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EDWARD J. SHAHADY, MD
University of Miami
Type 2 Diabetes, the Metabolic Syndrome,
Inflammation, and Arteriosclerosis:
Steps to Stem a Rising Epidemic
ABSTRACT: Most patients with the have the syndrome. Type 2 diabetes
Dr Shahady is a
clinical professor
metabolic syndrome have insulin resis- mellitus will develop in many of these
of family medicine tance, and diabetes will develop in persons.1,2
at the University of many of these persons. In both patients In the United States, diabetes is
Miami and asso- with the metabolic syndrome and those the fifth leading cause of death; the
ciate faculty at Tal- with diabetes, elevated levels of small, leading cause of kidney failure, non-
lahassee Memorial
Hospital Family
dense low-density lipoprotein choles- traumatic limb amputations, and
Practice Residency. terol (LDL-C) particles stimulate an in- blindness; and the foremost contrib-
He is also a mem- flammatory process that leads to plaque utor to cardiovascular disease
ber of the editorial instability and susceptibility to rupture, (CVD). CVD accounts for about 70%
board of CONSUL- thus triggering cardiovascular events. of deaths in adults with diabetes and
TANT, former pres-
ident of the Society
Measurement of high-sensitivity C-reac- is a stronger predictor than
of Teachers of tive protein can help stratify risk levels glycemic control of morbidity and
Family Medicine, in patients with the metabolic syndrome. use of health care resources in
and medical direc- Statins and aspirin are important op- these patients.3-6 Moreover, 3 com-
tor of the Diabetes tions in treating the inflammatory cas- ponents of the metabolic syn-
Master Clinician
Program of the
cade created by diabetes and the meta- drome—hypertension, glucose in-
Florida Academy bolic syndrome. Because of their bene- tolerance, and dyslipidemia—are
of Family Physi- ficial effects on glucose, blood pressure, major risk factors for CVD.
cians Foundation. inflammation, and lipid levels, thiazoli- Despite better understanding of
dinediones and metformin may have a the pathophysiology and manage-
role in the treatment of the metabolic ment of diabetes and the metabolic
syndrome. syndrome, patient outcomes have not
shown a parallel improvement.7,8
Only 30% to 35% of patients with dia-
Key words: diabetes, metabolic
betes achieve 1 or more of the Amer-
syndrome, arteriosclerosis
ican Diabetes Association goals for
the quality indicators of hemoglobin
Up to 10% of Americans older than 20 A1c, low-density lipoprotein choles-
years have type 2 diabetes, and more terol (LDL-C), and blood pressure
than 20% have the metabolic syn- (BP). Only 7% of patients achieve
drome.1,2 The prevalence of both dis- goal levels in all 3 indicators.9
eases has risen by 33% over the past Our current system of medical
decade as a result of an increasingly education and clinical care has not
sedentary lifestyle, the obesity epi- effectively addressed this issue. A
demic, the growth of ethnic groups at major shift in the way we care for pa-
risk for the disease, and the aging of tients is crucial to reduce the bur-
the population. The prevalence of the den of suffering associated with dia-
metabolic syndrome increases dra- betes and the metabolic syndrome
matically with age: 45% of persons and to forestall the development of
older than 60 years are thought to CVD.
www.ConsultantLive.com DECEMBER 2005 CONSULTANT 1579
Type 2 Diabetes,
the Metabolic Syndrome,
Inflammation, and
Arteriosclerosis:
Steps to Stem a
Rising Epidemic
later, he had a stroke. Five years after
Table – Criteria for diagnosis of the metabolic syndrome* that, at age 58 years, he had a mas-
sive MI and died.
