DIABETES AND CARDIOVASCULAR EVENTS
Type 2 diabetes (T2DM) is common in adults and is characterized by insulin resistance that results in hyperglycemia. Diabetes increases the risk of microvascular and macrovascular events. As a result, patients with diabetes have a higher risk of dying from cardiovascular disease and are at a higher risk for developing heart failure. The duration of diabetes and degree of glycemic control with diabetes is a significant predictor of future events. Thus, identification of patients at risk for diabetes, prediabetes, and new-onset diabetes allows for intensified therapy that may reduce the chances of developing diabetes and mitigate the risk of complications from diabetes. Patients are considered to have diabetes if they have a fasting plasma glucose of ≥126 mg/dL, oral glucose tolerance test with a 2-hour postprandial glucose ≥200 mg/dL, glycosylated hemoglobin of ≥6.5%, or random plasma glucose ≥200 mg/dL. Exercise, weight loss, and metformin improve insulin sensitivity and are effective strategies to reduce the risk of developing diabetes in patients with prediabetes. Drugs from two different classes have been shown to be effective in reducing cardiovascular events specifically in patients with diabetes. The sodium/glucose cotransport-2 inhibitors, liraglutide, and semaglutide have been shown to reduce cardiovascular events in patients with diabetes. Because of the high degree of cardiovascular disease in patients with diabetes, efforts to use drugs with proven cardiovascular benefit, together with intensive cardiovascular risk factor modification, offer the ability to reduce the incidence of cardiovascular events in this high-risk population of patients.
FIG 17.1 Diabetes mellitus and its complications: microvascular and macrovascular complications
Diabetes mellitus is the resultant state of insulin deficiency that
causes elevated blood glucose. The etiologies of this insulin deficiency can
broadly be classified as either type 1 or type 2 diabetes. Type 1 diabetes is
characterized by an autoimmune process that results in β-cell dysfunction and
inadequate insulin production. This form of diabetes frequently presents during
childhood or adolescence, and requires insulin supplementation due to the
inadequate production of insulin by the pancreas.
Type 2 diabetes (T2DM) is more common in adults and is characterized by
insulin resistance. Because most adult patients have T2DM, it is this group
that will be the focus of this chapter. All of the mechanisms that underlie the
development of insulin resistance have not been fully elucidated. It is likely
that the disease is caused by the interaction of multiple different factors,
including genetic, environmental, and lifestyle factors, all of which
contribute to the development of the disease. It is clear that obesity plays a
central role and decreases the body’s responsiveness to insulin. This decrease
in the response to insulin is known as insulin resistance, and patients with
insulin resistance are considered to have prediabetes. In patients with
prediabetes, higher levels of insulin are required to maintain glucose
homeostasis. These increased demands on the pancreas place the insulin-producing
β cells under stress. Ultimately, the pancreas is no longer able to produce
enough insulin to maintain euglycemia, and thus, hyperglycemia results. These
patients are considered to have progressed from prediabetes to T2DM. In
patients with longstanding and poorly controlled T2DM, insulin production can fall, exacerbating the insulin deficiency
and excess hepatic glucose production, which results in physiology that can
resemble T1DM. The presence of T2DM increases the risk of multiple adverse
health events, including death. Broadly speaking, diabetes complications can be
divided into those that are microvascular or macrovascular in origin (Fig.
17.1). Microvascular disorders include retinopathy (diabetes remains a leading
of blindness), nephropathy (which can lead to end-stage renal disease), and
neuropathy. Macrovascular complications from diabetes refer to those events
that are predominately seen in larger caliber vessels and include myocardial
infarction, stroke, and peripheral arterial disease. Patients with diabetes are at considerably higher risk of
atherosclerosis and ischemic events.
Multiple biological mechanisms link diabetes and atherosclerosis. The
higher burden of atherosclerosis seen in patients with diabetes is related
partially to the direct effects of hyperglycemia. Hyperglycemia increases the
proliferation of vascular smooth muscle cells that causes vascular beds to have
diffusely diseased vessels and decreased capacity for delivery of blood (Fig.
