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`SEPV
`
`CNS Drugé
`
`Supplement
`DRUG THERAPY IN NEUROLOGY AND PSYCHIATRY
`
`
`2005, Vol. 19, Supplement 1 (pp. 1-93)
`ISSN: 1172-7047
`
`Second-Generation (Atypical)
`Antipsychotics and Metabolic Effects
`A Comprehensive Literature Review
`
`GUEST EDITOR
`
`W. W. Fleischhacker
`
`Available Online
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`A .
`adls
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`INTERNATIONAL
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`A .
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`INTERNATIONAL
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`TM
`
`international Editorial Board
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`RJ. Eatdesmrini, Bfilfi‘tofit, MA, USA
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`P. Bach, Bil
`rad, Denmark
`M. Stealer, le to
`J, Billet, Mayrmod,
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`ti. Broadly, Ranclwick, Nfi‘J/‘J, Austrafia
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`l. Hindmawh, Codalming. England
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`CA
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`DA. Review,
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`Aim and Scope: CNS Drugs promotes rational pharmacotherapy and
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`eflective patient met
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`ancl
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`The journal includes:
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`Semfifiugmemfiafi (Atypieaié Antigsyehafieg
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`and MetaMEic Effeetg
`
`A Campmhemfive Literawre Review
`
`
`
`Gus st Edi tor
`
`W. Woifigang Fieiscizimrker
`
`Peer Review Panel
`
`Henry A. Nasmllah
`
`This publiml’im‘i has been made passiblc by an educational grant from Brismleycrs Squibb.
`
`
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`
`
`E (r'rmn'm Table of Content
`A
`A Fall Alez'i' Service l‘C
`. lintinfc
`ay ai‘ ww ..
`
`_
`Register far The {zeeA .
`CNS Drugs is indexed in Index Media/1.4,. Medlim, EMBASE’/Excerpm A/lediua, Gui/rem Canter:
`/Clinicrzl J‘s/{edicz'na Current
`
`
`
`Carnivals/Life S em'es, lnlermzlianai Pharmacm " ZAZ‘Islnu'ls, Science C‘ilaliun lndm‘, SciSwn‘l
`' arc}! Alert, PASCAL, the
`1‘
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`medical Dnuzmzmmzzon Swiss”, 5
`z'edzzd lbemmner Mr: Li? Iaibrmacz’é‘n Cientzfica (SIIC) and C119
`‘Z Abstracts. Individual articles
`are available thruugh the ADONlS document delivery service and Unline via {he V‘Jurld 'Wide W’eb lhrough lngentak Further
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`77913.35.
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`Surriemeefl: 2W ....
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`Cents-Brits
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`
`
`List 01‘ Contributors
`
`Second—Generation (Atypicai) Antipsychotics and Metabolic: Effects:
`A Comprehensive Literature Review ....................................1-93
`1% Newcomer
`
`Abetract
`
`1. Background: Obesity, 1115111111 Resistance, Diabetes and Dyeiipidaeiriias .....3
`1.1. Overweight and Obesity .......................................3
`1 2 Adipesity and the Effect of Fat Distributien ........................4
`1.3. Diabetes Meiiitus — a Growing Heaith Problem .....................5
`1 4 Dysiipidaernia .................................................8
`1.5. The Metabolic Syndrome ........................................9
`1 .6. (ardicwascuiar Disease [\isk Factmsm Patimts with Sthizmpiirenia
`.10
`2. Mental fitness; and Extiess iViiirtaiity ................................... 11
`2.]. Mortaiityin Mental iiiness ...................................... 11
`2.2.
`increaeed Rates Oi Metabeiic Disturbance Ameng Patients with
`Psychiatric Discriers; .......................................... 12
`Sean11 Methodology and Overview of Findings ........................ 15
`3.1.
`Searci1 Methodology ........................................... 15
`3.2. Types OF Reports .............................................. 15
`3.3.
`_.evels 01 Evidence ............................................. 16
`
`.3
`
`
`
`4
`
`Second-Generation Antipsychotics and Weight Gain .................... 16
`
`impact of VVegjht Cain, ......................................... 16
`4.1.
`42 Weight Gain in Children11, Adolescents and the. Eideriy ............. 17
`11.3. ’:ossibie Mechanisms of Antipgychotirmindwed Weight Gain and
`Met317011c Effects .............................................. 19
`
`5. FirstGeneration Antipsyc‘hotics ......................................21
`6.
`CiUZa )ine .........................................................21
`
`
`
`6.1. Bodyweight ...................................................22
`6.2. Diabetes (3111.1 Hy})erdi‘v{1113111151 ..................................22
`(-1.3. Aipid Leveis ..................................................32
`6.4. Cunciusivn ...................................................35
`
`7. Otanzapine35
`7.1. Sodeeightfi
`7.2. Diabetes and t-iypergtywemia 36
`7.3.
`lipid 1,.eveis ..................................................48
`7 .4. Conciusion ...................................................53
`
`8 R‘aFEUdOhe’D4
`8.1. Bodyweight ...................................................54
`8.2. Umbeiesundiivpugiycaamia 54
`8.3
`ind Leveis ..................................................62
`8.4.
`(30111211131011 ...................................................65
`
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`9. Quetiapim ........................................................65
`9.1 .
`Body‘weight ...................................................65
`92.
`7131113193 and Hypehgiycaemia ..................................66
`9.3.
`_,ipid Leve1s ..................................................159
`1.4.
