuretic peptide [51]. In light of the HF hospitalization signal found in these trials, the relationship between the DPP-4 inhibitors and this hormone (a signal for severity) may be worth further exploration. a-glucosidase inhibitors
Acarbose and miglitol are the two a-glucosidase inhibitors available in the USA. They work by competitively inhibiting the absorption of carbohydrates in the upper small bowel [54]. This leads to decreased postprandial blood glucose concentrations, which is thought to decrease cardiovascular events. They are listed among second-line agents by the American Association of Clinical Endocrinologists, but are not included in the American Diabetes Association/European Association for the Study of Diabetes Position Statement, likely due to their modest overall glucose-lowering effects, adverse effects and frequent dosing schedule. Expert Rev. Clin. Pharmacol. 7(2), (2014)
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Table 1. Cardiovascular outcomes and possible mechanisms. Drug/class
Cardiovascular outcomes
Strength of evidence
Possible mechanism of action
Metformin
Positive
Moderate/strong
Glucose lowering Improved endothelial function Decreased systemic inflammation Direct cardiac effects
Sulfonylureas
Negative (questionable)
Moderate (tolbutamide, glyburide)
Block ischemic preconditioning
Thiazolidinediones
Negative (heart failure)
Strong
Significant fluid retention
Pioglitazone
Positive
Strong
Improved lipid profile Decreased systemic inflammation
Rosiglitazone
Negative
Strong
PPAR selectivity Effects on lipid profile (LDL and triglycerides)
Dipeptidylpeptidase-4 inhibitors
Negative (questionable) (heart failure signal)
Weak (based on two preliminary postmarketing studies; awaiting final results)
Unknown
a-glucosidase inhibitors (acarbose)
Positive
Strong (compared with placebo)
Decreased postprandial blood glucose
Meglitinides
Neutral
Weak
N/A
Sodium-glucose cotransporter 2 inhibitors
Negative (questionable) (stroke signal)
Weak (based on preliminary postmarketing studies; awaiting final results)
Unknown
LDL: Low-density lipoprotein; N/A: Not applicable.
The results from the study to prevent noninsulin-dependent DM produced very promising results regarding acarbose and cardiovascular endpoints. It showed that acarbose significantly reduced the risk of MI by 2.41% (89% relative) and total cardiovascular events by 2.5% (47% relative) compared with placebo [55]. These results translate to numbers needed to treat of 207 and 135 per year. However, reduction in postprandial blood glucose was found to be a strong predictor of reduction of risk for these events. A subgroup analysis from this study also showed reduced carotid intima media thickness (cIMT) thickening over time [56]. Strengthening these results, a meta-analysis of seven studies that compared acarbose to placebo, also showed a 1.32% lower risk for MI (65% relative; [HR]: 0.36 [95% CI: 0.16–0.80]; p = 0.0120) and 3.3% lower risk for any cardiovascular event (35% relative; [HR]: 0.65 [95% CI: 0.48–0.88]; p = 0.0061). However, since the drug also lowered A1c by 0.5% more than placebo and postprandial blood glucose by 50 mg/dl, it cannot definitively be said that this effect was independent of glucoselowering effect, postprandial or otherwise [57]. The data, to date, are encouraging regarding acarbose and its positive cardiovascular effects, although the mechanism behind these effects is still unclear. As it has been found to have no effect on various biomarkers of inflammation and other cardiovascular risk factors, it is most likely that its positive effects do stem from its control of postprandial blood glucose elevations [58,59]. In spite of the relatively strong evidence available, informahealthcare.com
acarbose remains underused, likely due to its inconvenient dosing schedule and significant gastrointestinal adverse effect profile, which is unacceptable to many patients. Meglitinides
Nateglinide and repaglinide are the two drugs in the class known as meglitinides. They bind to the same receptor as, and work similarly to, the sulfonylureas, but the subsequent insulin release diminishes when circulating glucose concentrations are normal or low [60]. This glucose-dependant action and short duration make them a good therapeutic choice for patients who experience significant elevations in postprandial blood glucose values, even though they must be dosed frequently. In addition, there is significant evidence that links elevations in postprandial blood glucose to the development of coronary heart disease and cardiovascular events [61–63]. If pancreatic-specific sulfonylureas have a lower theoretical cardiovascular risk than nonspecific ones, then the meglitinides do as well. Not only do they bind to a different site on the sulfonylurea receptor, but they also have a higher affinity for pancreatic receptors than cardiac ones [64]. Repaglinide has been shown to decrease inflammatory markers (IL-6, C-reactive protein, adiponectin), platelet activation parameters (plasminogen activator inhibitor-1, soluble cellular adhesion molecules, von Willebrands factor) and components of the lipid profile (LDL and triglycerides), suggesting that it may have other cardiovascular benefits [65–67]. 229