17.2). Hyperglycemia also results in oxidative stress and the formation of
reactive oxygen species, which, in turn, promote lipid oxidation, endothelial
damage, inflammation, and progression of lipid-rich plaques. Finally,
alterations in lipid metabolism and
the association of hypertension and obesity that occur frequently in patients with diabetes also contribute
to the development of atherosclerosis and the increased risk of cardiovascular
events seen in this population.
In addition, it is becoming increasingly clear that patients with diabetes
are also at increased risk of heart failure. The relationship between diabetes
and heart failure has been known for some time; however, it was believed that
diabetes predominately increased the risk for ischemic cardiomyopathies
secondary to the higher rates of coronary artery disease seen in this
population. Although coronary artery disease remains a significant risk factor
for heart failure, it has been shown that the relationship between diabetes and
heart failure is independent of the presence of atherosclerosis. In the
REduction of Atherothrombosis for Continued Health (REACH) registry, which is a
large international registry of patients with either established
atherosclerosis or at high risk for atherosclerosis, patients with previous
myocardial infarction or stroke had higher rates of heart failure than patients
without established cardiovascular disease. However, the presence of diabetes
resulted in a similar relative increase in the risk of heart failure,
regardless of whether patients had a previous ischemic event or only had risk
factors for heart failure. Patients with diabetes are at risk for heart failure
with preserved ejection fraction, and this form of heart failure occurs
independently from coronary artery disease. Although diabetes also increases
the risk of other events (e.g., infections), preventing microvascular,
macrovascular, and heart failure complications are the dominant goals of the current therapies for diabetes.
EPIDEMIOLOGY
The prevalence of diabetes is increasing across the world. In 1980, it
was estimated that 108 million people had diabetes, and that is affected
approximately 4.3% of the world’s population. Over the past 25 years, the rate
of diabetes has grown exponentially, such that in 2014, it was estimated that
diabetes was present in 422 million people worldwide and affected approximately
9% of men and 8% of women. Although some of this increase is believed to be
secondary to aging of the population, overall increases in the prevalence of
obesity are thought to be a consider- able driver for the more than fourfold
increase in prevalence. The incidence rate of diabetes is expected to continue
to climb, and some studies have suggested that >700 million people may have
diabetes by 2025.
There are multiple risk factors for the development of diabetes,
including genetic predisposition, caloric intake and/or diet, and physical
activity (or the lack thereof). All of these issues factor into the risk of
developing diabetes. Ultimately, the rates of T2DM are closely linked with the
presence of obesity. Most increases in the prevalence of diabetes are at least
somewhat linked with the increasing incidence of obesity. Although diabetes and
obesity are increasing in the United States, the rates of diabetes are
increasing at the highest absolute rates in the developing world. This increase appears to be due, at least in
part, to the increase of high caloric
diets and decreases in energy use as these societies move from predominately
agrarian to more industrialized ways of life. Efforts to prevent the increase
in the prevalence of diabetes are focused on the developing world because these
increases are con- tributing significantly to the overall increase in the
incidence of diabetes.
Patients with diabetes have higher rates of death compared with patients
without diabetes. When evaluating the reasons for the differential rates of
death, the largest contributor to the excess in deaths in patients with
diabetes are cardiovascular events. Thus, targeting cardiovascular events is
likely the most effective strategy to improve out-comes in patients with
diabetes. Although rates of cardiovascular complications are declining, both in
the general population and in patients with diabetes, the large increases in
the number of patients with obesity and diabetes may threaten the long-term
decreases in the cardiovascular event
rate.
FIG 17.2 Atherosclerosis in diabetes.
CLINICAL PRESENTATION
The duration of diabetes and degree of glycemic control with diabetes is
a significant predictor of future diabetes complications. Previous studies have
shown that glycosylated hemoglobin (HbA1c), which is a marker of
glucose levels over the previous 3 months, predicts cardiovascular events in
patients both with and without established diabetes. The duration of diabetes
is also a significant independent predictor of future diabetes complications.
