Until 1995, insulin and sulfonylureas were the only classes of drugs available in the United States for the treatment of diabetes. Since then, insulin analogues, a new sulfonylurea, and four new classes of antidiabetic agents have been approved for use.⁹ There have also been huge advances in glucose monitoring technology, which facilitates patient self-management.¹⁰

Clinical trials have proven the benefits of cardiovascular risk factor intervention in the prevention and management of macrovascular disease, the major cause of death and disability in patients with diabetes.^11,12

Changes in the insurance industry and in federal and state legislation have resulted in improved coverage for diabetes medications, supplies, and education, facilitating efforts to achieve lower glycemic, blood pressure, and lipid targets.

This review provides a practical and constructive framework for the medical management of diabetes. Glycemic targets and lifestyle intervention, discussed in separate articles on p. 197 and p. 201, respectively, will not be included here. This article begins with a discussion of the available classes of antidiabetic agents and suggests steps that can be applied in the progressive management of hyperglycemia. A discussion of cardiovascular risk factor intervention follows, again with a brief overview of the available classes of agents and a stepped approach for the management of cardiovascular risk.

Most insulin now in use worldwide is of recombinant human origin. The pharmacokinetics of available formulations differ greatly, as summarized in Table 1. Lispro and aspart are rapid-acting insulin analogues with an onset of action in 5–15 min, peak activity in ~1 h, and a duration of activity of ~4 h. Regular insulin is ~50% as "fast" as the rapid-acting analogues, with onset in 30 min, a peak at 2–4 h, and a duration of action of 6–8 h or more. Intermediate-acting insulin (NPH and lente) is twice as slow as regular insulin, with an onset of action in 1–2 h, a peak at 4–8 h, and a duration of action of 12–16 h. Ultralente insulin is purportedly "long-acting," but the pharmacokinetics of human ultralente are not dramatically different from those of NPH or lente in the average patient. Glargine is a novel long-acting insulin analogue with distinctive properties. It provides for a flat, peakless profile of activity with a duration of action of >24 h in most patients.

Premixed insulins are more convenient and provide greater accuracy of mixing than patient-mixed insulin. In the United States, only 70/30 and 50/50 mixtures of NPH and regular insulin and a 75/25 mixture of lispro in its NPH-like formulation (NPL) are available. The profiles of activity for premixed insulins are as would be expected from the addition of the activities of their components.

Adverse events associated with insulin are well-known and include weight gain and hypoglycemia. However, using either fast-acting or long-acting insulin analogues results in a modest reduction in hypoglycemia. It should be noted that the absolute risk of severe hypoglycemia in patients with type 2 diabetes is small. This risk can be further minimized with appropriate patient education and home glucose monitoring at times when unrecognized hypoglycemia is most likely to occur—mid-sleep or during unplanned or strenuous activity. Rare patients develop allergies or irritation at injection sites (more common but rarely dose-limiting with glargine).

Newer insulin needles are more comfortable than those previously available because of their finer gauge, shorter length, sharper points, and smoother surfaces. Insulin pens make teaching patients to take insulin easier and offer exceptional convenience and accuracy. Most patients now find insulin therapy easier and more effective than they ever imagined.

The major differences among the many available products seem to relate to duration of action and to fairly subtle variation in hypoglycemic potential. In general, glipizide-GITS and glimepiride are preferred because they have once-daily dosing (without additional effect with twice-daily dosing) and carry a relatively low risk of hypoglycemia and weight gain.

Interestingly, glyburide is one of the most commonly prescribed antidiabetic agents worldwide, despite the fact that many other oral insulin secretagogues have been shown to have a significantly lower hypoglycemic potential than that of glyburide. The reasons for this are unclear.

First-generation sulfonylureas are not frequently prescribed because of their lower potency and the resulting higher risk of adverse effects and drug interactions.

An unusual characteristic of sulfonylureas is that the maximum marketed dose is generally two to four times higher than the maximally effective dose. There has been concern that sulfonylureas may result in increased cardiovascular events in patients with diabetes as a result of their activity on vascular and cardiac sulfonylurea receptors. There is some evidence to suggest that this is less likely to occur with glimepiride than with glyburide,¹⁵ but this is a rationale to avoid high-dose sulfonylurea therapy.