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cIMT is associated with stroke risk, and one study showed that nateglinide decreased cIMT in drug-naı¨ve patients [68]. The decrease was determined by the degree of A1c lowering, though, which suggests that glucose control was the likely cause of the change and not another mechanism of the drug. When compared to glyburide, repaglinide decreased cIMT more, and this decrease was associated with decreased postprandial glucose, but not fasting glucose or the degree of A1c lowering [65]. A large study that specifically compared nateglinide to placebo, however, showed no difference in the incidence of stroke risk [69]. This is the only trial that has measured the effect of either meglitinide on any actual cardiovascular outcome, so it is not currently possible to say what this class’s cardiovascular effects truly are. Sodium glucose cotransporter-2 inhibitors
The newest class of oral medications for Type 2 DM is the sodium glucose cotransporter-2 (SGLT-2) inhibitors. Canagliflozin (Invokana) and dapagliflozin (Farxiga) both work primarily by inducing urinary glucose excretion via inhibition of renal glucose reabsorption by SGLT-2. They generally lower A1c by 0.5–1% and have been shown to be effective as both monotherapy and add-on therapy in lowering blood glucose [70–72]. Based on Phase III trial results, this class of medications has positive effects on cardiovascular risk factors. Both drugs provide modest, dose-dependent weight loss of about 2–4% [70,71,73,74]. Systolic blood pressure is lowered by about 5 mmHg and diastolic by about 2 mmHg [71,74]. While these decreases were found to be statistically significant, the clinical relevance is questionable, and some have suggested that these effects are simply from the diuresis that the drug causes [75]. In addition, HDL was increased by about 6% in subjects taking canagliflozin, which was found to be statistically significant. Interestingly, in this same study, LDL was also increased by about the same amount, but no statistical analysis was done to determine the significance of this change compared with placebo. There is a meta-analysis that showed no increase in overall cardiovascular events with either drug in this class of medications in the 25 studies included [72]. This is consistent with the reports made to the FDA on behalf of both drugs at the time of their approval [75,76]. There was, however, a ‘signal’ for an increase in risk during the first 30 days of therapy for both drugs. Therefore, as per FDA directive, there are currently large, long-term postmarketing cardiovascular safety studies underway for both: the CANVAS trial for canagliflozin and DECLARE-TIMI for dapagliflozin. Results are expected within the next 2–3 years [76]. Currently, there are no explanations for the potential risk seen within the first 30 days of therapy with an SGLT-2 inhibitor,
230
and it is still too soon to state what the SGLT-2’s role in therapy will be, based upon their glucose-lowering ability or cardiovascular effects. Expert commentary & five-year view
As shown from the information presented here, and summarized in TABLE 1, none of the oral medications currently available for the treatment of Type 2 DM is ideal in reducing cardiovascular risk. Based upon the currently available data, metformin should continue to be used as first-line therapy due to its significant glucose-lowering effects, as well as its apparently beneficial cardiovascular effects. Other agents with potentially positive effects, such as a glucosidase inhibitors, are only marginally effective at their overall blood glucoselowering effects and are limited by adverse effects, but might become more commonly considered as add-on therapy in those patients who can tolerate them. Pioglitazone has shown positive cardiovascular effects on one hand, but a worsening of HF on the other, so is clearly not optimal for these highrisk patients. With the FDA’s specific guidelines regarding diabetes medications and cardiovascular outcomes, there should be fewer surprises of ill effects such as were seen with rosiglitazone. However, there are some potentially alarming ‘signals’ with some of the newer agents, like the DPP-4 inhibitors and the SGLT-1 inhibitors, but these nonsignificant trends must be further explored before any conclusions can be reached. At this time, both of these drug classes are effective options for lowering blood glucose, and further ‘me-too’ agents in these classes are sure to be expected in the very near future. There are also several potential brand new targets for drugs that may have effects beyond their glucose-lowering abilities. These include a family of proteins called wnt, nicotinamide and the related forkhead transcription factors and erythropoietin [77]. (Many patients with DM are deficient in erythropoietin, and it might protect vascular cells, although it does not appear to have any effect on glucose control.) Current treatment algorithms for Type 2 DM should continue to be updated and address new cardiovascular data that are made available, to ensure that the whole patient is being treated. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Expert Rev. Clin. Pharmacol. 7(2), (2014)
Cardiovascular risks & benefits with oral drugs for Type 2 DM
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Key issues • About half of those patients diagnosed with Type 2 diabetes will die from cardiovascular complications such as myocardial infarctions (MIs) or stroke. • The relationship between blood glucose control and cardiovascular (macrovascular) complications is not well established. However, currently available medications are evaluated based solely upon their glucose-lowering ability. • Metformin is generally considered to have positive cardiovascular effects based upon the results of the UK Prospective Diabetes Study, reducing MIs and all-cause mortality. • Older, nonpancreatic-specific sulfonylureas like tolbutamide and glyburide block the protective mechanism of ischemic preconditioning, Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Michigan University on 10/11/14 For personal use only.
