The 2019 ACC/AHA Guideline on the Prevention of Cardiovascular Disease includes management of diabetes mellitus as a key takeaway for cardiologists caring for patients with this comorbidity. New and emerging agents for reducing cardiovascular risk in this patient population, along with,optimization of their use, and their adverse effects are discussed in K2P’s newly updated topic Cardiovascular Management of Type II Diabetes, presented by Drs. Ty J. Gluckman and Howard Baum.
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Increasing the Role of Cardiologists in the Management of Type 2 Diabetes
A Paradigm Shift in Cardiovascular Risk Reduction
Faculty: Ty Gluckman, MD, FACC, FAHA
- Examine new and emerging agents for reducing cardiovascular risk in patients with type 2 diabetes mellitus and cardiovascular disease
- Discuss adverse effects of new and emerging agents for reducing cardiovascular risk in patients with type 2 diabetes mellitus and cardiovascular disease
Prevalence of Diabetes Mellitus
The prevalence of diabetes mellitus in the United States is a growing problem. As is shown here, this is a reflection of prevalence rates looking at either percentages or absolute numbers in millions of individuals from 1958 through 2015. And as one can see on this slide, the percentage of individuals with diabetes mellitus is approaching 8% as of 2015, amounting to almost 25 million Americans living in the United States with diabetes mellitus.
Positive Cardiovascular Outcomes Trials: SGLT2 Inhibitor
The cardiovascular risks associated with diabetes mellitus are substantial. This is a meta-analysis of 102 clinical trials evaluating the risk of cardiovascular events due to diabetes mellitus that came from the Emerging Risk Factors Collaboration. As is shown on this slide, in the upper portion, you can see the rates of coronary heart disease events, including coronary death and nonfatal heart attacks. In the case of stroke, post-ischemic, hemorrhagic, and an additionally unclassified stroke. And at the bottom, other vascular deaths. And as you can see from the point estimates and the respective confidence intervals, there is a statistically significant increased risk of coronary heart disease events, stroke events, as well as vascular deaths, highlighting the fact that diabetes mellitus is a potent risk factor for the development of adverse cardiovascular events.
Now, there are a number of mechanisms by which diabetes mellitus can increase cardiovascular risk, and this is what appears to be potentially a busy cartoon, but it highlights the fact that the interplay between hyperglycemia and insulin resistance, and in the upper portion, lead to endothelial dysfunction, vascular inflammation, which can increase atherothrombotic risk. The underpinnings of ultimately leading to insulin resistance can lead to abnormalities in different lipoproteins and lipids that can predispose to increased cardiovascular risk. There's also a predisposition to macrophage dysfunction and direct myocardial toxicity through diabetic cardiomyopathy as well as activation of multiple prothrombotic factors that ultimately can lead to increased atherothrombotic death risk as well. Overall, this slide highlights in totality a number of mechanisms by which diabetes can contribute to the increased cardiovascular risk previously observed.
Impact of Diabetes on Life Expectancy
This data comes from the Emerging Risk Factors Collaboration and includes a meta-analysis of 97 prospective studies evaluating the risk of cardiovascular events due to diabetes mellitus. As is shown on this slide, this actually reflects the probability of survival or survival curves for those in a reddish color, with diabetes, and a bluish color, without diabetes, for men on the left and women on the right, respectively. And importantly, what's shown is the presence of diabetes mellitus alone decreases the likelihood of survival amongst individuals of almost all age groups overall. And furthermore, cardiovascular disease is still the number one killer. The same meta-analysis demonstrates the distribution of different death types or reasons why individuals died, in men on the left and women on the right. And as you can see, vascular deaths account for the disproportionate majority of all deaths. And as is shown in addition to this, the number of absolute years lost and the impact of diabetes and, in particular, vascular deaths in terms of a magnitude of years life lost is more pronounced at younger ages for both men and women alike compared to at older ages.
Higher blood glucose is also associated with increased cardiovascular risk. Shown in the left is data from the Emerging Risk Factors Collaboration looking at rates of vascular death amongst 50 studies with a total of 16,000+ individuals that had died, showing that as the mean fasting glucose increases, the risk for vascular death increases as well. In a similar fashion, on the right, Strong Heart Study looks at the incident rate of cardiovascular disease events relative to the baseline hemoglobin A1c, showing that as the hemoglobin A1c rises, the risk for multiple cardiovascular events, including vascular death, rises.