Thus, identification of patients at risk for diabetes, prediabetes, and
new-onset diabetes allows for intensified therapy that may mitigate the risk of
long-term complications from diabetes.
The American Diabetes Association (ADA) has identified some important
risk factors associated with the development of diabetes: lack of physical
activity; patients of African American, Latino, Native American, Asian
American, Pacific Islander race or ethnicity; patients with a family history of
diabetes (particularly those with first-degree relatives who have diabetes); women previously diagnosed with
gestational disease; patients with hypertension; patients with low high-density
lipoprotein cholesterol (<35 mg/dL) and/or high triglycerides (>250 mg/
dL); patients with evidence of insulin resistance (HbA1C ≥5.7%);
patients with impaired glucose tolerance (glucose of 140–199 mg/dL on a 2-hour
glucose tolerance test) or impaired fasting glucose (100–125 mg/dL); patients
with severe obesity; patients with acanthosis nigricans and/or polycystic
ovarian syndrome; patients with hypertension (≥140/90 mm Hg or on treatment);
and patients with a known cardiovascular disease are all independent predictors
of having diabetes.
Current guidelines recommend screening for diabetes in patients who are
overweight and/or obese and have at least one of the previously mentioned risk
factors for diabetes. The diagnosis of diabetes requires the presence of at
least one of four different clinical findings: (1) fasting plasma glucose of
≥126 mg/dL; (2) oral glucose tolerance test (with equivalent of 75 g anhydrous
glucose dissolved in water) with a 2-hour postprandial glucose of ≥200 mg/dL;
(3) HbA1C ≥6.5%; or (4) random plasma glucose of ≥200 mg/dL.
Patients are considered to have prediabetes if the HbA1c is
between 5.7% and 6.4% (additional criteria for prediabetes include fasting
plasma glucose between 100 and 124 mg/dL or glucose tolerance test with 2-hour
glucose between 140 and 199 mg/dL). Patients with prediabetes are at increased
risk of developing diabetes over time, and patients with tests closer to the
upper range for prediabetes have a greater risk than patients with test results
that are closer to the lower range. Patients with diabetes should be encouraged
to begin exercise programs, work to lose weight, initiate therapies designed to
modify cardiovascular risk factors, and reduce the risk of cardiovascular
events. Previous studies have found that
exercise and weight loss are particularly efficacious in reducing the risk of developing diabetes.
FIG 17.3 Lesions in a diabetic foot.
MANAGEMENT AND THERAPY
The management of patients with diabetes depends upon whether patients
have prediabetes and/or insulin sensitivity or if they have developed T2DM. The
goals of therapy for patients with prediabetes focus on improving risk factor
control and preventing the progression from insulin resistance to diabetes.
Current recommendations focus on therapies shown to improve insulin
sensitivity. Exercise and weight loss improve insulin sensitivity and have been
shown to be effective strategies to reduce the risk of progression to diabetes.
In a trial of 3234 patients with elevated fasting and postload plasma but
without diabetes, patients randomized to lifestyle modification programs with
goals of ≥7% weight loss and 150 minutes of physical activity per week had
lower incidence of diabetes. In this same study, patients randomized to
metformin also had lower rates of diabetes compared with patients who had usual
care. However, the incidence of new-onset diabetes was lowest in those patients
who received lifestyle interventions. Thus, in patients with prediabetes,
lifestyle modifications and metformin form the foundation of current treatment
recommendations. In patients with prediabetes who have had a stroke or
transient ischemic attack, treatment with pioglitazone has been shown to be
effective in reducing the progression to diabetes and decreasing the risk of
future stroke or myocardial infarction.
In patients with established diabetes, the goals of therapy focus on the
prevention of the microvascular and macrovascular complications of diabetes.
