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Joslin’s Diabetes Deskbook, Updated 2nd Edition, Excerpt #30: Macrovascular Complications, Part 2

Apr 1, 2013

Richard S. Beaser, MD
Michael Johnstone, MD


The week’s excerpt answers the following questions: 

  • What is the relationship between triglyceride levels and the degree of insulin resistance?
  • Which lipid abnormalities are markers of coronary artery disease (CAD)?
  • What are the current goals for lipids for diabetic patients?
  • Can improved glucose control impact lipid control?

Macrovascular Complications


It has become increasingly apparent that the dyslipidemia that is often seen in people with diabetes significantly increases the risk of atherosclerotic cardiovascular disease. The pattern of lipoprotein abnormalities most commonly seen in people with diabetes includes:

  • elevated total cholesterol
  • decreased high-density lipoprotein (HDL) cholesterol levels
  • increased small, dense low-density lipoprotein (LDL)
  • elevated triglyceride levels

There seems to be a direct correlation between the triglyceride level and the degree of insulin resistance. In addition, this classic pattern of abnormalities described above may be altered by other factors, such as the degree of glucose control, obesity, physical inactivity, use of alcohol, use of medications that might affect lipid patterns, and genetic lipid abnormalities.

The presence of these lipid abnormalities (increased triglycerides and decreased HDL) is thought to be a marker for increased risk of coronary artery disease (CAD). It is not uncommon to find this pattern of lipid abnormalities present in people at the time they are diagnosed with type 2 diabetes, or even in those who do not currently have type 2 diabetes but who later develop it. However, whether or not these lipid alterations directly impact CAD risk has been the subject of debate. This pattern of abnormalities, it has been suggested, may really represent a measure of the severity of insulin resistance or perhaps a marker for the insulin resistance syndrome rather than a direct causal factor for macrovascular disease.

In fact, much of the focus of therapy has been on lowering the cholesterol levels of those with diabetes. While cholesterol and LDL cholesterol levels in people with diabetes are similar to those seen in the nondiabetic population, the Multiple Risk Factor Trial (MRFIT), a study examining the impact of macrovascular risk factors on the development of atherosclerosis, has clearly demonstrated the relationship between elevations of these levels and CAD risk in both populations. However, the baseline risk for the diabetic subgroup was two to four times greater, suggesting that there must be other factors in the diabetes population that further raise the frequency of this complication. These might include renal disease, hypertension, glucose control, and the presence of advanced glycation end products (AGEs), hypercoagulability, and obesity. In addition, people with diabetes, particularly type 2 diabetes, tend to have increases in the small, dense LDL particles which are thought to be more atherogenic.

In addition, clinical intervention to lower LDL cholesterol levels has been demonstrated to reduce CAD endpoints in a number of clinical trials that looked at treatment in a general population but also showed benefits in the diabetic subgroups. The Scandinavian Simvastatin Survival Study (4S), a secondary prevention trial, demonstrated that treatment to reduce elevated LDL cholesterol levels with an HMG CoA reductase inhibitor resulted in a decrease in incidence of, and mortality from, CAD. These benefits were also seen in the diabetic subgroup in this study. The Cholesterol and Recurrent Events (CARE) study showed similar results in patients with lower LDL levels, with a study population having more patients with diabetes. The Heart Protection Study (HPS), the largest study to date, confirmed these results in the subgroup analyses of 6000 patients with diabetes, more than 90% of whom had type 2 diabetes. Similar results were reported in the Collaborative Atorvastatin Diabetes Study (CARDS), a primary prevention trial conducted exclusively with patients with type 2 diabetes. More recently, the PROVE-IT and TNT trials suggest that a lower LDL level, that is, less than 70 mg/dl, for all patients with coronary artery disease is preferred. Since diabetes is considered to be a risk equivalent for coronary artery disease, lower LDL goals are likely to be indicated, particularly if accompanied by multiple other risk factors.

Goals of Treatment 

The CAD risk with elevated cholesterol levels has undergone numerous revisions in the last few years. As recently as the late 1970s, medical schools were still teaching the "normal" cholesterol levels based on the standard bell-shaped curve of the general population. However, during the ensuing decades, we learned that these so-called normal levels were not necessarily healthy, and thus desirable targets for lipid levels have been lowered. In addition, the therapeutic focus has shifted to LDL cholesterol.


