Cardiovascular safety of oral antidiabetic drugs





Naveed SATTAR, PhD,
FRCPath, FRCP

Scot H. SIMPSON, BSP
PharmD, MSc
Faculty of Pharmacy &
Pharmaceutical Sciences
Edmonton Clinic Health
Academy
University of Alberta
CANADA

Cardiovascular safety
of oral antidiabetic drugs

 

by S. H. Simpson, Canada

People with type 2 diabetes have a significantly higher risk of developing cardiovascular disease compared with the general population, which is important because this is a leading cause of morbidity and mortality. Although the glucose-lowering benefits of oral antidiabetic drugs have been well established in clinical trials, some of these drugs have been associated with an increased risk of cardiovascular events. Perhaps the most well-known example of this association is the link between rosiglitazone and risk of heart failure and myocardial infarction. There are also cardiovascular safety questions associated with sulfonylureas and our understanding of the cardiovascular safety of newer oral antidiabetic classes (dipeptidyl peptidase 4 inhibitors and sodium glucose cotransporter-2 inhibitors) is evolving. In contrast, metformin and acarbose do not appear to be associated with adverse cardiovascular events. Questions about cardiovascular safety prompted the Food and Drug Administration in the United States to require cardiovascular safety trials as part of the approval process for new antidiabetic drugs. In addition, there have been a large number of observational studies, randomized controlled trials, and meta-analyses examining the cardiovascular safety of antidiabetic drugs. This review examines the current issues and evidence related to cardiovascular safety for each class of oral antidiabetic drug. Understanding the potential cardiovascular risk associated with these drugs will help clinicians and patients with treatment decisions for type 2 diabetes.

Medicographia. 2016;38:28-36 (see French abstract on page 36)

Over 90% of people with diabetes have type 2 diabetes, which carries with it a twofold higher risk of adverse cardiovascular events, such as myocardial infarction, stroke, and heart failure compared with people without diabetes.1 In addition, the risk of all-cause death and cardiovascular-related death is significantly higher in people with diabetes compared with those without diabetes.2 The heightened risk of cardiovascular disease in people with diabetes is likely due to a clustering of cardiovascular risk factors, including obesity, hypertension, and dyslipidemia.3,4 Since cardiovascular disease is a leading cause of morbidity and mortality in people with diabetes,5 it is imperative that clinicians consider the cardiovascular implications of their treatment decisions.

Table I
Table I. Glycemic control strategy trials.

Abbreviations: ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; CAD, Coronary Artery Disease; CI, confidence interval; CV, Cardiovascular; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; HR, hazard ratio (intensive treatment versus control); MACE, major adverse cardiovascular event (cardiovascular death, myocardial infarction, or stroke); UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.
Based on data from references 9-14.

As glycemic control remains an important focal point for type 2 diabetes management, the majority of patients will require oral antidiabetic drugs to control hyperglycemia.6,7 Generally, there is strong clinical trial evidence demonstrating that oral antidiabetic drugs reduce hyperglycemia to a similar degree and significantly decrease the risk of microvascular complications.6,8 However, the strategy used to reduce blood glucose may affect a patient’s cardiovascular risk. For example, in the ACCORD study (Action to Control CardiOvascular Risk in Diabetes), patients with a median 10-year history of type 2 diabetes and mean HbA1c of 8.3% were treated to rapidly achieve glycemic targets of 6.0% (intervention group) or maintain their current glycemic control.9 Although the ACCORD study did not find a difference in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, there was a significantly higher rate of all-cause mortality in the intervention group compared with controls. Other studies examining intensive glycemic control strategies did not find a significant effect on cardiovascular risk (Table I).10-12 However, extended follow-up of these trials suggests that intensive treatment may have a legacy effect which is associated with a lower risk of major cardiovascular events.13,14

Despite this evolving evidence from intensive glycemic control studies, there is still uncertainty about possible cardiovascular effects related to type 2 diabetes management, especially regarding some oral antidiabetic drugs. For example, questions of cardiovascular safety for sulfonylureas have been circulating for over 40 years.15 The issue of cardiovascular safety gained substantial prominence when a link between rosiglitazone and risk of myocardial infarction was demonstrated.16 Indeed, concerns about the cardiovascular safety of antidiabetic drugs prompted the Food and Drug Association (FDA) in the United States (US) to require cardiovascular safety trials as part of the approval process for new antidiabetic drugs.17

Since publication of the Guidance for Industry document by the US FDA,17 a large number of observational studies, randomized controlled trials, and meta-analyses have been con- ducted to examine the cardiovascular safety of antidiabetic drugs. Most studies have used the composite of a major adverse cardiovascular event (MACE), which includes cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke as the primary outcome, while others have examined the effect of antidiabetic drugs on cardiovascular risk factors (blood pressure, weight, and lipid levels). The purpose of this review is to examine the current issues and evidence related to cardiovascular safety for each class of oral antidiabetic drug.