Sulfonylureas are arguably the most cost-effective glucose-lowering agents and therefore are clearly worthy of widespread use. I recommend trying to limit dosing to one-fourth maximal unless higher doses are clearly documented to yield significant benefits in glycemic control. Small doses of sulfonylurea (e.g., 0.5–1.0 mg of glimepiride or 2.5 mg of glipizide-GITS) are remarkably effective, particularly in patients on concomitant insulin-sensitizing therapy, and they are almost uniformly well tolerated.

Repaglinide is the only meglitinide approved for use in the United States. Nateglinide, a second agent with even quicker onset and shorter duration, is under review. The rationale for stimulating insulin secretion in a way that minimizes fasting hyperinsulinemia and maximizes postprandial control is compelling. However, repaglinide use in the United States has been modest, in part because it requires multiple daily doses, is more expensive than sulfonylureas, and has not been demonstrated to offer clear advantages in head-to-head trials with the preferred sulfonylureas.

The precise mechanism of action of metformin is unknown. Its major activity is to reduce hepatic insulin resistance and thereby glucose production. It has more inconsistently demonstrated effects to improve insulin sensitivity in peripheral tissues. Because of its modest duration of action, it is generally dosed at least twice daily. A sustained-release formulation is expected to be on the market by the time this is published.

Because biguanides do not increase insulin levels, they are not associated with a significant risk of hypoglycemia. The most common adverse events are gastrointestinal (GI), with nausea, diarrhea, crampy abdominal pain, and altered taste predominating. About one-third of patients have some GI distress, particularly early in their course of treatment. This can be minimized by starting with a low dose once daily with meals and titrating upward slowly (over weeks) to effective doses. Most patients note no adverse effects with metformin therapy, and at least 90% tolerate it adequately. Perhaps as a result of clinical or subclinical GI effects, metformin is associated with less weight gain than other antidiabetic agents.

The other issue of concern with metformin is lactic acidosis, which is rare and almost exclusively occurs in patients who are at high risk of developing lactic acidosis independent of metformin therapy. High-risk patients should avoid using metformin.¹⁷ Metformin is absolutely contraindicated in patients with renal insufficiency because it is cleared renally.¹⁸ The package insert states that metformin should not be used in males with a serum creatinine >1.5 mg/dl or in females at levels >1.4 mg/dl.

Obviously, there is a complex relationship between serum creatinine and renal function. Thus, I generally avoid metformin for patients with an estimated creatinine clearance by Cockcroft-Gault equation of <50 ml/min. I avoid using greater than half-maximal doses of metformin for patients with an estimated creatinine clearance between 50 and 70 ml/min. As a reminder, the equation holds that creatinine clearance equals [(140–age) X (weight in kg)] ÷ (72 X serum creatinine in mg/dl)] in males, multiplying by 0.85 in females. Therefore, a 30-year-old, 250-lb male construction worker with a creatinine of 1.6 mg/dl has a normal creatinine clearance of 103 ml/min, whereas an 80-year-old woman who weighs 110 lb with a creatinine of 0.8 mg/dl has a low creatinine clearance of 44 ml/min.

Metformin is also contraindicated in patients with congestive heart failure requiring treatment or with hepatic insufficiency and in the setting of alcohol abuse. Caution is required in the elderly, patients with acute illness, or those with poorly controlled chronic illness and in the setting of simultaneous treatment with nephrotoxic drugs (e.g., contrast dye).

The glucose-lowering efficacy and the prevalence of adverse GI effects increase proportionately in the 500–2,000 mg-per-day dose range. The maximal dose of 2,550 mg does not generally increase the benefits. A new formulation of metformin combined with glyburide has been developed to maximize glucose-lowering effectiveness and minimize GI effects and is available in tablets containing 250 mg/1.25 mg, 500 mg/2.5 mg, and 500 mg/5 mg of metformin and glyburide, respectively. The formulations containing proportionally lower glyburide doses (250/1.25 and 500/2.5 mg) seem to perform similarly to the higher-dose combinations and thus are preferred.