Risk factor Defining level
REEVALUATING RISK
Abdominal obesity (waist circumference) Given our current knowledge,
Men > 40 in could his MI, stroke, and premature
Women > 35 in death have been prevented? In trying
to make that assessment, let us go
Fasting triglyceride level ≥ 150 mg/dL
back and calculate his risk at age 42
Fasting HDL-C level years. According to the risk calcula-
Men < 40 mg/dL tor recommended by the National
Women < 50 mg/dL Cholesterol Education Program Ex-
pert Panel on Detection, Evaluation,
Blood pressure ≥ 130/85 mm Hg and Treatment of High Blood Cho-
lesterol in Adults (Adult Treatment
Fasting serum glucose level ≥ 110 mg/dL
Panel III [ATP III]), the patient’s risk
*Any 3 criteria establish the diagnosis. of a cardiovascular event in the next
HDL-C, high-density lipoprotein cholesterol. 10 years was 2% to 3%.10
From the Executive Summary of the Third Report of the National Cholesterol Education Program Expert These calculations are driven by
Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel III). JAMA. 2001.10
many factors, the most important of
which is age. Projecting age forward
with the calculator and not changing
A CASE IN POINT the above history, examination, and the risk factors, an increase in risk is
The following case, a typical one laboratory values, what is the pa- apparent. By age 55 years, the risk in-
seen in primary care, serves as a tient’s risk of a cardiovascular event? creases to 16%, and by age 60 years,
good framework to aid our under- How would you treat this man? it increases to 20%. However, if the
standing of the problem and how it Would you prescribe anything other patient’s diabetes had been included
might be addressed. than diet and exercise? in the calculation by age 50 years, the
A 42-year-old Hispanic man pre- The patient was advised to exer- risk would have been 20% at that age.
sented for a physical examination at cise and to reduce his intake of satu- Risk calculators can give a false sense
his wife’s urging, although he had no rated fat. During the next 8 years, he of security in younger persons; pro-
specific complaints. He had recently returned on several occasions for acute jecting forward gives a more realistic
gained 10 lb, which he attributed to conditions such as upper respiratory assessment.
the elimination of his daily walking tract infections and knee pain. His BP The other critical factor in this
and a new job that involved more had risen to 148/94 mm Hg, and hy- patient is his lipid profile. At first
deskwork. He had a family history of drochlorothiazide, 25 mg/d, was start- glance, his LDL-C level seems ideal.
diabetes, and his father had had a ed. No further laboratory tests were However, this is misleading because
stroke at age 60 years. performed during that period. it is a calculated value. The calcula-
The patient’s body mass index At age 50 years, he was admitted tion is not valid when the triglyceride
(BMI) was 29, his waist circumfer- to the hospital with a myocardial in- level is higher than 200 mg/dL; this
ence was 42 inches, and his BP was farction (MI). His serum glucose patient’s level was 300 mg/dL. ATP
138/88 mm Hg. Other examination level was 350 mg/dL; the hemoglo- III recommends using non–HDL-C
results were normal. His fasting lab- bin A1c was 9. His lipid levels were instead of LDL-C to help make man-
oratory results included a serum glu- unchanged. He was treated with met- agement decisions when triglyceride
cose level of 108 mg/dL; total cho- formin, and his hemoglobin A1c de- levels are higher than 200 mg/dL.10
lesterol, 190 mg/dL; LDL-C, 100 creased to 7.5. Because his LDL-C The non–HDL-C level is total choles-
mg/dL; high-density lipoprotein cho- level was 100 mg/dL, no treatment terol minus HDL-C, which in this pa-
lesterol (HDL-C), 30 mg/dL; and was prescribed for his other lipid ab- tient is 160 mg/dL (190 30 = 160).
triglycerides, 300 mg/dL. normalities. A -blocker was added The ideal non–HDL-C level is 100 to
Consider the following ques- for hypertension; his BP averaged 130 mg/dL in patients who are at ele-
tions as you continue reading: With about 140/85 mm Hg. Three years vated risk for CVD.
1580 CONSULTANT DECEMBER 2005 www.ConsultantLive.com
This patient also had athero- have placed him in a high-risk cate- sulin resistance, biologic impairment
genic dyslipidemia (high triglyceride gory that required aggressive treat- leads to decreased glucose uptake in
and low HDL-C levels). This combi- ment. His elevated BP warranted use skeletal muscle, increased release of
nation indicates a high concentration of an angiotensin-converting enzyme free fatty acids (FFAs) into the serum
of small, dense LDL-C particles that (ACE) inhibitor or angiotensin II re- from adipocytes, and a paradoxical
are highly atherogenic and can lead ceptor blocker (ARB), in addition to increased production of hepatic glu-
to significant CVD if not treated. the diuretic, to reduce his BP to cose because of hyperglycemia. Pan-
More aggressive treatment would more acceptable levels. Because he creatic insulin secretion is also blunt-
certainly have been warranted in this had diabetes, an acceptable goal ac- ed by the increase in FFAs.12 Figure
patient. At a minimum, in addition to cording to current recommendations 1 depicts the biologic impairment
significant changes in his diet and would be less than 130/80 mm Hg.11 and resulting metabolic defects in di-
level of physical activity, much closer abetes. Many of these defects are
follow-up of his lipid status and METABOLIC ABNORMALITIES also present in the metabolic syn-
hemoglobin A1c was warranted. If his IN THE METABOLIC SYNDROME drome. Note how the increase in
non–HDL-C level had failed to de- AND TYPE 2 DIABETES FFAs affects all the other metabolic
crease to 130 mg/dL or less with life- This patient had the metabolic defects.