Intensive Glycemic Control
The data is pooled data from the UKPDS, ADVANCE, ACCORD, and VADT trials looking in the top portion at major cardiovascular events and in the bottom portion looking at cardiovascular death. With regard to major cardiovascular events in a pooled meta-analysis, there is a small but statistically significant benefit of a reduction in major cardiovascular events from intensive glycemic control, with at least, for two of the studies, showing wide confidence intervals. However, in the bottom portion, you can see there is no significant benefit to intensive glycemic control with regard to cardiovascular death. Where intensive glycemic control appears to provide even greater benefit is on microvascular outcomes, and as is shown, a continuation of this analysis, looking at kidney-related outcomes in the top portion, showing a 20% relative risk reduction in the overall rate of a composite look at kidney adverse outcomes from use of intensive glycemic control that is statistically significant and a fairly statistically significant benefit to the use of intensive glycemic control as it relates to primary eye outcomes overall.
So for most cardiologists seeing patients with diabetes, either with or without established atherosclerotic cardiovascular disease, there are some forms of therapy that are fairly straightforward and others that maybe traditionally have not necessarily fallen within the camp for cardiology to assume in terms of management. Listed on this screen include a number of interventions that traditionally have been a mainstay of cardiovascular risk reduction for diabetics.
At the top is antiplatelet therapy, which has always been recommended in those with secondary prevention to reduce the risk of a subsequent adverse cardiovascular event. Low dose aspirin for primary prevention of atherosclerotic cardiovascular disease can be considered in select adults between the ages of 40 to 70 years of age at higher atherosclerotic cardiovascular disease risk in primary prevention but not amongst those at increased bleeding risk. And current guidelines suggest harm and thus aspirin should not be administered routinely in diabetic adults greater than 70 years of age, and in addition, harm exists and, thus, aspirin should not be administered in diabetic adults of any age facing particular increased bleeding risk.
Blood Pressure Control
With regard to blood pressure control, it's important that high blood pressure or hypertension be managed in patients with diabetes, and current guidelines recommend starting antihypertensive drug treatment for those individuals with a blood pressure greater than or equal to 130/80 millimeters of mercury, with a treatment goal less than 130 over less than 80 millimeters of mercury. All first-line classes can be useful and effective, including diuretics, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers, but ACE inhibitors or angiotensin receptor blockers can be considered in the presence of albuminuria.
In terms of statin therapy in adult patients with type 2 diabetes, moderate-intensity statin therapy is indicated for those 40 to 75 years of age, regardless of estimated 10-year atherosclerotic cardiovascular disease risk, with high-intensity statin therapy being reasonable for those 40 to 75 years of age with multiple atherosclerotic cardiovascular disease risk factors, and statin therapy may be reasonable for those less than 40 years of age, depending upon their risk factor profile, and in those greater than 75 years of age following a clinician-patient discussion to review the risks and benefits of therapy.
It's a given that the following interventions are appropriate, but often, this involves team-based approaches with others being involved in care as well. With regard to nutrition, individualized medical nutrition therapy programs are recommended as needed to achieve treatment goals for all diabetics and prediabetic patients. No single ideal dietary distribution of calories among carbohydrates, fats, and proteins is recommended for people with diabetes per se. Meal plans should be individualized while keeping in mind calorie metabolic goals, and a variety of eating patterns are acceptable for management of type 2 diabetes and prediabetes. With regard to weight management, it's important to prescribe diet, physical activity, and behavioral therapy to achieve and maintain at least a 5% weight loss in overweight or obese type 2 diabetic patients, and interventions should include a high-intensity program that's focused on achieving 500 to 750 kilocalories per day of energy deficit. Finally, diets should be individualized, as was listed above, with the intent of achieving the two above goals.
For those that use any form of tobacco, it's recommended to avoid all patients having exposure to cigarettes, e-cigarettes, or other tobacco products, and smoking cessation counseling and other treatments should be routine in diabetes care. And lastly, for many cardiologists, it's understood that blood glucose control is important, but for many cardiologists, it may not be routinely owned. And current guidelines recommend performing a hemoglobin A1c test at least two times per year, with a push to even doing this quarterly in patients not meeting goals or who have changed therapy. A reasonable A1c goal is less than 7% in many nonpregnant adults, with more stringent A1c goals being less than 6.5% being reasonable in selected patients, such as those with short duration of diabetes, long life expectancy, or no significant cardiovascular disease. In contrast, less stringent A1c goals, such as those less than 8% for hemoglobin A1c, may be appropriate in selected patients such as those with longstanding diabetes, short life expectancy, or extensive comorbid conditions.