possibly leading to an increase in cardiovascular mortality. Avoid these in patients with unstable angina, acute MI or undergoing elective angioplasty. • Rosiglitazone has been shown to increase the incidence of MI, while pioglitazone has proven cardiovascular benefits. Both, however, increase the incidence of heart failure. The differences may stem from activity at the PPAR-g receptor, effects on the lipid profile or on the inflammatory process. • New studies showed no differences in cardiovascular death or ischemic events when the DPP4-inhibitors were compared with placebo. However, there is a signal for an increase in heart failure hospitalizations for both saxagliptin and alogliptin, so use with caution. • Acarbose, an a-glucosidase inhibitor, reduces the risk of MI and total cardiovascular events. However, adverse effects and three-times daily dosing limit its usefulness. • Canagliflozin, the newest oral medication for Type 2 diabetes, may improve several risk factors for cardiovascular disease, although long-term studies are still ongoing. Preliminary results show a possible signal for an increase in stroke risk.
decrease in cardiovascular risk and is the basis for the claims that metformin has significant cardiovascular benefits.
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Cardiovascular risks and benefits with oral drugs for Type 2 diabetes mellitus Expert Rev. Clin. Pharmacol. 7(2), 225–233 (2014)
Emily Weidman-Evans*1,2, Steven M Metz3, Jeffery D Evans1,2 1 Department of Clinical and Administrative Sciences, University of Louisiana at Monroe College of Pharmacy, Louisiana 71201, LA, USA 2 Department of Family Medicine and Comprehensive Care, Louisiana State University Health-Shreveport, 1725 Claiborne Avenue, Shreveport, Louisiana 71103, LA, USA 3 University of Louisiana at Monroe College of Pharmacy, Louisiana 71201, LA, USA *Author for correspondence: Tel.: +1 318 632 2007 (Extn. 231) [email protected]
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Type 2 diabetes mellitus affects approximately 321 million people worldwide. It is estimated that about half of these patients will die from cardiovascular complications. In spite of these statistics, medications for diabetes are approved based not on outcomes, but on surrogate markers such as blood glucose or glycosylated hemoglobin. In recent years, however, the safety of diabetes medications has come under scrutiny, and more studies are being undertaken to determine the effect(s) of the medications on actual outcomes. In this review the authors review available study results for all of the currently approved classes of oral medications for Type 2 diabetes, and discuss the possible mechanisms for the findings. More studies are necessary for many of these classes, however, to make definitive recommendations regarding their cardiovascular effects. KEYWORDS: cardiovascular risk • diabetes • drugs • rosiglitazone • Type 2
Diabetes mellitus (DM) is a common and complicated condition that affects an estimated 347 million people worldwide [1]. About 90% of these have Type 2 DM. The WHO anticipates that DM will be the seventh leading cause of death by the year 2030, with about half of those diagnosed with the condition dying from cardiovascular complications such as myocardial infarction (MI) or stroke. There is strong evidence that aggressively lowering blood glucose into the target range will decrease the incidence of the microvascular complications of DM – nephropathy, retinopathy and neuropathy [2,3]. However, the data supporting a link between blood glucose control and cardiovascular or macrovascular disease are much more tenuous. After at least 10 years of follow-up, the UK Prospective Diabetes Study showed a reduction in MI related to glucose lowering [4]. However, other large trials have suggested that lowering blood glucose to near-normal or even optimal levels do not reduce cardiovascular events. The Veterans Affairs Diabetes Trial showed no difference in time to major cardiovascular event when A1c was lowered by 1.5% [5]. The Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Trial demonstrated a
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significant reduction in the combined end point of microvascular and macrovascular outcomes, but, when analyzed separately, this difference stemmed almost entirely from a reduction in nephropathy [3]. There was no difference in cardiovascular events. The Action to Control Cardiovascular Risk in Diabetes study was discontinued after 3.5 years due to a higher rate of death, from both any cause and cardiovascular causes, in those patients whose blood glucose was intensively managed, although no difference in the primary end point of major cardiovascular events was seen prior to study discontinuation [6]. (It is interesting to note that there was a statistically significant decrease in nonfatal MI in the intensively managed group in this study). In spite of this apparent lack of relationship between glucose lowering and cardiovascular outcomes, the majority of Phase III drug trials involve only the degree of glycated hemoglobin (HbA1c) lowering and are of much too short a duration (~12 months) to determine if the drug improves cardiovascular outcomes. In response to potential adverse effects seen with rosiglitazone (which will be discussed later), in 2008, the US FDA released its recommendations that manufacturers of new therapies for Type 2 DM provide evidence that their
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therapy will, at best, improve glucose control without increasing cardiovascular risk [7]. Ideally, though, blood glucose and cardiovascular complications will both be reduced as new therapies are developed. There are many measurable risk factors of cardiovascular disease associated with the insulin resistance of Type 2 DM, including endothelial function/hemostasis, dyslipidemia, hypertension and inflammation [8]. The goal of this review is to evaluate the currently available antihyperglycemic agents, their effect on actual cardiovascular outcomes and the potential mechanisms of these outcomes outside of their effects on blood glucose control. Metformin