Arguably, metformin has the best record of accomplishment among oral antidiabetic agents in outcomes studies. Among overweight subjects in the United Kingdom Prospective Diabetes Study (UKPDS), those randomized to metformin not only had similar improvements in microvascular outcomes as those randomized to insulin and sulfonylurea, but also demonstrated a reduction in diabetes-related deaths and myocardial infarction.⁷ The validity of this observation has been challenged because of unusual responses in a subsequent subrandomization. The benefit of metformin on macrovascular outcomes through mechanisms independent of glycemic control is certainly plausible and supported by such observations as metformin-associated reduction in LDL cholesterol, triglycerides, blood pressure, and procoagulant factors.

These agents are believed to work through binding and modulation of the activity of a family of nuclear transcription factors termed PPARs. They are associated with slow improvement in glycemic control over weeks to months in parallel with an improvement in insulin sensitivity and reduction of free fatty acid levels.

The glitizones vary in important ways in terms of potency, pharmacokinetics, metabolism, binding characteristics, and demonstrated lipid effects. Still, all are effective glucose-lowering agents that are remarkably well tolerated, with weight gain and fluid retention (and associated edema formation and hemodilution) as the only significant adverse effects.

There is no substantial evidence that the newer agents are associated with hepatotoxicity, but this record of safety has been established with careful monitoring of liver function tests. It is important to continue to recommend that the glitazones not be used in patients with active hepatocellular disease or in patients with unexplained serum alanine aminotransferase (ALT) levels >2.5 times the upper limit of normal and to recommend serum ALT monitoring before initiating therapy, every 2 months for the first year, and intermittently thereafter. Whether there are clinically important differences between the two available glitizones is hotly debated, but definitive answers await adequately powered head-to-head studies now underway.

The promise of the glitazones to potentially reverse the negative cardiovascular associations of insulin resistance in parallel with their demonstrated effect of improving insulin sensitivity is terribly exciting. Almost all of the available data on the vascular effects of this class come from studies with troglitazone and include tantalizing clinical associations including reduced carotid intimal medial thickness, normalization of vascular endothelial function, improvements in dyslipidemia, lower blood pressure, and improved fibrinolytic and coagulation parameters. Troglitazone has also been shown to improve insulin secretory dynamics in subjects with impaired glucose tolerance and to prevent the development of diabetes in women with a history of gestational diabetes. These observations provide hope that glitazone therapy may be useful in preventing diabetes or in halting the progression of diabetes, thus reducing the need for additional drug therapy over time. It is critical to recognize, however, that the proven effects of pioglitazone and rosiglitazone to date are limited to improvements in glycemic control and changes in lipid parameters.

The adverse effect that has caused the greatest concern with this class of drugs is weight gain. Careful study indicates that the weight gain observed with glitizone use is a result of subcutaneous and not visceral fat accumulation and that there is, in fact, a reduction in visceral, hepatic, and intramyocellular fat. Thus, glitizone-related weight gain could actually be beneficial or at least is likely to be more of a cosmetic than a cardiovascular concern.

Weight gain and fluid retention are more common and severe in patients with the greatest glycemic responses, making expectant management of these adverse effects mandatory. All patients prescribed glitazones should be counseled to intensify lifestyle efforts to minimize weight gain. With regards to edema, with appropriate caution, almost no one should need to withdraw from therapy as a result of fluid retention. Patients most likely to develop edema are those who have preexisting edema. Thus, women, overweight patients, and those with renal insufficiency and diastolic dysfunction are at greatest risk.

I teach patients with preexisting edema to assess for pitting edema at home nightly. For those who note a pattern of increasing edema at home, I instruct all to restrict sodium and tell many to increase their diuretic by some specified quantity on their own as needed.

For edematous patients and those at higher risk of fluid retention, I always start at the lowest marketed dose. I tell patients that they can double the dose if they have observed no glycemic effect after 2 or 3 weeks and have had no exacerbation of edema. When patients return for their 2-month ALT check, if the glycemic response has only been modest, we increase the dose of glitazone to the maximal dose and manage edema as needed. Most patients with mild edema respond to a low-dose thiazide diuretic (e.g., HCTZ, 25 mg). In patients with more extensive edema, a combination of low-dose thiazide diuretic with moderate dose-loop diuretic is sometimes required.

