A Provider’s Guide to Vascular Disease, Dyslipidemia, and Glycemic Dysregulation in Chronic Spinal Cord Injury

Abstract

Individuals with chronic spinal cord injury (SCI) are predisposed to accelerated atherogenesis, dyslipidemia, and glycemic dysregulation, although not enough is known about the etiologies or clinical consequences of these secondary effects of paralysis. While guidelines for the detection and treatment of cardiometabolic disease in SCI have recently been published, there has been a historical paucity of data-driven approaches to these conditions. This article will describe what is and not known about the cardiovascular disease and glycemic dysregulation that frequently attend SCI. It will conclude with a review of both guideline-driven and informal recommendations addressing the clinical care of people living with SCI.

Health Maintenance Checklist

1. Reduce the number of cardiometabolic risk factors to <3, including:

   1. Reduce body fat to achieve body mass index (BMI) ≤ 22 kg/m²;

   2. Reduce triglycerides to ≤ 150 mg/dL and increase HDL-C to ≥ 40 mg/dL;

   3. Reduce fasting blood glucose to ≤ 100 mg/dL and/or HbA1c to < 7%.

2. Encourageexercise≥ 150 minutes per week to increase energy expenditure sufficiently to achieve neutral of negative (fat loss) energy balance.

3. Encourage adoption of a heart-healthy diet with focus on fruits, vegetables, low-fat dairy, poultry, fish, legumes, and nuts to achieve neutral or negative (fat loss) energy balance.

4. Recommend limiting saturated fat to 5% to 6% of total caloric intake.

Episodic Care Key Points

1. Body fat determination with obesity surrogate of body mass index (BMI) ≥ 22 kg/m² should be assessed annually, and negative energy balance targeting diet (intake) and exercise (expenditure) implemented as needed for fat loss.

2. Fasting lipid profile or at minimum high-density lipoprotein cholesterol (HDL-C) and triglycerides should be assessed annually, with diet, exercise, and statin or extended-release niacin prescribed to achieve target triglycerides ≤150 mg/dL and HDL-C ≥40 mg/dL.

3. HbA1c every 3 years, with diet, exercise, and metformin (first-line agent) prescribed to achieve target HbA1c < 7%; second- and third-line agents may be required.

Case Report

A 45-year-old man with motor-complete C4 spinal cord injury (SCI) for 18 years comes to you for a new patient evaluation. He hasn’t been seen by a primary care physician for over 10 years. He has no family history of diabetes mellitus or heart disease, has no cardiopulmonary complaints, has never engaged in a consistent exercise or fitness program, and is not particularly mindful of his diet. On physical examination, his blood pressure is 94/60 mm Hg with a regular pulse of 64 beats per minute (bpm), his body mass index (BMI) is 27 kg/m², his heart and lung examinations are normal, and he has what appears to be central obesity. His low-density lipoprotein cholesterol (LDL-C) is 76 mg/dL, his high-density lipoprotein cholesterol (HDL-C) is 34 mg/dL, and his fasting triglyceride level is 170. His fasting blood sugar (FBS) is 91 mg/dL.

Accelerated Atherogenesis

The obligatory sarcopenia (loss of muscle tissue), osteopenia, blunted anabolism, and blunted sympathetic nervous system associated with SCI markedly reduce energy expenditure and are rarely compensated with a concomitant reduction in energy intake such that morbid obesity often ensues.¹ Because adipose tissue is less dense than muscle and bone, body weight does not accurately reflect obesity in persons with SCI, where a BMI of 25 kg/m² usually translates to >33% body fat.²

We know that adiposity drives the metabolic syndrome through the release of adipose-derived proinflammatory cytokines, adipokines, prothrombotic agents, and elevated non-esterified fatty acids and that this hormonal milieu results in accelerated atherogenesis due to vascular endothelial damage, dyslipidemia, hypertension, and insulin resistance in persons with SCI.^1,3,4 Bauman et al performed arm ergometry radionuclide stress testing in 20 asymptomatic middle-aged individuals with SCI and found 13 (65%) of the subjects had evidence of ischemia.⁵ Lee et al conducted thallium stress tests on 47 clinically asymptomatic participants. While stress test positivity was correlated with level and completeness of injury such that those with lower and motor incomplete SCI were less likely than those with higher and motor complete injuries to have evidence of ischemia, between 50% and 85% of tests were positive.⁶ Bell et al compared ankle-brachial index (ABI) and intima-media thickness (IMT) results in 105 people with SCI and 156 controls. Although there were no differences in upper extremity IMTs, ABIs and sublesional IMTs in participants with SCI demonstrated more advanced arterial disease.⁷ Orakzai et al assessed 91 middle-aged individuals with SCI and matched them against non-disabled controls with similar NCEP (National Cholesterol Education Program) risk profiles; those with SCI had significantly higher coronary artery calcium scores than did those without.⁸ To wit, people with chronic SCI are at increased risk for atherogenesis and ischemic heart disease.