Acarbose

Acarbose inhibits the α-glucosidase enzyme, which breaks down complex carbohydrates into monosaccharides that are rapidly absorbed from the gastrointestinal tract. When taken with meals, acarbose will effectively reduce postprandial glucose levels and help manage hyperglycemia. Initial reviews of the placebo-controlled studies suggested that acarbose use was associated with a significantly lower risk of myocardial infarction and other cardiovascular events.18 This reduction in cardiovascular risk was thought to be linked to reductions in blood pressure, postprandial hyperglycemia, and lipid levels, as well as a neutral effect on weight.19 However, a more comprehensive review of the literature was unable to find a difference in cardiovascular risk associated with any α-glucosidase inhibitors, including acarbose.20

While acarbose may have a neutral effect on body weight gain and other oral antidiabetic drugs like sulfonylureas and thiazolidinediones are associated with significant increases in weight,8 very few people with type 2 diabetes use this drug.21-23 Two major factors may explain the limited use of acarbose. First, relative to other oral antidiabetic drugs, acarbose is not as effective at lowering blood glucose.8 Second, and perhaps more importantly, significant gastrointestinal side effects like cramping and flatulence are quite undesirable and lead to substantial rates of treatment discontinuation.

Metformin

The exact mechanism of action for metformin is still not fully understood, though this drug reduces glucose production in the liver and affects adenosine 5’-monophosphate-activated protein kinase (AMPK) activity, a major cellular regulator of energy metabolism. Clinical practice guidelines recommend using metformin as a first-line agent because of its proven beneficial effects on hyperglycemia and risk of microvascular complications, neutral effect on weight, minimal risk of hypoglycemia, and favorable safety profile.6,8,24,25 Although lactic acidosis was a significant concern with an earlier biguanide, phenformin, after more than 50 years of clinical experience, there is no evidence to support a link with metformin.26

Two clinical trials have randomly allocated patients to metformin or a comparator and evaluated the risk of cardiovascular outcomes.24,27 In both studies, patients allocated to metformin use experienced significantly lower rates of cardiovascular events. Metformin has also been shown to significantly reduce lipid levels.28 More recently, interest in metformin has shifted to an examination of its safety in patients with heart failure. Renal dysfunction and heart failure have been longstanding contraindications for metformin use because of the perceived risk of lactic acidosis. However, there is good evidence that metformin is used in patients with these contraindications, with no change in the incidence of lactic acidosis.26 Moreover, observational studies have demonstrated that metformin use in patients with heart failure is associated with a lower risk of cardiovascular morbidity and mortality.26 It is also important to note that none of the patients allocated to metformin use in the UKPDS study (United Kingdom Prospective Diabetes Study) developed lactic acidosis.24 These observations may be influencing requests to regulatory agencies to revisit previous restrictions on metformin use in patients with heart failure or reduced renal function.6,26

Thiazolidinediones

Thiazolidinediones bind to peroxisome proliferator–activated receptor-ϒ, leading to receptor upregulation and improved insulin sensitivity in muscle, liver, and fat tissue. These drugs produce a significant reduction in blood glucose with minimal risk of hypoglycemia.8,25 Initial observations with thiazolidinediones suggested beneficial effects on blood pressure and lipid levels and early clinical trials reported possible reductions in cardiovascular events.29

In 2007, however, evidence emerged linking rosiglitazone to an increased risk of myocardial infarction and death.16 This observation was soon replicated by others and extended to include an association with heart failure risk.30,31 As these retrospective analyses were hypothesis-generating, a cardiovascular outcome trial was conducted to compare addition of rosiglitazone with metformin or sulfonylurea monotherapy with the combination of metformin and sulfonylurea.32 This study demonstrated that the risk of cardiovascular death or hospitalization for myocardial infarction or stroke was similar between treatment groups. However, hospitalization or death attributable to heart failure was significantly higher in patients allocated to rosiglitazone use.