Metformin is generally considered the preferred first-line treatment option for Type 2 diabetes, provided that no contraindications to therapy are present [9,10]. Metformin’s primary mechanism is via a decrease in hepatic glucose production, through hepatic insulin sensitization and/or inhibiting key enzymes in the gluconeogenesis pathway. It improves glucose tolerance by decreasing the absorption of glucose in the intestines and production in the liver. Improved insulin sensitivity also results in increased uptake and utilization of glucose in the periphery [11]. In 2008, the UK Prospective Diabetes Study long-term follow-up study found that metformin caused significant reductions in several outcomes compared with lifestyle intervention alone. It found that 122 patients must be treated for a year to prevent one diabetes-related event; 257 to prevent one MI; and 139 patients to prevent one death from any cause. This helped to solidify metformin’s place as first-line therapy [4]. There are several proposed mechanisms for this improvement in cardiovascular outcomes, based upon known risk markers. None of these hypotheses has been definitively proven, but all may contribute to the apparent cardiovascular benefits of metformin. It is generally thought that metformin has its beneficial effects via improvement of endothelial function and inflammation. This is supported by a study by de Jager et al., which found that metformin use significantly reduced the concentrations of von Willebrands factor, soluble cellular adhesion molecules (sVCAM-1 and sICAM-1), tissue plasminogen activator and plasminogen activator inhibitor-1 [12]. Metformin has also been shown to have beneficial effects on the lipid profile of patients with insulin resistance, reducing LDL by about 10% and increasing HDL by about 20% [8]. The magnitude of the change is dependent upon baseline values, so those patients with higher baseline values have a greater improvement. Metformin may also have direct cardiac effects. Animal studies have shown that metformin improves chronic AMPactivated protein kinase activation and cardiac autophagy, both of which help to preserve cardiac function in diabetic mice [13]. It is also through this AMP-activated protein kinase activation that metformin is thought to confer its anti-inflammatory effects, independent of blood glucose-lowering effects. Another study utilized tissue Doppler imaging in patients with diabetes 226
to assess improvement in left ventricular diastolic function while on metformin [14]. The study found that patients on metformin had a lower isovolumic relaxation time and slightly higher early diastolic longitudinal tissue velocity. Both of these factors come into play during the early part of diastole, where myocardial relaxation occurs (a very high energy process), and reflect the left ventricular relaxation rate. In spite of its established role in therapy and these positive effects on markers for cardiovascular risk, some questions have begun to emerge regarding metformin’s effect on actual cardiovascular outcomes. A large meta-analysis from 2009 that included only studies of 1 year or more duration found that metformin therapy did significantly reduce cardiovascular mortality compared with placebo or no therapy (MH-OR: 0.79 [95% CI: 0.64–0.98], p = 0.031), but not when compared with another active drug [15]. The authors concluded that these results show that it is the glucose-lowering ability of metformin that had positive effects on cardiovascular outcomes and not other mechanisms. Two other meta-analyses showed no effect of metformin therapy on cardiovascular morbidity or mortality [16,17]. At this time, however, it is still generally accepted that metformin has beneficial cardiovascular effects. Sulfonylureas
Sulfonylureas are one of the oldest and most well-established classes in the treatment of Type 2 DM. They are generally considered one of the ‘second-line’ agents from which to choose after metformin [9]. They work by blocking ATP-dependent K+ channels, leading to induce insulin secretion from the b-cells in the pancreas, and can result in hypoglycemia and weight gain, both of which are risk factors for cardiovascular events or disease, independent of DM [10,18,19]. In 1970, it was found that tolbutamide increased the incidence of cardiovascular mortality [20]. Since that time, tolbutamide and all subsequent drugs in this class have carried a black box warning on their official FDA labeling that warns of the potential risk for increased cardiovascular mortality. However, there is much controversy as to whether the effect is a classwide effect or specific to tolbutamide itself. A well-designed meta-analysis from 2013 showed no difference in cardiovascular death or MI even when compared with metformin. There was, however, an increase in overall all-cause mortality (MH-OR: 1.22 [95% CI: 1.01–1.49]; p = 0.047) and stroke (MH-OR: 1.28 [95% CI: 1.03–1.60]; p = 0.026) [18]. The individual trial designs and results vary greatly, though, and many do report negative cardiovascular outcomes. The authors point out that most included trial only reported the overall mortality and not the cause (cardiovascular or otherwise). The hypothesis as to why potential increases in negative cardiovascular outcomes occur with sulfonylureas involves the protective process of ischemic preconditioning, which is a cycle of sublethal myocardial ischemia and brief periods of reperfusion. When this occurs prior to a prolonged period of ischemia, infarct size is reduced and tissue damage minimized [21]. Older, nonspecific sulfonylureas such as tolbutamide and glyburide Expert Rev. Clin. Pharmacol. 7(2), (2014)
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June – Rosiglitazone (Avandia™) approved by the US FDA
1999
May – Nissen et al. meta-analysis. Increased incidence of MI, but not CV mortality [35]
2007
2008
June – RECORD trial published. No increase in CV death. Could not rule out link to MI [36]
2009
June – FDA black box warning re: CV events
June – FDA REMS program, limiting use to those already taking rosiglitazone or those for whom other drugs were not effective [37]
2010
2011
July – Nissen & Wolski metaanalysis, including RECORD data. Same results as 2007 metaanalysis [38]
June – RECORD reanalysis. Same results as original [39]
2012
November – FDA removes restrictions to access [42]
2013
June – FDA subcommittees† meet and vote to relax the restrictions of the REMS program [40]
Figure 1. Rosiglitazone: research and policy. † Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. CV: Cardiovascular; MI: Myocardial infarction; REMS: Risk Evaluation and Mitigation Strategy.