It is not surprising that cardiovascular disease has emerged as either the leading or second leading cause of mortality among people with SCI, accounting for between 18.4% and 25% of deaths.^9–11 Although heart disease is also the leading cause of death among all Americans, (accounting for approximately 23% of mortality), people with SCI live fewer years than do people without disability, so cardiovascular disease likely accounts for more years of life lost among those with injuries.¹² There have been no prospective studies investigating means of reducing morbidity and mortality due to vascular and coronary artery disease in people with SCI. Stillman et al conducted a retrospective evaluation of the mortality benefit of statin therapy among veterans with SCI; those who had taken a statin over the preceding 15 years had a 37% mortality rate and those who had not taken a statin had a 58% mortality rate.¹³ Even though these results were intriguing, the study was hampered by its methodologies and by the homogeneity of its subject pool.

Dyslipidemia in SCI

Chronic SCI is typically associated with a particular pattern of dyslipidemia, with normal or low total cholesterol but significantly reduced HDL-C.^1,3 Bauman et al studied 100 people with SCI and 50 able-bodied controls finding that HDL-C levels were significantly lower in participants with SCI than in those without, that over one-third (37%) of subjects with SCI had HDL-C levels below 35 mg/dL, and that 56% of participants with SCI had an LDL-C level below 130 mg/dL.¹⁴ Although this study’s subject pool was homogeneous, more recent work has confirmed its cardinal finding of an association between chronic SCI and depressed HDL-C levels. In analyses of 121 community-dwelling people with SCI (19.8% female, 38% African American, and 27.3% Hispanic), over 40% of subjects had low HDL-C levels and 64% had elevated LDL-C levels.^15,16 In a separate study of 41 subjects with motor complete paraplegia, 76% had HDL-C levels less than 40.¹⁷ More recently, of 473 veterans with SCI (mean age, 56 years, 50% with tetraplegia, 55% white, 34% African American), 69.7% were found to have HDL-C below 40 mg/dL.⁴ Conversely, in a report based on 3 years of National Health and Nutrition Examination Survey (NHANES) data, Toth et al estimated that only 23% of Americans without SCI have depressed HDL levels.¹⁸ Hence, the prevalence of depressed HDL-C is higher in people with SCI than in those without. The case study patient’s lipid profile may be quite typical given his chronic injury.

There has been virtually no work linking treatment of dyslipidemia in the setting of chronic SCI to improvements in morbidity and mortality. Nash et al demonstrated that extended-release niacin is a safe and tolerable means to increase HDL and decrease LDL levels in people living with SCI, but no disease endpoints were followed.¹⁹

Disordered Glycemic Regulation

In studies from the 1980s and 1990s, veterans with SCI were found to have high rates of diabetes mellitus (DM) and impaired glucose tolerance (IGT) on oral glucose tolerance tests (OGTT). Duckworth et al conducted OGTTs on 41 individuals with SCI, finding that 56.1% of them met criteria for DM.²⁰ Bauman et al conducted OGTTs on 100 veterans with chronic SCI and found 34% had IGT while 22% had frank DM.²¹ More recent investigations have yielded somewhat different results. In Stillman et al’s study of 19 individuals with chronic SCI, only one had DM when tested using an OGTT while an additional four had IGT.²² Conversely, Gater et al found that 49.8% of 473 veterans with SCI had FBG over 100 mg/dL, suggesting insulin resistance and/or impaired glucose tolerance.⁴ Of note, 76.7% of those veterans were found to be obese by the new standards of BMI for persons with SCI.²³

Insulin resistance in SCI appears to be the result of central obesity, which increases fatty acid metabolites and proinflammatory cytokines in liver and muscle. These factors impair the proximal portion of the phosphatidylinositol (PI) 3-kinase insulin cascade required to activate and translocate glucose receptors to the cell membranes, allowing the passage of glucose from the blood into the cell.^1,24 Previous work suggesting that chronic denervation or loss of skeletal muscle contributes to insulin resistance^20,21,25 lacks evidence of direct influence on the PI 3-kinase insulin cascade but likely is related to unrecognized adipose accumulation in the presence of diminished energy expenditure.^1,3 There is confusion as to the most meaningful means of testing people with SCI for IGT and DM. In both Bauman et al and Stillman et al, subjects with hyperglycemia on OGTT tended to have fasting euglycemia, indicating that screening people with SCI for DM using fasting plasma glucose (FPG) levels may yield false negative results.^21,22 Further, in Stillman et al, there was no correlation between OGTT and hemoglobin A1c (HbA1c) results, such that nine subjects had abnormalities of one test or the other, but only two had abnormalities of both. No one has yet correlated results of diabetic screening tests with presence of micro- or macrovascular disease in people living with SCI.