There are two available agents, acarbose and miglitol. Their use in the U.S. market has been limited by a number of factors, including the need for dosing at the beginning of each meal, flatulence as a common side effect, and modest glucose-lowering efficacy. These factors should be balanced against the AGIs' unique effect to lower postprandial glucose, thereby improving glycemia in essentially all patients without increasing weight or hypoglycemic risk.

To maximize the potential that these agents will be well tolerated, start with a low dose, such as one-fourth of the maximum dose once daily, and increase over a period of weeks to months to one-fourth to one-half maximal dose with each meal.

My approach in the absence of any patient factors is to follow the algorithm in Figure 1. There is a growing but incomplete body of evidence suggesting that approaches aimed at improving insulin action with metformin, thiazolidinediones, nutrition therapy, and exercise are likely to provide greater reductions in cardiovascular risk than similarly effective approaches to increase insulin levels. Thus, my default pathway is to use metformin and/or thiazolidinediones in essentially all patients. Combination of these agents can lead to impressive glucose lowering with essentially no risk of hypoglycemia (in the absence of insulin, sulfonylureas, and meglitinides), and thus their effect can be pushed fairly aggressively.

Figure 1. Algorithm for diabetes management (focus on glucose)

Patients with higher levels of glucose (generally fasting plasma glucose >200 mg/dl) will almost always require additional agents to increase insulin levels. Since insulin, sulfonylureas, and meglitinides provide much faster improvements in overall control than do metformin, glitazones, or AGIs, they are preferred in patients with higher levels of glucose either as monotherapy or as part of combined therapy. Starting simultaneously on a low dose of a glimepiride or glipizide-GITS and either metformin, a glitazone, or an AGI is a reasonable initial approach to patients with poor glycemic control.

In patients who have reasonable control of fasting and preprandial plasma glucose levels (>50% of values <130 mg/dl) but whose HbA_1c is still higher than desired (whether that be 6% or 8%), the problem is generally either one of inaccurate or ineffective monitoring or one of elevated postprandial glucose levels. Because getting patients to monitor their blood glucose postprandially can be difficult, it is important to remember that without specific therapy, almost all type 2 diabetic patients will have elevated postprandial glucose levels. In such patients, I lean toward targeting that abnormality with the use of an AGI, a short-acting insulin analogue, or occasionally, a meglitinide.

The most critical issue in long-term glycemic management is to continuously reassess with patients the adequacy of their control by examining glucose monitoring logs (with once-daily monitoring often being adequate) and HbA_1c results. Based on these data, treatment regimens can be continuously refined to achieve optimal control with the lowest dose of the least number of medications.

Most patients in specialty care will require two or more drugs to achieve recommended targets. Many patients will require three or more (particularly if you consider long- and short-acting insulin to be two different agents). Fortunately, almost all of the possible two-drug combinations and many of the three-drug combinations have been shown to be safe and effective in modest-sized studies. I start with one agent, add agents as needed to achieve goals, and then back titrate to optimize treatment after goals are achieved.

The selection of initial therapy should be based on mutually (patient and provider) recognized priorities. Increasingly, I use submaximal doses to increase the ratio of efficacy to adverse effects and recognize the potential synergy of sensitizers and secretagogues and the value of treatment of postprandial glucose in combination therapy.

When adding insulin in the management of patients with inadequately controlled glycemia, some practitioners prefer to stop the oral antidiabetic agents. I continue the oral agents and add an evening dose of insulin. In the past, I usually added bedtime NPH insulin. Increasingly in more overweight patients (>120% of ideal body weight), I have been using 70/30 insulin or, more recently, lispro mix 75/25 at supper.

The rationale for this approach is straightforward. Most overweight people with diabetes overeat at supper and are not active at night. Thus, the short-acting insulin component of the mixture helps with postprandial glucose disposal. This works quite well in most patients, although some do develop problems with nocturnal hypoglycemia. This is minimized with the lispro mixture. There are data to suggest that glargine given at bedtime can similarly lead to lower morning glucoses with less nocturnal hypoglycemia than NPH insulin, particularly in more overweight patients.