Early identification of retinopathy through diabetic eye examinations, detection of nephropathy with urine microalbumin, and diabetic foot examinations to identify
neuropathy and its complications are the cornerstones for preventing
microvascular complications (Fig. 17.3). Glycemic
control and glucose-lowering drugs are particularly important in preventing the
microvascular complications of diabetes. In the United Kingdom Prospective
Diabetes Study (UKPDS), microvascular events such as diabetic nephropathy
were reduced with intensive glucose control. Although this study was performed
in an era in which there were limited drugs for diabetes, and cardiovascular
risk factors were not as aggressively controlled, there is a continued role for
glycemic control in reducing microvascular complications.
The impact of glucose control on cardiovascular and other macrovascular
events remains less clear. Previous studies have shown a clear association
between the degree of glycemic control and the risk for cardiovascular events;
yet, there are less data on whether glycemic control can reduce the risk of
cardiovascular events. In the UKPDS trial, patients randomized to intensive
glucose lowering had evidence of lower rates of myocardial infarction. However,
this benefit was not seen during the initial trial, and only became evident
after 10 years of follow-up. Similar studies, such as the Action to Control
Cardiovascular Risk in Diabetes
(ACCORD) trial, the Veterans Affairs Diabetes Trial (VADT), and Action in
Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation
(ADVANCE) trial, which randomized a more contemporary cohort of patients either
to an intensive or routine glucose-lowering strategy, also did not show lower
rates of either cardiovascular death or myocardial infarction. When pooled
together in a meta-analysis, these studies suggested that intensive glycemic control likely does reduce myocardial infarction.
Current treatment guidelines for the treatment of diabetes recommend
metformin as a first-line therapy for lowering glucose in patients with
diabetes. Metformin is effective in lowering blood glucose, and a small trial
has provided some evidence, albeit with a small number of events, that it may
also reduce cardiovascular events. It remains the first-line therapy based upon
the long history of use that has provided observational evidence of safety and
efficacy with regard to glucose control. Although there is limited evidence for
reductions in cardiovascular events, metformin is widely available and
affordable, making it a reasonable choice for the initial treatment of patients
with diabetes.
Most patients with diabetes will either have such poorly controlled
glucose when diagnosed with diabetes that they will require more than one drug
or will have progression of diabetes over time, making further therapies
necessary. Current treatment guidelines support the concept of individualizing
diabetes therapy based on individual patient factors. In patients at risk of
cardiovascular disease, using therapies that have been shown to reduce
cardiovascular risk should take a precedence over those therapies that have
only been found to be effective in improving glucose control.
Sodium/Glucose Cotransport-2 Inhibitors
Currently, drugs from two different classes have been shown to be
effective in reducing cardiovascular events in patients with diabetes. The
sodium/glucose cotransport-2 inhibitors (SGLT-2i) have been shown to reduce
cardiovascular events in patients with diabetes with either established
atherosclerosis or who are at high risk for developing cardiovascular disease. These drugs work by inhibiting the SGLT-2 cotransporter, which is found in the
proximal tubule of the kidney.
When functioning normally, this cotransporter serves to re-uptake glucose
that has been filtered by the kidney. Inhibition of this cotransporter results
in glycosuria, which causes a mild osmotic diuretic effect and reductions in
blood pressure and weight.
Thus far, two large cardiovascular outcome trials found that treatment
with empagliflozin (Empagliflozin Cardiovascular Outcome Event Trial in Type 2
Diabetes Mellitus Patients—Removing Excess Glucose [EMPA-REG]) and
canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS]) reduces
major cardiovascular events, as well as hospitalization for heart failure and
progression of renal disease. In the Comparative Effectiveness of Cardiovascular
Outcomes (CVD- REAL) study, a large
observational study of 1.4 million patients with diabetes from six different
countries, patients with diabetes initiated on SGLT-2i had a lower risk of
death and hospitalization for heart failure, which provided further support for
the role of SGLT-2i in the treatment of patients with diabetes. These drugs
were the first class of drugs designed specifically to lower glucose that were
found to be effective in reducing the risk of cardiovascular disease. Because
of the nature of these drugs, it seems unlikely that the beneficial effects
were related to reductions in glucose control. The exact mechanism by which
these drugs improved cardiovascular outcomes remains unclear, but might be
secondary to effects on weight, blood pressure, and progression of renal
disease.