Recommendations

Multiple exercise studies, including aerobic arm crank exercise, upper extremity resistance training, body weight-supported treadmill training, lower extremity functional electrical stimulation cycling, or resistance training have demonstrated minimal or modest improvement in fitness and cardiometabolic profiles for persons with SCI,^26–31 but few have considered the influence of activity on whole body energy balance. Energy balance represents the relationship between whole body energy expenditure and energy intake; when the latter exceeds the former, energy is stored as adipose tissue, the driving force of the metabolic syndrome. As such, the American College of Sports Medicine and Dietary Guidelines of America recommendation of 150 minutes of exercise per week are likely insufficient for persons with SCI based on their obligatory sarcopenia and osteopenia, which markedly reduces their energy expenditure.³² Nonetheless, a minimum amount of exercise should be recommended until such time as there is clarity with regard to exercise-induced energy expenditure. A compendium of physical activity expenditures for persons with SCI is available for consideration.³² However, simply increasing energy expenditure appears insufficient for long-term body composition changes without concomitant reduction in energy intake. Unfortunately, caloric reduction sufficient to achieve neutral or negative energy balance for persons with SCI may further compromise intake of essential micronutrients.^33,34 In the absence of convincing data, we recommend (a) aiming for neutral or negative energy balance, (b) targeting 150 minutes of exercise each week, and (c) suggesting foods with lower caloric but high nutrient density.

There is very little clarity about the treatment of dyslipidemia in the setting of SCI. One concern is that there have been no prospective clinical trials demonstrating reductions in morbidity or mortality with treatment of suboptimal lipid levels in individuals with SCI. A second concern is that traditional cardiovascular risk factors seem to underestimate actual cardiac risk in people with chronic SCI^4,35 and that a threshold treatment level of LDL has never been established in SCI.²³ Although a single retrospective study demonstrated that statin use confers a substantial mortality benefit for people with SCI,¹³ those findings ought not to establish or change practice patterns until they are reproduced. In the absence of firm evidence for treatment of SCI-related dyslipidemias, we suggest adherence to the 2018 ACC/AHA Multisociety Guidelines on the Management of Blood Cholesterol.³⁶ In short, heart healthy lifestyles ought to be globally encouraged, individuals with clinical vascular disease should be treated, as tolerated, with high intensity statins, and people with LDL levels greater than or equal to 190 mg/dL should be offered high intensity statins, regardless of calculated 10-year atherosclerotic cardiovascular disease (ASCVD) risk. In addition, adults age 40 or older with LDL levels greater than or equal to 70 mg/dL and a 10-year calculated ASCVD risk of at least 7.5% ought to be offered treatment with a moderate intensity statin. We generally recommend annual assessment of lipids and cardiovascular risk.

Recent guidelines suggest that it is equally valid to screen people with SCI for IGT and DM with FPG, OGTT, and HbA1c²³; we feel that HbA1c is the most useful and, of the three modalities, has the advantage of not requiring a fast. Given that many people with SCI may have normal FPG in the setting of glycemic dysregulation and that the postprandial (hence, transient) glycemic excursions experienced by many individuals with injuries have not been correlated with risk for small or large vessel disease, HbA1c likely yields the most accurate assessment of chronic glycemic control. Given the elevated risk of IGT and DM over the course of an injury, we agree with Nash et al that people with SCI ought to be screened for disordered glycemic control at least every 3 years.²³ As is the case with noninjured patients, HbA1c of 5.7% or greater is diagnostic of prediabetes and a value of 6.5% or greater is indicative of frank DM.

Metformin is the preferred first-line agent for treatment of DM with an HbA1c greater than 7%. There are no firm recommendations concerning use of second- or third-line agents should metformin therapy not result in adequate glycemic control. Sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, or basal insulin may all be effective “add on” medications, although none has been specifically studied in people with SCI.

Case Resolution

We initially presented a case of a middle-aged man with chronic motor complete SCI, morbid obesity, a slight hypertriglyceridemia, and a normal FPG. We would recommend instituting dietary changes—likely supported by consultation with a nutritionist with knowledge of SCI and indirect calorimetry —to accurately evaluate daily caloric requirements and a roadmap to weight loss. Further, this patient would benefit from FES-supported exercise for at least 150 minutes each week with a primary goal of increasing energy expenditure sufficient to achieve negative energy balance for fat loss and periodic screening for glycemic dysregulation with an HbA1c level.

Conclusion

The cardiometabolic effects of SCI remain greatly understudied, and this presents both challenges and opportunities. There are sufficient data to support lifestyle and screening interventions for people living with SCI, yet a number of potentially care-altering questions remain unanswered.