Many patients subsequently require more complex regimens: twice-daily injections, split-mix insulin, multiple-injection regimens, or rarely, pump therapy. It should be noted that a minority of patients with type 2 diabetes have a better response to morning insulin than to an evening injection.

Because patients take care of diabetes on their own and providers merely teach them how to do it, it is important that patients and providers be on the same wavelength regarding a plan for reaching their mutual therapy goals. Patient biases and concerns should be addressed when trying to determine which agent to prescribe. These biases can be elucidated in patient interviews through discussions of various strategies.

1. Minimal cost strategy. For many patients, particularly the elderly, the cost of drugs is an overwhelming issue. Diet and exercise can be extremely effective and almost free therapies. Beyond that, the least expensive diabetes drugs are the sulfonylureas. Thus, a minimum cost strategy would almost certainly start with a sulfonylurea and progress with the addition of bedtime or pre-supper insulin, and finally two or more insulin shots a day. This strategy was successfully employed in the VA Cooperative Study in which excellent control was achieved in the context of a comprehensive program of diabetes education.

Though insulin is relatively inexpensive, it is not free. In terms of cost, there would certainly be a rationale for exploring the addition of metformin or a thiazolidinedione once an insulin dose of ~1 U/kg is reached.

2. Minimal weight gain strategy. Weight gain associated with diabetes therapy is of concern to most clinicians and is often an overriding issue with patients. A strategy to minimize weight gain would employ metformin or an AGI as initial therapy, with the addition of the other agent if one was inadequate. Because sulfonylureas and repaglinide seem to have a modest weight-sparing effect in combination therapy with insulin, one or the other could be added before insulin administration in such a strategy. Remember that the weight gain associated with thiazolidinediones, while certainly a cosmetic issue, may not be relevant to cardiovascular health.

3. Minimal injection strategy. The desire to avoid insulin injections at any cost is unfortunately quite common among diabetes patients. In this strategy, sulfonylureas, metformin, AGIs, and thiazolidinediones could be added in any order. Insulin, probably as a bedtime or pre-supper dose to minimize the inconvenience, would only be added as salvage therapy. Using thiazolidinediones early in the course of diabetes in hopes that it may reduce the rate of progressive -cell dysfunction is rational but unproved.

It is important to try to dispel notions that insulin therapy is difficult, ominous, or fraught with peril by highlighting its efficacy and the great strides that have been made in insulin formulations and delivery devices. Most patients will require insulin in their lifetime to achieve glycemic targets.

4. Minimal circulating insulin strategy. The concern over possible atherogenic effects of insulin has been widely publicized in the lay press and by the pharmaceutical industry. The relationship between circulating insulin levels and cardiovascular risk in nondiabetic populations is incontrovertible but probably subsumed by insulin resistance and not driven by insulin per se. However, no clinical data suggest that exogenous insulin is toxic. In any case, this strategy is analogous to the minimal injection strategy except that the order of introduction of agents is perhaps important. The thiazolidinediones have the greatest efficacy in reducing insulin resistance, with metformin second, AGIs third, and insulin secretagogues increasing peripheral insulin levels less than injected insulin.

5. Minimal patient effort strategy. Many patients are only capable of making a minimal effort with regard to controlling their diabetes. Questioning patients about their pill-taking history and their realistic ability to comply with prescribed frequency of therapy is important. Taking a once-a-day sulfonylurea and/or thiazolidinedione requires the least patient effort. Bedtime insulin is actually relatively well accepted by patients driven by this consideration. Developing strategies to improve adherence and increase motivation is a long-term goal for this population.

6. Hypoglycemia avoidance strategy. This is another important consideration for many patients. The AGIs have been reported in small studies to reduce "reactive" hypoglycemia. Other oral agents could be added in any order, with the exception that secretagogues would be added last, their dose minimized, and glyburide avoided.