(glibenclamide) seem to negate this protective effect by blocking the K+ channel in the myocardium [19,22]. Based upon animal models, the benefits of ischemic preconditioning seem to be maintained with newer, pancreatic-specific sulfonylureas, such as glimepiride and gliclazide (not available in the USA) [23,24]. This is supported by some retrospective studies comparing these newer agents to glyburide, which show that glimepiride or gliclazide has lower rates of cardiovascularrelated outcomes [25,26]. On the other hand, another cohort study matched patients treated with glyburide at the time of their hospitalization for MI or percutaneous coronary intervention to patients treated with gliclazide and found no difference in their composite endpoint of death or hospitalization for MI or heart failure [27]. Of note, there is some controversy regarding combining a sulfonylurea with metformin. The results of two meta-analyses show that the combination may actually increase cardiovascular mortality [15,28], while other observational studies designed specifically for this aim show no increased risk [29,30]. One case–control study even suggests that the combination lowers the risk of cardiovascular mortality compared with sulfonylurea therapy alone [31]. Overall, sulfonylureas are likely a safe option for most patients with Type 2 DM (alone or in combination with other drugs), except for those with unstable angina pectoris, acute MI or undergoing elective angioplasty [32]. Using the newer, more selective drugs in the class, such as glimepiride, should be recommended. Thiazolidinediones
The two currently available thiazolidinediones (TZDs), pioglitazone and rosiglitazone, vary greatly in their apparent cardiovascular informahealthcare.com
safety profiles. They are both selective PPARg agonists that rely on the presence of insulin in order to work [33]. By decreasing insulin resistance in the liver and periphery, pioglitazone decreases hepatic glucose output and increases insulin-dependent glucose disposal. In recent years, studies have suggested that rosiglitazone has an increased risk of negative cardiovascular effects, specifically an increased risk of MI, and raised concerns about the TZDs as a class [34]. Controversy has surrounded this alleged link between rosiglitazone and MI. In an attempt to resolve the conflict that existed between individual studies, Nissen et al. published a meta-analysis in 2007 that included 42 [35]. It showed a statistically significant increase in the incidence of MI with rosiglitazone, with a number needed to harm of about 50. There was no significant increase in cardiovascular mortality. FIGURE 1 shows the research and policy changes that followed [35–40]. The debate continued into 2013, when, at the June Joint Meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, it was voted to recommend to the FDA to relax the requirements of the REMS program for rosiglitazone [40,41]. In November 2013, the FDA lifted the restrictions for access to rosiglitazone [42]. Conversely, some studies have shown that pioglitazone actually has several positive cardiovascular effects. In the PROACTIVE study, it was found that while pioglitazone did not reduce the risk for coronary and peripheral vascular events, it did significantly reduce the risk of the composite endpoint of MI, stroke and death by 2.5% (18.4% relative; hazard ratio [HR]: 0.84 [95% CI: 0.72–0.98]; p = 0.027) [43]. These results are supported by a large meta-analysis that showed 227
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that pioglitazone is associated with a significantly lower risk of the same composite endpoint by 1.36% (24% relative; [HR]: 0.82 [95% CI: 0.72–0.94]; p = 0.005) [44]. In contrast, the PROACTIVE study and the Lincoff meta-analysis found that pioglitazone increased the incidence of hospitalization for HF (by 22 and 33%, respectively). Both rosiglitazone and pioglitazone have a black box warning for this serious problem [43,45]. Several potential causes of the cardiovascular differences between the two TZDs have been proposed. One theory addresses the selectivity of rosiglitazone for PPARg compared with PPARa. Rosiglitazone binds 200-times more to PPARg than PPARa [46]. Pioglitazone only binds between two and six-times more to PPARg than PPARa. This selectivity is apparently important, as other PPARg selective medications, such as the glitazars, have also been linked to poor cardiovascular outcomes [46], while PPARa agonists, such as fenofibrate, actually have been shown to decrease cardiovascular complications [47]. Another potential cause is the difference in lipid profiles in patients treated with rosiglitazone versus pioglitazone. One small study showed that pioglitazone decreased LDL by nearly 13.6 mg/dl (9.5%), while rosiglitazone increased it by 5.39 mg/dl (4%). Both drugs decreased the highly atherogenic VLDL, but the decrease seen with pioglitazone was much larger (33.3 vs 6.6%) [48]. Another larger and longer term study showed an increase in LDL in subjects taking both drugs, but the increase in those taking pioglitazone was significantly less than in those taking rosiglitazone (12.5 vs 21.4 mg/dl; p < 0.001) [49]. Lastly, while both of the TZDs are potent insulin sensitizers, it is possible that pioglitazone possesses stronger anti-inflammatory effects than rosiglitazone. The study by Vijay et al. showed much more pronounced decreases in both C-reactive protein (42.7 vs 27.2%) and TNFa (65.9 vs 35.4%) in those subjects taking pioglitazone [48]. As of now, the only recommendation that can be made for patients not already on rosiglitazone, but needing a potent insulin sensitizer is to start pioglitazone. Rosiglitazone is still not available in the USA except to patients who were previously on it and do not have a clear reason not to use other agents. Even though the FDA has reversed its two previous decisions about concerns over cardiovascular risk and rosiglitazone, pioglitazone is still probably a better option for most patients (without HF), as it appears to reduce cardiovascular risk as opposed to possibly increasing it. Dipeptidyl peptidase-4 inhibitors
