Heart In Diabetes 2019:

Need to Amplify Peripheral Artery Disease as a Risk of CVD in Diabetes

with with Laurence S. Sperling, MD, Pam R. Taub, MD, C. Low Wang, MD

One of the key lessons to emerge from the 2018 cholesterol guideline is the need to focus clinical care on diabetes complications, beginning with the range of challenging arising from hyperlipidemia.1

When you realize that 25-35% of patients who are eligible for statins are not getting them, the challenge in improving our clinical approach to diabetes management becomes much more clear,1 says Laurence S. Sperling, MD, Katz Professor in Preventive Cardiology and director of the Center for Health Disease Prevention at Emory University, and co-chair 2018 ACC/AHA Multisociety Guideline on the Management of Blood Cholesterol,2 at the 3rd annual Heart in Diabetes Conference in Philadelphia, Pennsylvania.

Insights into Treatment Enhancers for Hyperlipidemia in Type 2 Diabetes  

“We need to foster more consistent guideline-driven treatments that are informed by discussion with the patient and use of clinical judgement in personalizing care, as well as implementing cost-value statements to better inform our clinical management strategies,” says Dr. Sperling.  

For example, value-based recommendations aimed at reducing low lipoprotein cholesterol (LDL-C) by 50% (to achieve 70 mg/dL threshold Secondary prevention) will require optimizing intensive statin therapy, particularly in patients with a LDL-C greater than 190 mg/dL and a moderate statin for LDL over 100 mg/dL. When a statin isn’t sufficient, then adding a PSCK9 inhibitor, as needed.1,2

In addition, residual risk that takes into account sociodemographic factors should be used as it offers a more accurate predicator of possible response to therapy, and will guide selection of appropriate interventions.1,2 This is particularly necessary in managing patients with metabolic syndrome (Mets) as these patients who have type 2 diabetes (T2D) are at higher risk for hypertriglyceridemia, he says.

And to refute a popular misconception circulating in the consumer press, “statins don’t cause diabetes but may nudge suspectable individuals over so interventions are needed to address cardiovascular disease (CVD) risk to lessen the potentiation of type 2 diabetes,” says Dr. Sperling.

At what stage in the development of type 2 diabetes does the risk for atherosclerotic cardiovascular complications increase? Here is a list of influential risk factors:

Insulin resistance syndrome is implicated in the dysregulation of:

  • Body weight --> Obesity (visceral adiposity)
  • Impaired glucose tolerance -> type 2 diabetes
  • Blood pressure --> Hypertension
  • Serum cholesterol à hyperlipidemia
  • Increased PAI-1
  • Liver function --> NAFLD/NASH
  • Inflammation
  • ASCVD
  • Hyperinsulinemia -->One drug, pioglitazone, can address the full spectrum of insulin resistance. 

Complex Atherosclerotic Patients Need Lower LDL with PCSK9 Plus Statins

To reinforce the need to consider PCSK9 inhibitors for high risk patients, Pam R. Taub, MD, FACC, associate professor of medicine at the Sulpizio Family Cardiovascular Center at the University of California/San Diego Medical Center, and director of the Step Family Foundation Cardiovascular Rehabilitation and Wellness Center in La Jolla, California, offered another caveat:3

“Atherosclerosis is a diffuse disease driven by inflammation, atherogenic lipoproteins, and platelet aggregation in the acute phase, meaning patients will move from stable to unstable plaque development. As such, it is important to consider this disease from multiple angles—suggesting that a focus solely on LDL-C is not enough to reduce residual risk, especially in individuals with diabetes and peripheral artery disease.”

Furthermore, to adequately address the constellation of medical factors facing patients with T2D, she challenged clinical reliance on stress testing and angiography as “lousy” tests that offer little clinical insight regarding plague status and serum cholesterol variables.3

“Most patients will present with partial stenosis, so they are harboring less than 50% lesions that are not picked up in standard testing, so I recommend calculating non-HDL, which I call the “poor man’s” value, to get the same information while avoiding an expensive blood test that will likely not reimbursed so isn’t an option for many patients,” she says. “Plaque stabilization may best be achieved with the addition of PCSK9 with statin therapy as the new paradigm to lower LDL optimally and with no adverse impact on neurocognitive function.”

Statins are fine for the management of elevated LDL-C but patients with multivessel coronary artery disease and PAD will derive greater benefit from the addition of a PCSK9 (ie, alirocumab and evolocumab have demonstrated greater absolute risk reduction) when diabetes is also present.5,6

“Since peripheral artery disease is a key aspect of atherosclerotic heart disease in patients with T2D, these complex patients will require multiple drug management to address the hyperlipidemia beyond LDL-C, in order to fulling benefit from a reduction in risk of first events and total events,” she says.

In one limitation of the FOURIER trial, however, Dr. Taub says, “women were underrepresented, making up only 25% of the cohort, so the risk reduction may not bear out quite the same in these patients.”6

Patients with peripheral artery disease have the worst outcomes, yet are receiving suboptimal treatment including poor blood pressure control and insufficient lipid management, clinical management must include PCSK9 inhibition to gain the benefit of a 42% RRR in amputations; thus, this should become the standard of care,” says Dr. Taub.