style changes, statin therapy should syndrome. The Table lists 5 diagnos- Initially, patients with insulin re-
have been strongly considered. tic criteria; only 3 are required to sistance produce large amounts of in-
A test for high-sensitivity C-re- make the diagnosis. This patient had sulin that prevent hyperglycemia. In
active protein (hsCRP) is more sen- all 5 criteria. many of these patients, pancreatic
sitive than the test for CRP and Most patients with the metabolic function eventually will deteriorate
would also have helped guide this syndrome have insulin resistance,1,2 and hyperglycemia and diabetes will
patient’s treatment. An elevated and diabetes will develop in many of develop. However, the other abnor-
value (ie, higher than 3 mg/L) would these persons. In patients with in- malities—such as atherogenic dys-
Increased Lipotoxicity:
FFAs exacerbate Increased FFAs
decreased uptake affect all
other areas
Skeletal muscle:
Decreased glucose uptake Adipose tissue:
Increased lipolysis
increases FFAs
Liver:
Increased Pancreas:
glucose production Decreased insulin
secretion
Increased FFAs raise glucose Increased FFAs raise glucose
production production
Serum glucose
FFA, free fatty acid.
Adapted from Inzucchi SE. JAMA. 2002.38
Figure 1 – Type 2 diabetes results from coexisting defects at multiple organ sites: resistance to insulin action in muscle, defective pan-
creatic insulin secretion, and unrestrained hepatic glucose production, all of which are exacerbated by defective insulin action in fat.
www.ConsultantLive.com DECEMBER 2005 CONSULTANT 1581
Type 2 Diabetes,
the Metabolic Syndrome,
Inflammation, and
Arteriosclerosis:
Steps to Stem a
Rising Epidemic
lipidemia and hypertension—are in release FFAs into the plasma. The reductions of LDL-C to below 70
place long before hyperglycemia ap- increase in circulating FFAs con- mg/dL in patients who have the
pears and increases the risk of CVD. tributes to a rise in hepatic triglyc- metabolic syndrome and coronary
Unfortunately, it is not unusual for a eride levels, which in turn enhances heart disease.20
diagnosis of diabetes not to be made the production of small, dense LDL- According to a recent statement
until after patients have a stroke or C particles.15 The dysfunctional from the American Diabetes Associa-
MI, as in the case discussed here. If adipocytes also release inflammato- tion, until randomized controlled tri-
the risk of CVD is recognized and ry cytokines, such as tumor necrosis als have been completed, no appro-
treatment initiated earlier, the inci- factor and interleukin-6.16 priate pharmacologic treatment for
dence of cardiovascular events will Markers of inflammation. the metabolic syndrome can be rec-
decrease. hsCRP is a surrogate marker for in- ommended.21 In contrast, the Amer-
flammation and cardiovascular risk. ican Heart Association/National
ROLE OF INFLAMMATION Levels of hsCRP higher than 3 mg/L Heart, Lung, and Blood Institute re-
IN CVD are stronger predictors of future cently recommended drug therapy if
At one time, we believed that events than are LDL-C and non–HDL- lifestyle changes fail to modify risk
gradual narrowing of the arteries C levels.17 Values higher than 10 factors.22 I think that clinicians should
over time led to cardiovascular mg/L indicate a noncardiovascular use their own judgment and balance
events such as stroke and MI. We cause; in this case, the test should be the potential benefits against the
now understand that arterial obstruc- repeated in a few weeks. Elevated lev- risks of pharmacologic therapy. In pa-
tion occurs acutely, secondary to rup- els of hsCRP predict type 2 diabetes tients with multiple risk factors, the
ture of an arterial plaque and forma- and can help stratify risk levels in pa- evidence overwhelmingly indicates
tion of a clot that obstructs the ar- tients with the metabolic syndrome that risk reduction will reduce mor-
tery.13 Atherosclerosis is a dynamic and a family history of heart disease. bidity and mortality. Certain treat-
inflammatory disease in which meta- It is helpful to measure hsCRP in pa- ment options—such as therapeutic
bolic risk factors such as LDL-C in- tients who seem to be at low or inter- lifestyle changes, aspirin, statins,
teract with immune mechanisms to mediate risk, such as the man in the ACE inhibitors, and ARBs—are less
threaten the structural integrity of case discussed here. If the hsCRP controversial than the use of met-
plaque and precipitate cardiovascular level is high, more aggressive treat- formin and the glitazones. The fol-
events.14 The small, dense LDL-C par- ment is indicated. Two recent studies lowing discussion should help in the
ticles, which are more numerous in suggest that hsCRP may be used to decision-making process.