The dipeptidyl peptidase-4 (DPP-4) inhibitors involve the first ‘new’ oral medications to be approved by the FDA for Type 2 DM since the FDA’s guidance document urging manufacturers of medications for diabetes to evaluate cardiovascular risk was released in 2008 [7]. The document also states that ‘sponsors should demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk’. 228
With a new mechanism of action, they work by increasing circulating concentrations of glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide [50]. These hormones increase glucose-dependent insulin synthesis and secretion, suppress glucagon secretion and slow gastric emptying. After gaining FDA approval based upon their glucoselowering effects, the manufacturers of the drugs within this class undertook Phase IV trials to demonstrate their cardiovascular safety. The DPP-4 inhibitors were actually expected to show positive cardiovascular outcomes in their follow-up study results. This conjecture was based upon preliminary data which showed improvement in several known cardiovascular risk factors, such as improved endothelial function, diminished oxidative stress and reduced platelet aggregation [51]. In early September 2013, the results of two of these major studies were simultaneously released. In SAVOR-TIMI 53, saxagliptin was shown to have no impact on the rate of cardiovascular death and ischemic events compared with placebo when administered with metformin [52]. However, the rate of hospitalization for HF was increased with saxagliptin from 2.8 to 3.5% (p = 0.007). In the EXAMINE study, which involved high-risk patients with a recent diagnosis of acute coronary syndrome, similar rates of cardiovascular death and ischemic events between alogliptin and placebo were shown [53]. A later post hoc analysis did show a small, nonsignificant increase in HF hospitalization in the EXAMINE study, as well. Currently, the DPP-4 inhibitors continue to have an established place as a second-line option for Type 2 DM [9,10]. While it is encouraging that the drugs in this new class did not have negative impact on their primary cardiovascular outcomes (the composite rates of ischemic events and/or cardiovascular death), it is disappointing that they did not show any improvement, either. In addition, it is unclear why hospitalizations for HF might have increased in SAVOR-TIMI 53 and EXAMINE. It is known that DPP-4 is responsible, in part, for the enzymatic inactivation of b-natriuretic peptide and also that increases in glucagon-like peptide-1 can decrease b-natriuretic peptide [51]. In light of the HF hospitalization signal found in these trials, the relationship between the DPP-4 inhibitors and this hormone (a signal for severity) may be worth further exploration. a-glucosidase inhibitors
Acarbose and miglitol are the two a-glucosidase inhibitors available in the USA. They work by competitively inhibiting the absorption of carbohydrates in the upper small bowel [54]. This leads to decreased postprandial blood glucose concentrations, which is thought to decrease cardiovascular events. They are listed among second-line agents by the American Association of Clinical Endocrinologists, but are not included in the American Diabetes Association/European Association for the Study of Diabetes Position Statement, likely due to their modest overall glucose-lowering effects, adverse effects and frequent dosing schedule. Expert Rev. Clin. Pharmacol. 7(2), (2014)
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Table 1. Cardiovascular outcomes and possible mechanisms. Drug/class
Cardiovascular outcomes
Strength of evidence
Possible mechanism of action
Metformin
Positive
Moderate/strong
Glucose lowering Improved endothelial function Decreased systemic inflammation Direct cardiac effects
Sulfonylureas
Negative (questionable)
Moderate (tolbutamide, glyburide)
Block ischemic preconditioning
Thiazolidinediones
Negative (heart failure)
Strong
Significant fluid retention
Pioglitazone
Positive
Strong
Improved lipid profile Decreased systemic inflammation
Rosiglitazone
Negative
Strong
PPAR selectivity Effects on lipid profile (LDL and triglycerides)
Dipeptidylpeptidase-4 inhibitors
Negative (questionable) (heart failure signal)
Weak (based on two preliminary postmarketing studies; awaiting final results)
Unknown
a-glucosidase inhibitors (acarbose)
Positive
Strong (compared with placebo)
Decreased postprandial blood glucose
Meglitinides
Neutral
Weak
N/A
Sodium-glucose cotransporter 2 inhibitors
Negative (questionable) (stroke signal)
Weak (based on preliminary postmarketing studies; awaiting final results)
Unknown
LDL: Low-density lipoprotein; N/A: Not applicable.