Need to Amplify Peripheral Artery Disease as a Risk of CVD in Diabetes  

The risk factors associated with PAD are similar to that of coronary heart disease and cerebrovascular disease, increasing morbidity and mortality, with diabetes, hypertension, and smoking further exacerbating risk. incident PAD will arise in 20.5% of patients, according to findings from the BARI 2D trial,7 and half of patients with critical limb ischemia have diabetes, based on results of the EUCLID study.8

Cecelia C. Low Wang, MD, professor of medicine at the University of Colorado in Aurora, Colorado, and elite clinician scientist at CPC Clinical Research, spoke with EndocrineWeb about the challenge of addressing peripheral artery disease (PAD), a potentially devastating condition that we don’t pay enough attention to—particularly in individuals with diabetes—even as it represents a key aspect of atherosclerosis, as much as does ischemic stroke and heart disease.”

For every 1% rise in hemoglobin A1c (HbA1c), there is a 14.2% increase in risk of 3-point MACE in individuals with type 2 diabetes, with all patients at significant risk of developing peripheral artery disease.9 The condition in these patients is more severe with significantly worse outcomes, such as increased risk of foot ulcers, amputations, and a doubling in mortality.

Additionally, recent trends point to intermittent claudication as the most common symptom of PAD but noninvasive measures, such as the ankle-brachial index, indicate that asymptomatic PAD is several times more common, rising precipitously as individuals reach their 60s, Dr. Wang says.

Outcomes of Two Key PAD Trials: BARI 2D and EUCLID

From the BARI 2D trial, incident PAD was found to be 20.5%,7 and the most recent data on PAD in people with diabetes from the EUCLID study raises the stakes to nearly 50% of these patients developing critical limb ischemia,8 says Dr. Wang, in reinforcing the dire need for clinicians to turn their attention to addressing PAD in anyone with diabetes, particularly the longer term, older patient.

The efficacy of monotherapy with ticagrelor or clopidogrel was assessed among 13,885 patients with peripheral artery disease, focusing on the subset of patients diagnosed with critical limb ischemia, a EUCLID trial extension using Ticagrelor.9 The primary endpoints were cardiovascular death, myocardial infarction (MI), and ischemic stroke, and any patient requiring revascularization or amputation for within three months of the study start were not enrolled in this study.

Participants who had PAD were found to have higher rates of myocardial infarction and acute limb ischemia, with similar composite rates of cardiovascular death, MI, and stroke when compared with patients enrolled based on the ankle-brachial index criterion.10  No significant differences were found between ticagrelor and clopidogrel for reduction of cardiovascular or acute limb events.

The subgroup consisted of nearly 5% of participating patients who exhibited pain at rest (58.8%), significant tissue loss (9.0%), and minimal tissue loss (32.2%), and experienced significantly higher rates of both cardiovascular mortality and morbidity.9 This reinforces the necessity of devoting greater clinical attention to identifying and treating patients with PID to lessen their risk of cardiac events, says Dr. Wang.

“Patients who are at risk for PAD included those with diabetes, cigarette smokers, and individuals with other risk factors for atherosclerotic cardiovascular disease, such as hypertension or hyperlipidemia. The prevalence of PAD is similar in men and women, although men appear to have greater severity and symptomatology,”10  she says. There is a marked increase in the rate of PAD in women, with a strong ethnic difference.

“I think the reason that PAD goes under-recognized, under-diagnosed, and under-treated is that we have been more focused on heart disease and stroke, but there are three telltale signs that may alert clinicians: Claudication; smooth, shiny skin on the legs; decreased profile pulses,”11 says Dr. Wang.

“Individuals who present with any of these symptoms typically are not necessarily identified  as having peripheral artery disease yet we really need to diagnose these patients with ankle brachial index and consider further evaluation as they would benefit greatly from aggressive lipid lowering therapy, antihypertensives as well as paying attention to other aspects such as smoking cessation,” she says.

Despite Uncertainties, Consider Treatment to Lower ASCVD  

All patients with PAD should be treated! And, not according to age limits, which is bad practice since physiological conditions of a person will vary greatly across the age continuum. You patient can be a young 80 or an old 60, indicative of a wide variability,12 says Paul S. Jellinger, MD, MACE, professor of medicine at the University of Miami Miller School of Medicine and the Center for Diabetes & Endocrine Care, at the 3rd annual Heart in Diabetes Conference.

“There is a great need to deliver cardionephroprotective effects in these patients so aim for drugs with dual efficacy to best integrate guideline recommendations for hypoglycemia, lifestyle and cardiovascular benefits,says Dr. Jellinger.

When PAD presents in a patient with diabetes, the condition is more severe and has significantly worse outcomes, noting a doubling in the rate of deaths estimated at (51.7% versus 25.6%, with and without diabetes, respectively; P < 0.002) particular with regard to foot ulcers (P < 0.001) and number of amputations (P < 0.0001),13 he says.

In summary, Dr Wang says that despite current therapies employed to lower ASCVD risk, individiuals with type 2 diabetes and PAD are at greater risk for adverse cardiovascular outcomes and adverse limb events, exacerbated by poor glucose control. Clinicians must morve to address the elevated risks for MACE in these patients.

Dr. Taub receives fees from Sanofi/Regeneron, Amgen, Pfizer, Boehringer Ingelheim, Novo Nordisk, Amarin, and Janssen. Dr. Jellinger reports fees received from Amgen, Regeneron, and Dr. Wang 

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