Although pioglitazone does not appear to have the same level of cardiovascular risk as rosiglitazone,31 there appears to be a higher risk of fractures and cancer.6 Thiazolidinediones are also associated with fluid retention and significant weight gain.8,25 Introduction of other classes of antidiabetic drugs, along with concerns of the various adverse effects are likely behind the observed decline in thiazolidinedione use over the past few years.21-23

Sulfonylureas and nonsulfonylurea secretagogues

Sulfonylureas and nonsulfonylurea secretagogues bind to sulfonylurea receptors on pancreatic β-cells and promote insulin release by closing ATP-sensitive potassium (KATP) chan nels.33 These drugs are commonly used to help control hyperglycemia in type 2 diabetes and their popularity is likely due to decades of experience, strong evidence demonstrating efficacy, and familiarity with known side effects of hypoglycemia and weight gain.12,15,21-23 Interestingly, sulfonylureas are frequently used even though questions of cardiovascular safety were raised over 40 years ago.15 Concern began when the University Group Diabetes Program (UGDP) investigators reported a significantly higher rate of cardiovascular deaths in patients using tolbutamide compared with placebo.34 The UKPDS seemed to quell these concerns when similar rates of myocardial infarction, stroke, and death were reported in patients using a sulfonylurea for intensive treatment compared with conventional treatment.12 It is important to note, however, that the UKPDS tested glucose targets and by the end of the study many patients in the conventional treatment arm were using sulfonylureas to maintain a fasting blood glucose level 35 Thus, the question of cardiovascular safety remains unanswered in clinical trials.

Given the uncertainty surrounding sulfonylurea cardiovascular safety, it is not surprising that there have been numerous observational studies and post hoc analyses of randomized controlled trials examining this issue. Observations from these studies have been summarized in 7 meta-analyses (Table II). 25,36-41 Although summaries from randomized controlled trials would suggest there is no significant difference in cardiovascular risk between sulfonylureas and comparators, it is important to note that almost all of these studies were small and were short-term evaluations of glycemic response to therapy. Therefore, these studies were neither designed nor adequately powered to examine a cardiovascular safety question.15 In contrast, observational studies may be large enough to detect differences in cardiovascular risk, but their designs have well-known limitations and results should be considered hypothesis-generating. Collectively, these studies provide some evidence that risk of cardiovascular events may be higher in people taking sulfonylureas compared with other antidiabetic drugs. However, this hypothesis should be tested in a properly designed trial. Although two ongoing trials are designed to compare the cardiovascular risk between sulfonylureas and other oral antidiabetic drugs, these studies may not completely answer the safety question since there is no placebo arm.42,43

Table II
Table II. Meta-analyses examining the association between sulfonylureas and cardiovascular events.

Abbreviations: CV, cardiovascular; DPP4, dipeptidyl peptidase 4; MACE, major cardiovascular event; NR, not reported; RCT, randomized controlled trial; SU, sulfonylurea.
Based on data from references 25 and 36-41.

Two biological mechanisms may explain why the risk of adverse cardiovascular events is higher in patients using sulfonylureas. First, hypoglycemia leads to alterations in myocyte physiology, which will prolong the QT interval and increase the risk of disrhythmias.44 In addition, catecholamine release in response to hypoglycemia can promote vasoconstriction and tachycardia, which in turn increases the risk of myocardial ischemia.44,45 Hypoglycemia is a well-recognized adverse effect of all oral antidiabetic agents and occurs most frequently with sulfonylureas.46 Although few studies have directly compared the risk of hypoglycemia between sulfonylureas, a systematic review and meta-analysis of these data reported that glyburide had the highest risk among sulfonylureas.47 The second mechanism involves an extension of the beneficial pharmacologic activity of sulfonylureas and nonsulfonylurea secretagogues. Binding to receptors on other excitable cell types, such as cardiac myocytes and vascular smooth muscle, may interfere with ischemic conditioning, an endogenous protective mechanism that enables cardiac myocytes to survive ischemia- reperfusion injury from a myocardial infarction.33,48 Reviews of the pharmacologic properties of sulfonylureas have suggested that these drugs differ with respect to tissue-specific affinities.49,50 Indeed, when both the tissue-specific affinities and steady state concentrations of the usual therapeutic dose are considered, there are important differences among sulfonylureas.51 Some sulfonylureas, like glyburide, will bind to both pancreatic and cardiac sulfonylurea receptors and promote closure of KATP channels in both tissues when given at usual therapeutic doses. In contrast, others, like gliclazide, will selectively bind to pancreatic sulfonylurea receptors and promote KATP channel closure only in the pancreas at usual therapeutic doses.51

Figure 1
Figure 1. Rankogram of sulfonylureas and risk of all-cause mortality.