The results from the study to prevent noninsulin-dependent DM produced very promising results regarding acarbose and cardiovascular endpoints. It showed that acarbose significantly reduced the risk of MI by 2.41% (89% relative) and total cardiovascular events by 2.5% (47% relative) compared with placebo [55]. These results translate to numbers needed to treat of 207 and 135 per year. However, reduction in postprandial blood glucose was found to be a strong predictor of reduction of risk for these events. A subgroup analysis from this study also showed reduced carotid intima media thickness (cIMT) thickening over time [56]. Strengthening these results, a meta-analysis of seven studies that compared acarbose to placebo, also showed a 1.32% lower risk for MI (65% relative; [HR]: 0.36 [95% CI: 0.16–0.80]; p = 0.0120) and 3.3% lower risk for any cardiovascular event (35% relative; [HR]: 0.65 [95% CI: 0.48–0.88]; p = 0.0061). However, since the drug also lowered A1c by 0.5% more than placebo and postprandial blood glucose by 50 mg/dl, it cannot definitively be said that this effect was independent of glucoselowering effect, postprandial or otherwise [57]. The data, to date, are encouraging regarding acarbose and its positive cardiovascular effects, although the mechanism behind these effects is still unclear. As it has been found to have no effect on various biomarkers of inflammation and other cardiovascular risk factors, it is most likely that its positive effects do stem from its control of postprandial blood glucose elevations [58,59]. In spite of the relatively strong evidence available, informahealthcare.com
acarbose remains underused, likely due to its inconvenient dosing schedule and significant gastrointestinal adverse effect profile, which is unacceptable to many patients. Meglitinides
Nateglinide and repaglinide are the two drugs in the class known as meglitinides. They bind to the same receptor as, and work similarly to, the sulfonylureas, but the subsequent insulin release diminishes when circulating glucose concentrations are normal or low [60]. This glucose-dependant action and short duration make them a good therapeutic choice for patients who experience significant elevations in postprandial blood glucose values, even though they must be dosed frequently. In addition, there is significant evidence that links elevations in postprandial blood glucose to the development of coronary heart disease and cardiovascular events [61–63]. If pancreatic-specific sulfonylureas have a lower theoretical cardiovascular risk than nonspecific ones, then the meglitinides do as well. Not only do they bind to a different site on the sulfonylurea receptor, but they also have a higher affinity for pancreatic receptors than cardiac ones [64]. Repaglinide has been shown to decrease inflammatory markers (IL-6, C-reactive protein, adiponectin), platelet activation parameters (plasminogen activator inhibitor-1, soluble cellular adhesion molecules, von Willebrands factor) and components of the lipid profile (LDL and triglycerides), suggesting that it may have other cardiovascular benefits [65–67]. 229
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cIMT is associated with stroke risk, and one study showed that nateglinide decreased cIMT in drug-naı¨ve patients [68]. The decrease was determined by the degree of A1c lowering, though, which suggests that glucose control was the likely cause of the change and not another mechanism of the drug. When compared to glyburide, repaglinide decreased cIMT more, and this decrease was associated with decreased postprandial glucose, but not fasting glucose or the degree of A1c lowering [65]. A large study that specifically compared nateglinide to placebo, however, showed no difference in the incidence of stroke risk [69]. This is the only trial that has measured the effect of either meglitinide on any actual cardiovascular outcome, so it is not currently possible to say what this class’s cardiovascular effects truly are. Sodium glucose cotransporter-2 inhibitors
The newest class of oral medications for Type 2 DM is the sodium glucose cotransporter-2 (SGLT-2) inhibitors. Canagliflozin (Invokana) and dapagliflozin (Farxiga) both work primarily by inducing urinary glucose excretion via inhibition of renal glucose reabsorption by SGLT-2. They generally lower A1c by 0.5–1% and have been shown to be effective as both monotherapy and add-on therapy in lowering blood glucose [70–72]. Based on Phase III trial results, this class of medications has positive effects on cardiovascular risk factors. Both drugs provide modest, dose-dependent weight loss of about 2–4% [70,71,73,74]. Systolic blood pressure is lowered by about 5 mmHg and diastolic by about 2 mmHg [71,74]. While these decreases were found to be statistically significant, the clinical relevance is questionable, and some have suggested that these effects are simply from the diuresis that the drug causes [75]. In addition, HDL was increased by about 6% in subjects taking canagliflozin, which was found to be statistically significant. Interestingly, in this same study, LDL was also increased by about the same amount, but no statistical analysis was done to determine the significance of this change compared with placebo. There is a meta-analysis that showed no increase in overall cardiovascular events with either drug in this class of medications in the 25 studies included [72]. This is consistent with the reports made to the FDA on behalf of both drugs at the time of their approval [75,76]. There was, however, a ‘signal’ for an increase in risk during the first 30 days of therapy for both drugs. Therefore, as per FDA directive, there are currently large, long-term postmarketing cardiovascular safety studies underway for both: the CANVAS trial for canagliflozin and DECLARE-TIMI for dapagliflozin. Results are expected within the next 2–3 years [76]. Currently, there are no explanations for the potential risk seen within the first 30 days of therapy with an SGLT-2 inhibitor,