the metabolic syndrome and dia- monitor patients and gauge the effec- Lifestyle changes. These chang-
betes, stimulate inflammatory cells to tiveness of therapy. The REVERSAL es form the basis for treatment of
secrete degrading enzymes that de- study demonstrated that hsCRP pre- the metabolic syndrome. Weight
plete collagen in the intima of the ar- dicted progression of atherosclerosis loss and exercise in patients with
terial wall. This leads to plaque insta- independent of LDL-C levels.18 The truncal/visceral obesity are associ-
bility and susceptibility to rupture.14 PROVE-IT study demonstrated an in- ated with substantial reductions in
The key to plaque stability is the creased incidence of cardiovascular major atherogenic risk factors. A
fibrous cap: the thicker the cap, the events with higher hsCRP levels and 10% loss of body weight corre-
more stable the plaque. The integrity a decreased incidence with lower sponds roughly to a 30% loss of adi-
of the fibrous cap depends on the bal- hsCRP levels.19 More long-term stud- pose tissue. A decrease in the
ance of synthesis and breakdown of ies are needed to support an evi- amount of adipose tissue leads to a
the matrix materials in the cap. In- dence-based recommendation. decrease in levels of hsCRP and
flammatory forces shift this balance other inflammatory cytokines,
toward the breakdown of matrix ma- POSSIBLE TREATMENT which results in improved endothe-
terials and plaque rupture. Thin fi- OPTIONS lial function, decreased BP, lower
brous caps contain an increased num- The only evidence-based treat- levels of LDL-C, and increased lev-
ber of inflammatory cells and are ment for the metabolic syndrome is els of HDL-C.23 When advising pa-
more susceptible to rupture.14 lifestyle changes. No drugs are cur- tients, remember how difficult it is
Adipocytes (fat cells) are the rently indicated for this syndrome; for them to start and sustain any
site of the inflammatory process. however, drugs are approved for spe- changes. Patients usually think that
The adipocytes become dysfunction- cific components of the syndrome. they do not have the ability to suc-
al because of insulin resistance and The ATP III guidelines recommend ceed. Change is more likely to
1582 CONSULTANT DECEMBER 2005 www.ConsultantLive.com
Type 2 Diabetes,
the Metabolic Syndrome,
Inflammation, and
Arteriosclerosis:
Steps to Stem a
Rising Epidemic
Figure 2 – The
pharmacologic
approaches to the
metabolic defects
in type 2 diabetes
are shown here.
TZDs: increase glucose
uptake in sketetal muscle TZDs: decreased
lipolysis in adipose
tissue decreases FFA
Serum glucose
Metformin: reduces
glucose production in liver
Secretagogues:
TZDs, thiazolidinediones; FFA, free fatty acid. increase insulin
Adapted from Inzucchi SE. JAMA. 2002.38
secretion in pancreas
occur if a clinician first gains a pa- with diabetes or the metabolic syn- ACE inhibitors and ARBs.