Knowledge Check Question #1
- In addition to reductions in major adverse cardiovascular events, I'm going to ask you to select antidiabetic agents listed on the right below, that had been shown to reduce the incidents of cardiovascular death and heart failure related hospitalization by matching the antidiabetic agents with the observed clinical trial outcomes on the left. These outcomes include separately:
- Cardiovascular death and heart failure related hospitalization
- Cardiovascular death
- Neither cardiovascular death or heart failure hospitalization
- Heart failure related hospitalization
The respective medications include:
And the correct answers are:
- Cardiovascular death and heart failure related hospitalization reduction relate back to use of A. empagliflozin
- Cardiovascular death reduction was observed with C. liraglutide
- Use of D. semaglutide was associated with neither a reduction in cardiovascular death nor heart failure hospitalization
- B. Canagliflozin was associated with heart failure related hospitalization as an additional benefit beyond its major adverse cardiac event reduction overall.
Knowledge Check Question #2
Match the adverse effect with the respective agent. Enlisted below on the right, you will see either one or two medications listed, on the left, respective adverse effects or adverse events that are potentially associated with the use of these agents. These adverse effects include:
- Genital infection
- GI upset
- Risk of amputation in patients with peripheral vascular disease
- Retinopathy complication
And on the right-hand side, the potential matched medication pairs or singular medications include:
- Canagliflozin and empagliflozin
- Canagliflozin alone
- Liraglutide with semaglutide
- Semaglutide alone
And as seen here, the SGLT2 inhibitors, in this case including:
- A. Canagliflozin and empagliflozin can potentially increase the risk for genital infections
- GLP-1 receptor agonists including C. liraglutide and semaglutide can increase the risk of GI upset
- B. Canagliflozin, different from other SGLT2 inhibitors, was observed to increase the risk of amputation in patients with peripheral vascular disease
- D. Semaglutide can increase the risk of retinopathy related complications
Long-Term Cardiovascular Outcomes Trials
Now, it's important to understand that, in 2008, there was a guidance document issued by the FDA for industry that really called all newer therapies and established therapies to conduct long-term cardiovascular outcomes trials primarily to determine the safety of these respective agents in patients with diabetes mellitus as it relates to cardiovascular events. It was recommended these cardiovascular outcomes trials be prospective and blinded, evaluate hard cardiovascular endpoints, including mortality, myocardial infarction stroke rates, they enroll patients at higher cardiovascular risk, these include those individuals with diabetes and multiple cardiovascular risk factors and/or those with established atherosclerotic cardiovascular disease, that patients be evaluated for greater than or equal to two years, and that subgroups be evaluated for efficacy and safety. As is shown in the right, it's just a timetable of a number of different drugs belonging to a number of different classes that are color coded with a legend listed, highlighting an outpouring of different investigations meeting the requirements set out by the FDA more than 10 years ago.
Two different drug classes showing DPP-4 inhibitors, including saxagliptin, alogliptin, sitagliptin, and linagliptin, and then a dual PPAR agonist at the bottom, looking at five respective trials showing the respective agents, the drug classes, the major adverse cardiac events that were evaluated in the respective trials, the rates of those events in the active arm versus the comparator arm, and then the hazard ratio both for superiority and noninferiority. With the understanding that most of these trials were powered for noninferiority, and as is the case for each of the DPP-4 inhibitors, as one can see, P Value was statistically significant for noninferiority, but none of these achieved superiority with regard to standard care. And it's going to be looked at a little bit later, I've included the far right, the rates of heart failure hospitalization hazard ratios overall, and for the most part, there was no difference in the rates of this with the exception of saxagliptin that saw a statistically significant 27% relative increase in the rates of heart failure hospitalization in the SAVOR-TIMI 53 trial.
Additional therapies, including two GLP-1 receptor agonists at the top and an SGLT2 inhibitor at the bottom, as is listed similar to the prior slide, the agent class, major adverse cardiac event definition, the rates in the active and comparator arms, and as is listed here, each of these three agents achieved statistical significance for noninferiority, but none of these were able to achieve superiority overall. And as one can see, there is no difference in the rates of heart failure hospitalization for the first two agents, with a statistically lower rate of heart failure hospitalization for dapagliflozin based on data from a DECLARE-TIMI 58 trial.
For the next several slides, we're going to be highlighting different trials examining different therapies for which there were positive cardiovascular outcomes trials, namely these were designed as noninferiority trial designs under the issued guidance document from the FDA in 2008, but it was demonstrated there was statistically significant benefit in terms of reducing the rates of major adverse cardiovascular events in these respective trials. In the first trial, the LEADER trial, this was a trial of over 9,000 patients with diabetes mellitus at high cardiovascular risk randomized to liraglutide versus placebo for a median of 3.1 years. Liraglutide was associated with a significant benefit and achieving superiority for the MACE advantage as shown in the bottom portions at the far left, with an additional statistically significant reduction in the rate of cardiovascular death but no significant improvement in the rate of heart failure hospitalization. On the right, you can see that there was no difference in the rates of any adverse events and there was no significant difference in the rate of hypoglycemic episodes overall.