7. Postprandial targeting strategy. Achieving postprandial glucose targets is generally associated with better control than just meeting premeal targets. This can only be achieved with specific postprandial targeting, which generally but not always requires postprandial monitoring. Techniques that can improve postprandial control include lowering the carbohydrate content of meals, adding fiber, substituting monounsaturated fats for carbohydrates, encouraging physical activity after meals, adding AGIs with meals, and using short-acting insulin preferentially over intermediate-acting insulin and rapid-acting insulin analogues (e.g., lispro) preferentially over regular insulin.²¹ Whether repaglinide is associated with better postprandial control than glimepiride or glipizide-GITS is controversial but can be tested in individual patients.

Thoroughly addressing each of these topics is beyond the scope of this review. Following are generally accepted treatment guidelines and suggestions for an overall approach to the treatment of each factor. Behavioral, nutritional, and exercise-related approaches to risk factor reduction will not be discussed at all other than to say that they are effective when done well and clearly part and parcel of a comprehensive approach to diabetes management. The physiological benefit from even modest changes in nutrient intake, weight, activity level, and smoking behavior can be substantial.

All patients over the age of 18 with substantial disease duration or multiple cardiovascular risk factors should be treated with aspirin in doses between 81 and 650 mg/day, except for individuals with a contraindication for aspirin therapy (bleeding diatheses, chronic anticoagulation, active ulcer disease, allergy). I use low-dose therapy in patients without known vascular disease who have good glycemic control and higher doses in patients with known vascular disease, particularly if it is clinically active or in patients with poor glycemic control. The role of anticoagulation and nonaspirin antiplatelet agents, such as clopidogrel, ticlodipine, and persantine is ill defined but certainly worthy of careful consideration in patients with active vascular disorders.

There is clinical trial support for the benefit of systolic blood pressure lowering to levels approaching 140 mmHg²⁷ and diastolic blood pressure levels approaching 80 mmHg.²⁸ As is the case for glycemia, epidemiological analysis suggests no lower limit or threshold to the benefit of blood pressure lowering in diabetes.²⁹ The ACCORD trial will address whether targeting a systolic blood pressure of 120 mmHg reduces cardiovascular events more than does targeting 140 mmHg.

Based on the results of recent clinical trials, I employ a once-daily tissue ACE inhibitor as initial therapy (ramipril, quinapril, and benazepril are preferred agents) and titrate the dose up to at least half-maximal dose. If that is inadequate to control blood pressure, I use a low-dose thiazide diuretic (e.g., hydrochlorothiazide 12.5–25 mg once daily). In patients with known coronary disease, I use once-daily selective -blockers (e.g., atenolol, metoprolol-XL) because of demonstrated cardioprotective effect except in the setting of severe hypoglycemia. Long-acting dihydropyridine calcium channel blockers (e.g., amlodipine, felodipine) have been shown to be effective in reducing cardiovascular risk in combination with ACE inhibitors and are both highly effective and well tolerated.

These four classes of agents (arguably in the order presented) have the greatest evidence of providing benefit in patients with diabetes. If additional or alternative agents (e.g., centrally acting adrenergic agents, alpha blockers, nondihydropyridine calcium channel blockers, angiotensin 2 receptor blockers) are needed to achieve targets, I use them as needed. I am impressed by the efficacy of loop diuretics as additive therapy in helping achieve blood pressure targets, particularly in patients with microalbuminuria or edema.

Generally I titrate antihypertensive agents monthly to at least half-maximal doses (or to the highest-dose tablet tolerated) before adding another agent. An important caution is that after each drug initiation or titration and at least annually, orthostatic vital signs including measurement of blood pressure after 2 min standing is critical. Many patients have supine hypertension that can potentially be prevented by elevating the head of the bed. Similarly, and perhaps because I often rely on diuretics, numerous patients develop orthostasis often without classic symptoms but with complaints of feeling poorly or weak. In patients treated with ACE inhibitors or diuretics, I measure serum potassium and creatinine ~2–6 weeks after initiation and at the end of titration as well as intermittently (1–4 times a year).