Glucagon-Like Peptide–1
Agonists
Some agonists of glucagon-like peptide–1 (GLP-1) have also been shown to
improve outcomes in patients with diabetes. The physiological role of GLP-1 is
to help maintain glucose homeostasis and glycogen storage. The ingestion of
food results in the release of GLP-1, which lowers plasma glucose by increasing
insulin secretion and glycogen storage. Agonists of GLP-1 and dipeptidyl
peptidase IV (DPP-IV) inhibitors (drugs that block the breakdown of GLP-1,
which results in higher levels of biologically active GLP-1), have been found
to be effective in lowering plasma glucose. Two specific GLP-1 agonists,
liraglutide and semaglutide, have been shown to reduce cardiovascular events in
patients with diabetes. These benefits have not been seen with other GLP-1
agonists or with DPP-IV inhibitors. In the Liraglutide Effect and Action in
Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial, patients
treated with liraglutide had a lower risk of cardiovascular death, myocardial
infarction, or stroke (13.0% vs. 14.9%; hazard ratio [HR]: 0.87; 95% confidence
interval [CI]: 0.78–0.97), with consistent effects
on cardiovascular death (4.7% vs. 6.0%; HR: 0.78; 95% CI: 0.66–0.93), myocardial infarction (HR:
0.86; 95% CI: 0.73–1.00; P = 0.046),
and stroke (HR: 0.86; 95% CI: 0.71–1.06). Semaglutide is a longer acting GLP-1
agonist that was studied in a small randomized
clinical trial that also showed reductions in cardiovascular events.
The exact mechanism by which liraglutide and semaglutide reduce major
cardiovascular events has not been fully elucidated. GLP-1 receptors have been
found in a variety of different cardiovascular tissues. Animal models suggest
that GLP-1 agonists may activate molecular pathways that are important for
myocardial survival. Human studies with intravenous GLP-1 at a pharmacological
dose found improvements in left ventricular function, maximum oxygen uptake,
and physical performance in subjects with congestive heart failure, as well as
reductions in blood pressure in patients with hypertension. These studies raise
the potential for a nonglycemic mechanism of cardiovascular benefit.
Hypertension Control
In addition to the SGLT-2i and GLP-1 agonists, patients with diabetes and established cardiovascular disease should
have aggressive cardiovascular risk
factor modification. Patients with blood pressures >120 mm Hg (systolic) or
>80 mm Hg (diastolic) should increase exercise, lose weight, and decrease
salt intake. Results from a large meta-analysis of 40 trials of
antihypertensive therapy have found that the pharmacological treatment of
hypertension is most beneficial in patients with diabetes who have a baseline
blood pressure of >140 mm Hg. There are some studies that have suggested
achieving a goal blood pressure of 130 mm Hg rather than 140 mm Hg, which could
result in a small reduction in the percentage of cardiovascular events and
stroke. However, current ADA guidelines recommend the initiation of
antihypertensive therapy for patients with blood pressures >140 mm Hg
(systolic) or >90 mm Hg (diastolic).
Lipid-Lowering Therapy
Lipid-lowering therapy is an important aspect in the prevention of
cardiovascular disease in patients with diabetes. In patients with diabetes and
established cardiovascular disease, lowering low-density lipoprotein
cholesterol (LDL-C) to extremely low levels reduces the risk of cardiovascular events. In the Improved Reduction of Out-comes: Vytorin Efficacy
International Trial (IMPROVE-IT), patients with an acute coronary syndrome were
randomized to either simvastatin 40 mg/ezetimibe 10 mg or simvastatin 40 mg.
Patients with diabetes who were treated with ezetimibe had lower rates of
cardiovascular death, myocardial infarction, unstable angina that required
hospitalization, coronary revascularization, or stroke at 7 years (45.5% vs.