Positive Cardiovascular Care Outcomes
For the next several slides, we'll be highlighting a number of trials for which there were positive cardiovascular outcomes in follow-up to the 2008 mandate by the FDA. As is shown here, is the LEADER trial, a trial that enrolled over 9,000 patients with diabetes mellitus at high cardiovascular risk that were randomized to liraglutide versus placebo for a median of 3.1 years. And in the left portion of the lower portion of this slide, you can see efficacy outcomes and on the right-hand portion, adverse events associated with exposure to either placebo or the active agent. On the left-hand portion, you can see that treatment with liraglutide achieved superiority in reducing the rates of major adverse cardiac events, and additionally, there was a significant improvement in the cardiovascular death rate. There was no significant difference in the rates of heart failure hospitalization. And on the right, you can see, there was no difference in the rates of any adverse events or in hypoglycemic episodes.
This was followed by another GLP-1 receptor agonist, semaglutide study in the sustained fixed trial that took over 3,200 patients with diabetes mellitus randomized to semaglutide versus placebo for 2 years. This trial was able to demonstrate superiority such that individuals who received semaglutide were associated with a significant reduction in the rates of major adverse cardiac events, but there was no significant difference in the rates of cardiovascular death or heart failure hospitalization. There was no significant difference in rates of serious or any adverse events nor in hypoglycemic episodes for those receiving semaglutide compared to placebo.
And finally, in the REWIND trial, this was a trial over 9,900 patients with diabetes mellitus and a previous cardiovascular event or risk factors for cardiovascular events randomized to dulaglutide or placebo. Similar to the prior slides, one can see that treatment with dulaglutide was associated with a significant reduction or superiority with regard to major adverse cardiac events, no significant difference in the rates of cardiovascular death or in rates of hospitalization for heart failure or urgent visit, and in addition, there was no significant difference in the rates of adverse events leading to drug discontinuation or in severe hypoglycemia.
EMPA-REG Outcomes Trial
Continuing this trend but switching to a different drug class, the SGLT2 inhibitors, this first was led off with the EMPA-REG outcomes trial, a trial of over 7,000 patients with diabetes mellitus at high cardiovascular risk randomized to empagliflozin versus placebo for a median of 3.1 years. Treatment with empagliflozin, in the turquoise color, compared to placebo, in purple, was associated with superiority with a significant reduction in the rates of major adverse cardiac events, and similarly, a significant reduction in the rate of cardiovascular death. Finally, different from what was observed for the GLP-1 receptor agonist, treatment with empagliflozin in this trial demonstrated a significant reduction in heart failure hospitalization. There also, amongst individuals receiving empagliflozin, was a significant reduction in any adverse event with no difference in rates of hypoglycemia.
And in follow-up, this is another trial that evaluated an SGLT2 inhibitor demonstrating positive outcomes. In the CANVAS trial, over 10,000 patients with diabetes mellitus at high cardiovascular risk were randomized to canagliflozin versus placebo for a mean of 3.6 years. Treatment with canagliflozin was associated with a significant reduction or superiority in the major adverse cardiac event rate from those receiving canagliflozin compared to placebo. There was no significant difference in the rates of cardiovascular death, but there was a significant reduction in the rate of heart failure hospitalization, and there was a significant reduction in the rate of adverse events of a serious nature from those receiving canagliflozin compared to placebo, with no significant difference in the rates of any hypoglycemia.
Review: Drug Classes
So in summary, in reviewing the respective drug classes that had been shown to have significant benefit in reducing the rates of major adverse cardiac events amongst diabetics either with established cardiovascular disease or with multiple cardiovascular risk factors, it's important to understand that GLP-1 receptor agonists represent the first drug class reviewed. This stands for glucagon-like peptide-1 receptor agonists, and essentially, this drug mimics the effects of an incretin hormone GLP-1. GLP-1 is released by the small intestine in response to food intake. This leads to increased insulin secretion, increased satiety, and decreased glucagon release, and in fact, slows gastric emptying as well. SGLT2 inhibitors work by a different mechanism. And importantly, SGLT2 stands for sodium-glucose transporter 2 inhibitor, and the SGLT2 receptor is responsible for 90% of glucose reabsorption in the kidney. This leads ultimately to decreased glucose reabsorption, and in effect, achieves modest diuresis.