The LDL cholesterol levels at which therapeutic intervention is recommended have undergone downward revisions. The current recommendations of the ADA, based on the presence or absence of existing macrovascular disease, are listed in Table 15-1. In May, 2001, the National Cholesterol Education Program (NCEP) published the "Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults" (available on line at or as NIH publication No. 01–3670, May 2001), which included an update in the approach to treatment of dyslipidemia in people with diabetes. This report makes the following points:

  • People with diabetes who do not have coronary heart disease (CHD), many of whom display multiple risk factors, are equivalent in risk of CHD to those without diabetes who have CHD.
  • Persons with multiple metabolic risk factors (metabolic syndrome) are candidates for intensified therapeutic lifestyle changes.
  • An LDL cholesterol remains the primary goal of therapy, with optimal target for people with diabetes <100 mg/dl.
  • The category of low HDL has been raised from <35 mg/dl to <40 mg/dl.
  • Treatment beyond LDL-lowering for persons with triglycerides >150 mg/dl is recommended.
  • The complete lipoprotein profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) is the preferred initial screening test, rather than just screening with total cholesterol and HDL alone.
Clearly, the downward trend of LDL goals continues. As suggested above, PROVE-IT and TNT suggest that the goal for LDL should be 70 mg/dl in patients with coronary artery disease. An update of the NCEP Adult Treatment Panel III guidelines in 2004 noted LDL <70 as a therapeutic option in patients at very high risk, including those people who have established CAD in the presence of diabetes or those with multiple risk-conferring components of the metabolic syndrome. 

A second therapeutic goal should be raising the HDL level, although available tools — primarily lifestyle changes, glucose control, and nicotinic acid, are often either less effective than those for lowering LDL cholesterol or relatively contraindicated (nicotinic acid at high dose) in people with type 2 diabetes. Triglyceride lowering is also recommended by the ADA, although direct impact of this intervention on clinical outcomes is less well demonstrated.

Nonpharmacologic Treatment 

As with treatments to control glucose levels, the first-line therapy for dyslipidemias is medical nutrition therapy (MNT) and physical activity, with a focus on weight loss. These interventions can effectively impact the typical dyslipidemic pattern seen in diabetes by lowering triglyceride levels and raising levels of HDL cholesterol, as well as by lowering LDL cholesterol.

The recommended nutritional adjustments for people with dyslipidemia include reductions in the proportions of saturated fat and a compensatory increase in the carbohydrate and/or monounsaturated fat levels. Keep in mind, however, the difficulty and limitations of this approach. The challenges of maximizing and sustaining patient compliance aside, the American Heart Association suggests that such interventions may reduce LDL cholesterol by up to 15-25 mg/dl. Therefore, if the LDL is greater than this interval above target, the likelihood of achieving desired improvements with lifestyle changes alone is small.

However, the impact of nonpharmacologic interventions on triglyceride levels may be more significant. A reduction in total calorie intake and initiation of an exercise program in an overweight person that leads to a reduction of even 5 to 10 pounds can substantially reduce triglyceride levels.

Pharmacologic Treatment 

The pharmacologic treatment approach to dyslipidemias in patients with diabetes is summarized in Table 15-2. There are a number of choices within each group, particularly the HMG CoA reductase inhibitors ("statins"). While the similarities within these groups outweigh the differences from a clinical standpoint, individualized choices are often made on the basis of slight differences in effect, dosing, or cost. For the statins in particular, higher doses may also have a significant effect in lowering triglycerides.

While the majority of the patients with diabetes and dyslipidemia have type 2 diabetes, much of the advice given also applies to those with type 1 diabetes. In particular, patients with type 1 diabetes may also benefit from the effects of improved glucose control.



Monitoring Lipids 

For people with diabetes and no history of dyslipidemia, monitoring their lipid levels yearly should suffice. If values are at desirable levels, then this frequency should be sufficient to pick up changes soon enough to initiate appropriate treatment. However, there are a number of considerations that might suggest the need to monitor more often. Certainly, values suggestive of the development of the early stages of the diabetic dyslipidemic pattern might warrant increased frequency. Evidence of end-organ effects in this setting would lend further weight to this approach. Changing glucose control would also warrant more frequent testing. In particular, a patient with suboptimal glucose control and elevated lipids might achieve some lipid improvement just from the establishment of a proper diabetes management program. Thus, the initial therapeutic focus for patients with poorly controlled diabetes accompanied by dyslipidemia is often improvement of glucose control. Concurrent monitoring of lipid levels will determine whether or not the lipid-lowering response to improved glucose control is sufficient to avoid the need for additional pharmacologic intervention.

Monitoring should be done by way of a fasting test for serum total cholesterol, triglycerides, and HDL cholesterol. Newer methodology for a direct LDL cholesterol measurement has increased the accuracy of this determination. However, if this measurement is not available or convenient, the LDL cholesterol can be calculated indirectly via the following Friedewald formula:

Total cholesterol – [(triglycerides/5) + HDL cholesterol] = LDL cholesterol estimate

Note: This formula is not valid if the triglyceride level is greater than 400 mg/dl. 

If the LDL-cholesterol goal is achieved, but the triglyceride level remains between 200 and 500 mg/dl, it is recommended that a secondary goal of non-HDL-cholesterol be pursued. The Non-HDL-cholesterol level is the total cholesterol minus the HDL-cholesterol level. The target for non-HDL-cholesterol is 30 mg/dl above the LDL-cholesterol target.

Next Joslin Text: Chapter 15 Macrovascular Complications include: Hypercoagulability — Preventive Strategies — Obesity — Diabetes as a Macrovascular Risk Factor

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