tient’s trust and confidence, then drome have normal levels of LDL-C; These agents, which effectively treat
gives advice. however, regardless of the initial val- hypertension, are first-line therapy
Aspirin. Aspirin therapy is rec- ues, lower is better in patients who in persons with diabetes. Both class-
ommended for patients who are at are at risk for a cardiovascular event. es of drugs reduce insulin resistance
moderate to high risk for cardiovas- Studies have demonstrated that and thus may benefit patients who
cular events, including those with the production of nitric oxide begins to are at high risk for diabetes, such as
metabolic syndrome. Adipose tissue drop when LDL-C levels are above those with the metabolic syndrome.
in patients with the metabolic syn- 60 mg/dL.27 Nitric oxide is a power- A recent meta-analysis of 11 trials (6
drome or diabetes produces in- ful vasodilator and decreases inflam- used ACE inhibitors and 5 used
creased amounts of plasminogen ac- mation at the endothelial level. Oxi- ARBs) demonstrated a decreased
tivator inhibitor (PAI)-1.16 Elevated dized LDL-C (one of the main cul- risk of diabetes.29 Reduction of in-
levels of PAI-1 increase the risk of prits in endothelial dysfunction) is sulin resistance and a decreased risk
clotting when a plaque ruptures; as- created at the expense of nitric of diabetes are compelling reasons
pirin reduces the risk. Aspirin also oxide creation. The Heart Protection to consider ACE inhibitors and
lowers the elevated levels of hsCRP Study and the ASCOT-LLA study ARBs in patients with the metabolic
typically found in high-risk patients; support the recommendation of syndrome.
this reduction is associated with a sig- lower LDL-C levels in at-risk pa- Oral antidiabetic agents. Figure
nificantly decreased risk of MI and tients.26,28 These studies also rein- 2 shows the specific sites of action of
stroke.24 force the idea that effective reduc- oral antidiabetic agents. Because dia-
Statins. Hyperglycemia is a tion of cardiovascular risk depends betes develops in many patients with
weak predictor of CVD compared on global risk assessment. The the metabolic syndrome and both
with hypertension and hyperlipid- metabolic syndrome offers a means conditions are strongly related to in-
emia. Statins are an important option of assessing global risk. sulin resistance, it seems reasonable
in treating the inflammatory cascade Two recent studies demonstrat- to consider using the same therapeu-
created by diabetes and the metabol- ed that statin therapy decreased tic agents that are effective in dia-
ic syndrome. These agents decrease hsCRP and LDL-C levels, and that betes for the metabolic syndrome.
LDL-C levels and reduce the risk of this reduction stabilized plaque and The biguanides and the thiazolidine-
CVD and stroke.25,26 Many patients reduced the risk of rupture.18,19 diones not only reduce serum glu-
1584 CONSULTANT DECEMBER 2005 www.ConsultantLive.com
Type 2 Diabetes,
the Metabolic Syndrome,
Inflammation, and
Arteriosclerosis:
Steps to Stem a
Rising Epidemic
cose levels but also mitigate some jection of diabetes burden through 2050: impact of 22. Grundy SM, Cleeman JI, Daniels SR, et al. Di-
changing demography and disease prevalence in agnosis and management of the metabolic syn-
of the risk factors for CVD, which the US. Diabetes Care. 2001;24:1936-1940. drome. An AHA/NHLBI Scientific Statement. Circu-
makes them attractive options for the 3. Mokdad AH, Ford ES, Bowman BA, et al. Dia- lation. 2005;112:2735-2752.
betes trends in the US: 1990-1998. Diabetes Care. 23. Despres JP, Lemieux I, Prud’homme D. Treat-
metabolic syndrome. 2000;23:1278-1283. ment of obesity: need to focus on high risk abdomi-
Metformin acts principally on the 4. Selby JV, Grumbach K, Quesenberry CJ Jr, et al. nally obese patients. BMJ. 2001;322:716-720.
Differences in resource use and costs of primary 24. Ridker PM, Cushman M, Stampfer MJ, et al.
hepatic production of glucose by in- care in a large HMO according to physician special- Inflammation, aspirin, and the risk of cardiovascular
hibiting gluconeogenesis. It has a ty. Health Serv Res. 1999;34:503-518. disease in apparently healthy men. N Engl J Med.