Considering the important differences in pharmacologic properties among sulfonylureas, it is interesting that the majority of studies examining cardiovascular safety have grouped sulfonylureas together.15 When considered separately, there are significant differences in cardiovascular risk among sulfonylureas.52 When information from both direct and indirect comparisons among sulfonylureas is combined, gliclazide appears to have the lowest risk of cardiovascular morbidity and mortality, followed by glimepiride, glipizide, and glyburide (Figure 1).52 Based on these observations, it is important to consider sulfonylureas as individual agents when examining the adverse cardiovascular effects of these drugs.

Dipeptidyl peptidase 4 inhibitors

Dipeptidyl peptidase 4 (DPP4) inhibitors reduce metabolism of glucagon-like peptide-1 (GLP-1), a hormone released by the small intestine in response to meals.53 Inhibition of GLP-1 metabolism increases GLP-1 circulating levels, which in turn potentiates the release of insulin and reduces the postprandial rise in blood glucose. In premarketing clinical trials, DPP4 inhibitors provided similar reductions in blood glucose compared with other oral antidiabetic drugs. The major side effects of these drugs appeared to be gastrointestinal and possible safety concerns with pancreatitis and pancreatic neoplasia;6 however, since this class of drug was introduced at the time of the changes in FDA requirements for approval, additional cardiovascular safety trials were initiated for alogliptin, linagliptin, saxagliptin, and sitagliptin.

Cardiovascular safety studies mandated in the 2008 FDA requirements must demonstrate that a new antidiabetic drug is safe, or in other words, does not increase the risk of cardiovascular events beyond an acceptable threshold.17 Unlike traditional cardiovascular outcome studies that are designed to find benefit, safety trials must demonstrate that the new drug is not inferior when compared with placebo. Since the antidiabetic drug investigated in these studies will affect glucose levels, patients in both groups are treated to maintain similar levels of glycemic control. Clinicians are allowed to change background antidiabetic regimens at their discretion during the study. A cardiovascular safety trial is considered successful if there is no significant difference in risk of events between treatment and placebo groups and the upper limit of the 95% confidence interval does not cross 1.3.17,54

Three cardiovascular safety trials of DPP4 inhibitors have been published and a fourth study is ongoing, with results expected in 2018 (Table III, page 34).55-58 In general, these studies enrolled patients with type 2 diabetes and an elevated level of cardiovascular risk (Figure 2). At the end of the three published trials, glycemic control was slightly better in the DPP4 treatment groups compared with placebo (P1c reached a clinically important difference of >0.5%.55,57,58 Regarding the primary outcome of cardiovascular safety, all three studies demonstrated noninferiority versus placebo, with upper limits of the 95% confidence intervals Table III). The study examining saxagliptin did observe a significantly higher rate of hospitalization for heart failure compared with placebo;57 however, this observation has not been replicated in other clinical trials.56,58 At this point it is uncertain if the observed risk of heart failure is a true safety signal or due to random error.

SGLT-2 inhibitors

Sodium glucose cotransporter-2 (SGLT-2) inhibitors reduce hyperglycemia in people with type 2 diabetes by decreasing glucose reabsorption in the renal tubule.59 In premarketing clinical trials, SGLT-2 inhibitors significantly reduced blood glucose with a low risk of hypoglycemia.60 These agents also had favorable effects on cardiovascular risk factors by reducing body weight and blood pressure.60 The major side effect observed in these trials was an increased risk of urinary tract infections. In addition, there are emerging questions of ketoacidosis, which has led to a safety warning issued by the US FDA.61

Decreasing glucose reabsorption in the kidneys produces glycosuria, resulting in a loss of 200-300 kilocalories per day.62 Clinical trials have consistently demonstrated a weight reduction associated with SGLT-2 inhibitor use, with the weighted mean difference in body weight reduction from baseline ranging from 1.7 to 1.9 kilograms when compared with placebo and 1.1 kilograms when compared with sulfonylureas.60 From these studies, it appears that weight loss occurs primarily in the first 3 to 6 months of therapy and then remains stable for the duration of the observation period. In addition to weight loss, important changes in visceral fat mass also occur. Body composition studies of 1 to 2 years’ duration have shown that the reduction in weight associated with SGLT-2 inhibitor use was due to reductions in visceral fat or subcutaneous fat.63-65 The contributions of visceral fat changes to cardiovascular risk remain unknown, however.66

Figure 2
Figure 2. Baseline cardiovascular risk of patients enrolled in cardio-vascular outcome trials.