Dosing, Contraindications, & Adverse Effects
In the upper portion are the 3 GLP-1 receptor agonists listed in alphabetical order, followed at the bottom by the 2 SGLT2 inhibitors listed in alphabetical order. In the upper portion, you can see that the GLP-1 receptor agonists, in this case, for these 3 agents associated with significant benefit, are injectable agents, and the maximum recommended dose of these agents is listed in the subsequent column preceded by the minimum dose. Contraindications to these agents are listed. And then finally, the more common adverse effects are listed in the far right.
In contrast, SGLT2 inhibitors are oral agents that are administered daily with minimum and maximum doses listed. Of note, most commonly, these agents may have contraindication in more advanced forms of renal impairments or for those with end-stage renal disease and/or dialysis. And finally, the most common adverse effects for this class of drugs include genital infections, with the observation of a risk of amputation in patients with peripheral vascular disease amongst those receiving canagliflozin.
As a result of the totality of data that was borne out from the respective trials previously presented, we are now seeing these agents beginning to garner new indications above and beyond what they've historically been approved for, namely being an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. And in the case of liraglutide, we've seen approval with an expanded indication to reduce the risk of major adverse cardiac events in adults with type 2 diabetes and established cardiovascular disease.
In the case of semaglutide, the FDA has reviewed an NDA for an indication to reduce a risk that has been proposed for reducing major adverse cardiac events. In the case of canagliflozin, we've seen an expanded indication to reduce the risk of major adverse cardiac events in adults with type 2 diabetes and established cardiovascular disease. And additionally, the ability to reduce the risk of end-stage kidney disease as is reflected by worsening of renal function, as well as the composited additional includes cardiovascular death and heart failure hospitalization, along with doubling of serum creatinine in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria. Lastly, empagliflozin has been given an expanded indication to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.
Amongst patients who have cardiovascular disease and, additionally, type 2 diabetes mellitus, given the positive significant benefit afforded by, on the left, SGLT2 inhibitors illustrate at the time, with the data being available for empagliflozin, and on the right, the injectable GLP-1 receptor agonists at the time, limited to the use of liraglutide, can provide incremental cardiovascular risk reduction that has led to an expanded label indication for these drugs in helping to mitigate the risk of adverse cardiovascular events. It's also important to note, these individuals should be referred to their primary care physician or endocrinologist, and in collaboration, a cardiologist can play a very important role in helping to mitigate or lessen the risk of adverse cardiovascular events.
Initiation of traditional glucose-lowering medications may afford benefit in type 2 diabetes mellitus. This includes subgroups in those with atherosclerotic cardiovascular disease, heart failure or chronic kidney disease, those in whom there's an urgent need to lower blood sugar, those with a compelling need to minimize weight gain or promote weight loss overall.
For the cardiologist, it's important to realize that amongst those individuals in whom, in particular, ASCVD predominates, a GLP-1 receptor agonist with proven cardiovascular disease benefit and/or an SGLT2 inhibitor with proven cardiovascular disease benefit, provided their estimated GFR is adequate, are recommended therapies. If those individuals persist in having a hemoglobin A1c above target, there are a number of other add-on options that can be considered. And on the right, for those with heart failure or chronic kidney disease predominating, it's preferable to use an SGLT2 inhibitor with evidence of reducing heart failure and/or chronic kidney disease progression based upon a previously reviewed cardiovascular outcomes trials, or if an SGLT2 inhibitor is not tolerated or contraindicated based upon a lessened estimated GFR, a GLP-1 receptor agonist with proven cardiovascular disease benefit can be considered.
And so the three key fundamentals for cardiologists is awareness of the link between diabetes mellitus and cardiovascular disease and even heightened risk amongst those individuals that happened to have diabetes mellitus with established cardiovascular disease. The importance is that cardiologists take action, which may occur in the form of recommending to their endocrinologist and primary care physician to consider therapies associated with cardiovascular risk reduction, including GLP-1 receptor agonists and/or SGLT2 inhibitors with established benefit based on large outcomes trials, or the prescribing of those antidiabetic agents associated with cardiovascular disease risk reduction from the outset, and then following these individuals in conjunction with their primary care provider and their endocrinologist in order to, on an ongoing basis, mitigate their cardiovascular risk.
- Examine new and emerging agents for reducing cardiovascular risk in patients with type 2 diabetes mellitus and cardiovascular disease.
- Discuss the potential adverse effects associated with these agents when used to mitigate cardiovascular risk in those with diabetes mellitus.