40.0%; HR: 0.86; 95% CI: 0.78–0.94). The effects of ezetimibe in patients with
diabetes was greater than in patients without diabetes (P value
[interaction] = .02). Further reductions in cardiovascular events have also
been shown with proprotein convertase subtilisin/kexin type 9 (PCSK9)
inhibitors, which have been studied for use, in addition to statins. In the
Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with
Elevated Risk (FOURIER) trial, patients treated with evolocumab, a PCSK9
inhibitor, had a mean LDL-C of 30 mg/dL and significantly lower rates of
cardiovascular events. Although there are no specific trials in patients with
diabetes, in the FOURIER trial, a large proportion of patients had diabetes
(37%). Taken together, these studies suggest that patients with diabetes
benefit from aggressive lowering of LDL-C.
Current guidelines recommend that intensive statin therapy should be used
for all patients with diabetes and known cardiovascular disease or those with
risk factors for cardiovascular disease who are younger than 75 years old.
Moderate intensity statins should be used in patients 40 to 75 years old without
risk factors for cardiovascular disease. Because of the data on ezetimibe and
PCSK9 inhibitors when used in addition to statin medications, it is highly
likely that future guidelines may move toward recommendations that support a
low goal LDL-C in patients with diabetes.
Antiplatelet Medications
Antiplatelet therapy reduces the risk of future cardiovascular events in
patients at high risk of cardiovascular disease without established
atherosclerosis and in patients with established atherosclerosis. Aspirin is
recommended for long-term use in patients with diabetes who have had either a
previous ischemic event or known atherosclerosis. The benefit of aspirin in
patients with diabetes who have no evidence of atherosclerosis is less clear.
As such, current recommendations support the use of aspirin in patients with a
10% risk of cardiovascular disease during the next 10 years of follow-up.
Traditionally, patients with diabetes who are 50 years or older are considered
to be at increased risk if they have at least one other cardiovascular risk
factor (family history of early atherosclerosis, hypertension, smoking,
dyslipidemia, or albuminuria). In those patients with diabetes who are younger
than 50 years old and have lar risk
factors, aspirin therapy is not recommended.
Following a myocardial infarction,
lifelong aspirin and additional antiplatelet therapy with a P2Y12
inhibitor for at least 1 year is indicated. Because of the high rate of
recurrent cardiovascular events in patients with diabetes, this population has
particular benefit from more intensive antiplatelet therapy with ticagrelor and
prasugrel. Although patients in clinical practice are often treated with only
12 months of dual antiplatelet therapy, patients with diabetes should be
considered for long-term therapy. Patients with diabetes in the Prevention of
Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor
Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial
Infarction 54 (PEGASUS-TIMI 54) trial, which evaluated the usefulness of
long-term ticagrelor in patients 1 to 3 years after an acute myocardial
infarction, had lower rates of cardiovascular events, including cardiovascular
death. This supports longer duration or more intensive antiplatelet therapy in patients with diabetes and a previous
myocardial infarction.
FUTURE DIRECTIONS
There have been significant advances in the care of patients with
diabetes that have resulted in an overall decline in the rates of
cardiovascular events. However, these improvements are threatened by the
prevalence of diabetes with an increasing overall number of cardiovascular
events. Future efforts to improve outcomes in patients with established T2DM
will focus on methods to more accurately prevent diabetes. Current prevention
strategies focus mostly on risk stratification by identifying events that have
already occurred (e.g., previous myocardial infarction). Moving forward, using
cardiovascular biomarkers such as high-sensitivity troponin or B-type
natriuretic peptide may allow more accurate prediction of which patients are at
highest risk of future cardiovascular events and who could benefit from more
intensive therapies.
New pharmacotherapies such GLP-1 agonists and SGLT-2i have been shown to
reduce cardiovascular risk in patients with diabetes and established
cardiovascular disease. Further work is needed to understand whether these same
cardiovascular benefits can be seen in patients without established
cardiovascular disease and possibly even in patients with only prediabetes. In
addition, it will important to better understand the mechanism of action in
these drugs to explore additional targets that could provide further benefit,
and so that clinicians can better understand
how to most effectively use these therapies.