5. Brown JB, Nichols GA, Glauber HS, Bakst AW. 1997;336:973-979.
small effect on muscle uptake of glu- Type 2 diabetes: incremental medical care costs 25. Colhoun HM, Betteridge DJ, Durrington PN,
cose.30 In the UK Prospective Dia- during the first 8 years after diagnosis. Diabetes et al. Primary prevention of cardiovascular disease
Care. 1999;22:1116-1124. with atorvastatin in type 2 diabetes in the Collabora-
betes Study (UKPDS), patients treat- 6. Selby JV, Ray GT, Zhang D, Colby CJ. Excess tive Atorvastatin Diabetes Study (CARDS): multi-
ed with metformin had a 30% reduc- costs of medical care for patients with diabetes in a centre randomised placebo-controlled trial. Lancet.
managed care population. Diabetes Care. 1997;20: 2004;364:685-696.
tion in cardiovascular events and 1396-1402. 26. Collins R, Armitage J, Parish S, et al; Heart
mortality compared with those who 7. Shahady EJ. Letter to the editor. JAMA. 2001; Protection Study Collaborative Group. MRC/BHF
286:1834. Heart Protection Study of cholesterol-lowering with
received conventional treatment.31 8. Institute of Medicine. Crossing the Quality Chasm: simvastatin in 5963 people with diabetes: a random-
Metformin also reduces levels of A New Health System for the 21st Century. Washing- ised placebo-controlled trial. Lancet. 2003;361:
ton, DC: National Academy Press; 2001. 2005-2016.
triglycerides and LDL-C.32 9. Saydah SH, Fradkin J, Cowie CC. Poor control of 27. Vergnani L, Hatrik S, Ricci F, et al. Effect of
The thiazolidinediones act pri- risk factors for vascular disease among adults with native and oxidized low-density lipoprotein on
previously diagnosed diabetes. JAMA. 2004;291: endothelial nitric oxide and superoxide production:
marily on adipocytes by decreasing 335-342. key role of L-arginine availability. Circulation. 2000;
lipolysis and the production of FFAs. 10. Executive Summary of the Third Report of 101:1261-1266.
the National Cholesterol Education Program Expert 28. Sever PS, Dahlof B, Poulter NR, et al. Preven-
The decrease in FFAs enhances the Panel on Detection, Evaluation, and Treatment of tion of coronary and stroke events with atorvastatin
muscle uptake of glucose and pro- High Blood Cholesterol in Adults (Adult Treatment in hypertensive patients who have average or lower-
Panel III). JAMA. 2001;285:2486-2497. than-average cholesterol concentrations in the
motes beta-cell function in the pan- 11. Clobanian AV, Bakris GL, Black HR, et al. The Anglo-Scandinavian Cardiac Outcomes Trial—Lipid
creas. These agents may also pre- Seventh Report of the Joint National Committee on Lowering Arm (ASCOT-LLA): a multicentre ran-
Prevention, Detection, Evaluation, and Treatment domised controlled trial. Lancet. 2003;361:1149-1158.
serve beta-cell function by decreas- of High Blood Pressure: the JNC 7 Report. JAMA. 29. Gillespie EL, White CM, Kardas M, et al. The
ing apoptosis of beta cells.33 2003;289:2560-2572. impact of ACE inhibitors or angiotensin II type 1
12. Boden G, Shulman GI. Free fatty acids in obesi- receptor blockers on the development of new-onset
Thiazolidinediones increase ty and type 2 diabetes: defining their role in the de- type 2 diabetes. Diabetes Care. 2005;28:2261-2266.
HDL-C and LDL-C levels; pioglita- velopment of insulin resistance and beta-cell dys- 30. Hundal RS, Krssak M, Dufour S, et al. Mecha-
function. Eur J Clin Invest. 2002;32(suppl 3):14-23. nism by which metformin reduces glucose produc-
zone decreases triglyceride levels.34 13. Skalen K, Gustafsson M, Rydberg EK, et al. tion in type 2 diabetes. Diabetes. 2000;49:2063-2069.