After confirming an increased LDL, I initiate LDL-lowering therapy with an HMG CoA-reductase inhibitor, or "statin." These are very well tolerated, although occasional patients note myalgias or nonspecific neuropsychological changes as adverse effects. Unless the reaction is severe, I try a second agent from the class to rechallenge after withdrawal of the first. Statins have been shown to reduce cardiovascular events and mortality in diabetes. Resins are moderately effective in LDL-lowering and can be used as alternatives in statin-intolerant patients or as additional therapy. A newer resin (colesevelam) is better tolerated than older products, which tend to be associated with frequent, dose-limiting GI effects. Intermittent liver function test monitoring is suggested, as is caution in using these agents in subjects with known hepatocellular disease.

The second common lipid disorder in diabetes is sometimes referred to as "diabetic dyslipidemia." It includes high triglycerides, low HDL cholesterol or apolipoprotien A, and phenotypically abnormally small and dense LDL particles. To adequately assess this phenotype, a lipid panel must be measured in the fasting state, optimally with patients taking nothing by mouth except water for 14 h.

Randomized prospective trials in nondiabetic populations have suggested that specific therapy for this pattern of lipid disorders is effective in reducing cardiovascular risk, though none of the trials are of adequate size to provide definitive answers for patients with diabetes.³³ Most authorities suggest targeting HDL cholesterol levels >45 mg/dl, and some further recommend aiming for levels 10 mg/dl higher in females. This can be an exceptionally difficult target to achieve. As an example, in the VA-HIT study with addition of gemfibrozil, the average HDL achieved was only 34 mg/dl. Nevertheless, significant benefit in cardiovascular risk reduction was observed even though targets were not attained.

The national recommendation is to target triglyceride levels <200 mg/dl. Epidemiological data suggest that the atherogenic small, dense LDL phenotype is common in people with triglyceride levels >140 mg/dl. Thus, there may be benefit to more stringent targets. In the VA-HIT study, the triglyceride level achieved on treatment was ~115 mg/dl.

Diabetic dyslipidemia often responds well to diet, exercise, and glycemic control. I defer specific therapy of HDL and triglycerides until glycemia is optimized or until only slow progress is being made. The outcomes trials to date have involved the use of gemfibrozil and niacin. Recently, better tolerated once-daily products from the same classes have been released. These include fenofibrate and extended-released niacin.^34,35

Fibrates have generally been employed in the treatment of diabetic dyslipidemia because of concerns that high-dose niacin results in a deterioration of glycemic control. Recent studies with both niacin and branded sustained-release niacin suggest that they are well tolerated and do not cause significant deterioration in glycemic control.³⁶ Moderate-dose niacin (500–1,500 mg/day) results in substantial increases in HDL cholesterol and reductions in triglyceride.

Combinations of niacin, fibrates, and statins have been employed clinically but are not well studied. There are reports of rhabdomyolysis in combination therapy. I counsel patients to be alert for muscle soreness and tenderness, particularly diffusely in large muscle groups, and to come in for measurements of creatinine kinase (CK) if such symptoms occur. Generally, when such complaints arise, the elevation in CK is modest (two to ten times the upper limit of normal) and may resolve spontaneously if associated with episodes of increased physical exertion.

Intermittent LFT monitoring is recommended with niacin and fibrate therapy as well. Estrogen replacement therapy and treatment with some selective estrogen receptor modulators is associated with an increase in HDL in postmenopausal women, although often with a moderate increase in triglycerides. No prospective trials have evaluated estrogen effects on cardiovascular events in diabetic women. Nevertheless, many advocate their use. The issue of whether fibrates are safe and provide additional cardiovascular benefit in subjects already treated to LDL targets will be addressed in the ACCORD study.

Careful and consistent support, detailed patient education, and excellent communication are necessary to help keep patients and providers motivated to achieve these multiple and simultaneous goals. Flow sheets, preferably with computer support, are essential to keep up with interventions, patient responses, and monitoring requirements.

The clinical trial evidence and epidemiological data supporting these targets and approaches as single interventions are compelling and evolving. Trials now underway will elucidate the benefits of more comprehensive efforts. The revolution in diabetes management launched with the publication of the Diabetes Control and Complications Trial in 1993 continues today. The future holds the promise of easier implementation of such therapies and the possibility that people with diabetes will continue to live longer and better.