230
and it is still too soon to state what the SGLT-2’s role in therapy will be, based upon their glucose-lowering ability or cardiovascular effects. Expert commentary & five-year view
As shown from the information presented here, and summarized in TABLE 1, none of the oral medications currently available for the treatment of Type 2 DM is ideal in reducing cardiovascular risk. Based upon the currently available data, metformin should continue to be used as first-line therapy due to its significant glucose-lowering effects, as well as its apparently beneficial cardiovascular effects. Other agents with potentially positive effects, such as a glucosidase inhibitors, are only marginally effective at their overall blood glucoselowering effects and are limited by adverse effects, but might become more commonly considered as add-on therapy in those patients who can tolerate them. Pioglitazone has shown positive cardiovascular effects on one hand, but a worsening of HF on the other, so is clearly not optimal for these highrisk patients. With the FDA’s specific guidelines regarding diabetes medications and cardiovascular outcomes, there should be fewer surprises of ill effects such as were seen with rosiglitazone. However, there are some potentially alarming ‘signals’ with some of the newer agents, like the DPP-4 inhibitors and the SGLT-1 inhibitors, but these nonsignificant trends must be further explored before any conclusions can be reached. At this time, both of these drug classes are effective options for lowering blood glucose, and further ‘me-too’ agents in these classes are sure to be expected in the very near future. There are also several potential brand new targets for drugs that may have effects beyond their glucose-lowering abilities. These include a family of proteins called wnt, nicotinamide and the related forkhead transcription factors and erythropoietin [77]. (Many patients with DM are deficient in erythropoietin, and it might protect vascular cells, although it does not appear to have any effect on glucose control.) Current treatment algorithms for Type 2 DM should continue to be updated and address new cardiovascular data that are made available, to ensure that the whole patient is being treated. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Expert Rev. Clin. Pharmacol. 7(2), (2014)
Cardiovascular risks & benefits with oral drugs for Type 2 DM
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Key issues • About half of those patients diagnosed with Type 2 diabetes will die from cardiovascular complications such as myocardial infarctions (MIs) or stroke. • The relationship between blood glucose control and cardiovascular (macrovascular) complications is not well established. However, currently available medications are evaluated based solely upon their glucose-lowering ability. • Metformin is generally considered to have positive cardiovascular effects based upon the results of the UK Prospective Diabetes Study, reducing MIs and all-cause mortality. • Older, nonpancreatic-specific sulfonylureas like tolbutamide and glyburide block the protective mechanism of ischemic preconditioning, Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Michigan University on 10/11/14 For personal use only.
possibly leading to an increase in cardiovascular mortality. Avoid these in patients with unstable angina, acute MI or undergoing elective angioplasty. • Rosiglitazone has been shown to increase the incidence of MI, while pioglitazone has proven cardiovascular benefits. Both, however, increase the incidence of heart failure. The differences may stem from activity at the PPAR-g receptor, effects on the lipid profile or on the inflammatory process. • New studies showed no differences in cardiovascular death or ischemic events when the DPP4-inhibitors were compared with placebo. However, there is a signal for an increase in heart failure hospitalizations for both saxagliptin and alogliptin, so use with caution. • Acarbose, an a-glucosidase inhibitor, reduces the risk of MI and total cardiovascular events. However, adverse effects and three-times daily dosing limit its usefulness. • Canagliflozin, the newest oral medication for Type 2 diabetes, may improve several risk factors for cardiovascular disease, although long-term studies are still ongoing. Preliminary results show a possible signal for an increase in stroke risk.
decrease in cardiovascular risk and is the basis for the claims that metformin has significant cardiovascular benefits.
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