The thiazolidinediones also increase Subendothelial retention of atherogenic lipoproteins 31. Effect of intensive blood-glucose control with
in early atherosclerosis. Nature. 2002;417:750-754. metformin on complications in overweight patients
endothelium-derived nitric oxide pro- 14. Libby P, Ridker PM, Maseri A. Inflammation with type 2 diabetes (UKPDS 34). UK Prospective
duction. Nitric oxide raises HDL-C and atherosclerosis. Circulation. 2002;105:1135-1143. Diabetes Study (UKPDS) Group. Lancet. 1998;352:
15. Laws A, Hoen HM, Selby JV, et al. Differences 854-865.
levels and lowers triglyceride levels. 32. Robinson AC, Burke J, Robinson S, et al. The
in insulin suppression of free fatty acid levels by gen-
Decreased nitric oxide production in der and glucose tolerance status. Relation to plasma effects of metformin on glycemic control and serum
triglyceride and apolipoprotein B concentrations. In- lipids in insulin-treated NIDDM patients with subop-
diabetes contributes to hypertension timal metabolic control. Diabetes Care. 1998;21:
sulin Resistance Atherosclerosis Study (IRAS) inves-
and endothelial dysfunction.35 tigators. Arterioscler Thromb Vasc Biol. 1997;17:64-71. 701-705.
16. Bays H, Mandarino L, DeFronzo RA. Role of 33. Buchanan TA, Xiang AH, Peters RK, et al.
Thus, although the thiazolidine- Preservation of pancreatic beta-cell function and
the adipocyte, free fatty acids, and ectopic fat in
diones and metformin are used to pathogenesis of type 2 diabetes mellitus: peroxiso- prevention of type 2 diabetes by pharmacological
mal proliferator-activated receptor agonists provide treatment of insulin resistance in high-risk Hispanic
treat the hyperglycemia of diabetes, women. Diabetes. 2002;51:2796-2803.
a rational therapeutic approach. J Clin Endocrinol
they may—because of their multiple Metab. 2004;89:463-478. 34. Freed MI, Ratner R, Marcovina SM, et al. Ef-
17. Nash DT. C-reactive protein: a promising new fects of rosiglitazone alone and in combination with
effects on lipids, hypertension, and atorvastatin on the metabolic abnormalities in type 2
marker of cardiovascular risk? Consultant. 2005;45:
endothelial function—have a role in 453-460. diabetes mellitus. Am J Cardiol. 2002;90:947-952.
35. Vita JA, Frei B, Holbrook M, et al. L-2-Oxothia-
the treatment of the metabolic syn- 18. Nissen SE, Tuzcu EM, Schoenhagen P, et al.
zolidine-4-carboxylic acid reverses endothelial dys-
Statin therapy, LDL cholesterol, C-reactive protein,
drome.33 Polycystic ovary syndrome and coronary artery disease. N Engl J Med. 2005; function in patients with coronary artery disease.
J Clin Invest. 1998;101:1408-1414.
is a good example of a disorder in 352:29-38.
36. Nothnagle M, Taylor JS. Does metformin im-
19. Ridker PM, Cannon CP, Morrow D, et al. C-re-
which both of these drugs positively active protein levels and outcomes after statin thera- prove clinical features of polycystic ovary syndrome?
Am Fam Physician. 2003;68:2163-2164.
affect an insulin-resistant state.36,37 ■ py. N Engl J Med. 2005;352:20-28.
37. Ortega-Gonzalez C, Luna S, Hernandez L, et al.
20. Grundy SM, Cleeman JI, Merz CN, et al. Impli-
Responses of serum androgen and insulin resistance
cations of recent clinical trials for the National Cho-
to metformin and pioglitazone in obese, insulin-resis-
lesterol Education Program Adult Treatment Panel
tant women with polycystic ovary syndrome.
REFERENCES: III guidelines. Circulation. 2004;110:227-239.
J Clin Endocrinol Metab. 2005;90:1360-1365.
1. Ford ES, Giles WH, Dietz WH. Prevalence of the 21. Kahn R, Buse J, Ferrannini E, Stern M. The
38. Inzucchi SE. Oral antihyperglycemic therapy
metabolic syndrome among US adults: findings metabolic syndrome: time for a critical appraisal:
for type 2 diabetes: scientific review. JAMA. 2002;
from the third National Health and Nutrition Exami- joint statement from the American Diabetes Associ- 287:360-372.
nation Survey. JAMA. 2002;287:356-359. ation and the European Association for the Study of
2. Boyle JP, Honeycutt AA, Narayan KM, et al. Pro- Diabetes. Diabetes Care. 2005;28:2289-2304.
1586 CONSULTANT DECEMBER 2005 www.ConsultantLive.com