Abbreviations: CANVAS, CANagliflozin cardioVascular Assessment Study; CARMELINA, CArdiovascular and Renal Microvascular outcomE study with LINAgliptin; DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events- Thrombolysis In Myocardial Infarction; EMPA-Reg OutcomeTM, empagliflozin cardiovascular outcome event trial in type 2 diabetes mellitus patients; EXAMINE, EXamination of cArdiovascular outcoMes with alogliptIN versus standard carE; HDL-C, high-density lipoprotein cholesterol; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus-Thrombolysis In Myocardial Infarction; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.
Based on data from references 55-58 and 67-69.

The weighted mean difference in systolic blood pressure reduction ranged from 3 to 5 mm Hg when SGLT-2 inhibitors were compared with placebo, while diastolic blood pressure decreased by 2 mm Hg.60 An important observation from these studies is that heart rate did not increase in response to the lower blood pressure. The mechanism for the blood pressure reduction, however, is not known, though the mild diuresis associated with SGLT-2 inhibitor use may play a role.66

Currently there are four clinical trials examining the risk of cardiovascular events with SGLT-2 inhibitor use compared with placebo in patients at high risk of cardiovascular events (Table III; Figure 2).67-69 While the EMPA-REG OutcomeTM study is now completed,69 the remaining three studies will not produce results for several years. All studies are using MACE as the primary outcome, with the exception of EMPA-REG OutcomeTM, which included hospitalization for unstable angina in the composite outcome.68,69

Table III
Table III. Cardiovascular outcome trials.

Abbreviations: CANVAS, CANagliflozin cardioVascular Assessment Study; CARMELINA, CArdiovascular and Renal Microvascular outcomE study with LINAgliptin; CVOT, CardioVascular Outcome Trial; DECLARE= Dapagliflozin Effect on CardiovascuLAR Events; DPP4, dipeptidyl peptidase 4; EXAMINE, EXamination of cArdiovascular outcoMes with alogliptIN versus standard carE; HF, heart failure; MACE=Major Adverse Cardiovascular Event (cardiovascular death, myocardial infarction, or stroke); SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus-ThrombolysIs in Myocardial Infarction; SGLT-2, sodium glucose cotransporter-2; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; UA, unstable angina; UL, upper limit of 95% confidence interval.
Based on data from references 55-58 and 67-69.

 

Conclusion

Risk of cardiovascular disease is an important consideration for clinicians when managing patients with type 2 diabetes. Although most oral antidiabetic drugs have similar effects on hyperglycemia and reduce the risk of microvascular complications, there are cardiovascular safety concerns associated with some of these drugs. Understanding the potential cardiovascular risk associated with oral antidiabetic drugs will help clinicians and patients with treatment decisions for type 2 diabetes. Overall, metformin appears to have the best benefit- to-risk profile, which is consistent with its place as first-line therapy in clinical practice guideline recommendations.6 Acarbose does not appear to increase the risk of adverse cardiovascular events; however, the unfavorable gastrointestinal side effects limit its usefulness in type 2 diabetes management. Newer classes of oral antidiabetic drugs—the DPP4 inhibitors and SGLT-2 inhibitors—do not appear to increase the risk of adverse cardiovascular events, though the evidence to support this premise is still evolving. Current evidence suggests that sulfonylurea use is associated with an increased risk of adverse cardiovascular events; however, this risk varies among individual drugs, with the lowest risk associated with gliclazide.15,51,52 Thiazolidinediones, especially rosiglitazone, increase the risk of heart failure, stroke, and myocardial infarction and therefore should be avoided in patients at risk of cardiovascular disease.16,31

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Keywords: adverse reactions; cardiovascular disease; hypoglycemic agent; risk assessment; type 2 diabetes