`71501351011 ................................................... 70
`95. Conclusion ................................................... 71
`
`
`
`10. Zohhepine .......................................................... 72
`10.1, Bodyweight..,......,........¢................u......u........72
`1 )2 Diabetes.and E'Iypergb'caienfia ..................................72
`
`
`
`11.A11115111pride73
`11.11 Bodywe1ghh73
`11.21 Diabetes and Hf,/pe1giycaemia .................................. 73
`11.31 sipid Leve‘is ................................................... 73
`11.41 Discussion .................................................... 73
`11.51 C1:111<:1usio11 ................................................... 73
`
`12. Ziprasidone ........................................................ 74
`12.1. Sodyweight.H...“..u......1..u......u..u......1.H......1..7/1
`12.2, Diabetes and E-Ij,/pe1g1ycaemia .................................. 74
`12.3.
`ind Levds .................................................. 75
`12.4. Discussion .................................................... 77
`12.5. Canchision ................................................... 77
`
`
`
`13.. Aripiphazele ....................................................... 78
`13.1. Eodyweight ................................................... 78
`13.2.3121‘0131‘153 and vaerglycaemia .................................. 78
`13.3 -1p1d Leve15 .................................................. 79
`
`13.4. AnhipsyChohicMada ed Metabofic$161115 .........................80
`1. .5. Discussion ....................................................81
`_ 6. Comiusion ...................................................81
`14, General Discussion .................................................81
`
`14.1. Guidance for Patient Monitoring ...............................84
`14.2. Condusion ...................................................85
`
`Ackrowiedgements ....................................................86
`Disc:1051119 .............................................................86
`Reherences .............................................................86
`
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`GUEST EDITOR
`
`W. Wolfgang Fleischhacker
`Professar of Psychiatry, Departmcm‘ 0f Bioiagimi Psychiatry, Innsbruck University Clinics, Innsbruck,
`Austria
`
`PEER REVIEW PANEL
`
`Erlenry Nasraflah
`Associm‘e Dmn, I’mfessor of Psychiatry, Niezirvlogy 5’ Neuroscience, Hnizrersify 0f {firzcipztim‘i Medical
`Cerifer, Cincimmti, Ohio, USA
`
`CONTREBUTORS
`
`joim W. Newmmer
`Dmartmerit 0f Psychiatry, Wushirzgtmt University School 0f Mcdicirie, St. Lewis, Missouri, USA
`
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`§eennelmGeneratien (Atynieall
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`Antipsynhntics and
`etahnlic Effects
`A Cnmfnrehensive Literatnre Review
`
`[elm W. Newcomer
`
`Department of Psychiatry, washingten University School of Medicine; St l..otiis, Missouri, USA
`
`Ab$llGCi
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`
`
`increasing numbers of reports concerning diabetes, lseteacidesis, liypergl},’caehiia
`and lipid tiysregulatien in patients treated with second—generation (or atypical)
` _ asshciatinn between these
`antipsychntics have raised concerns about a pnssr
`metabolic effects and treatment with these medicatinns. This comprehensive litera-
`ture review cnnsiclers the evidence for and against an association between glucose
`0r lipid dysregtilatinn and eight separate second-generation antipsychntics current-
`ly availahle in the US and/tar Europe, specifically clazapine, nlanzapine, rlsperi—
`done, qttetianine, zntepine, mnisulpride, ziprasidcne and aripipraznle This review
`also includes an assessment of the potential contributory role of treatment—induced
`weight gain in cntifer ing risk fer liyperglycaetnia and dyslipidaeinia during treat—
`ment with different antipsychotic medicatinns.
`
`Substantial evidence from a variety of human populations, including some recent
`ccnlinnatnry evidence in treated psychiatric patients, indicates that, increased adi—
`posity is associated with a variety of adverse physiological effects,
`including
`decreases in insulin Sensitivity and changes in plasma glucose and lipid levels
`‘3
`
`Comparisnn
`F mean weight changes and relative pe, centages of patients experi—
`encing specific levels of weight increase ll‘O‘Ell controlled, randntnisett clinical trials
`rent second-
`
`indicates that weight gain liability varies signifcantly acrnss the d
`generation antipsychntic a gents Clozaninc and nlanzapinc treatment are associated
`with the greatest risk of clinically significant weight gain, with other agents pro—
`ducing relatively lower levels of ii
`' Risperitlenet qttetiapineq amisnlpride '
`
`
`
`
`
`zotepihe generally how low to moderate levels of mean weight ; 'in and a mo
`st
`risk (if clinically significant increases in weight Zinrasidonc and aripiprazole treat—
`ment are generally associated with minimal mean weight gain and the lowest risl;
`of more significant increases.
`
`Published studies including u neentrellet’l observatiens, large retrospective database
`analyses and controlled experimental studies? including randomised clinical trials)
`indicate that the different sccnnd-gcncratinn antipsychntics arc assnciated with Clif—
`
`fering effects Oi") glucose and lipid metab "‘ ‘ ii. These studies offer gene
`ly con--
`
`sistent evidence that cluzapine and; ()lanzapine treatment are assnciated; with an
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`Net “enter
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`atria. inconsistent results
`
`’ ‘
`
`increased risk of diabetes inellitus and dysli
`generally smaller effect in studies Where an effect is reported, suggest limited if any
`increased risl; for treatment—induced diabetes tnellitus and dyslipidaeniia during
`risperidone treatment” despite a comparable voltnne of published data. A similarly
`smaller and inconsistent signal suggests limited if any increased risk of diabetes or
`
`dyslipidaetnia during quetiapine treatment, but thi‘
`is based on less published data
`than is available for risperidone. The absence ol retrospective database studies, and lit-
`
`tle or no relevant published data from clinical trials? ‘ dies it difficult to draw con—
`clusions concerning risk for zotepine or antisulpride, although ainisulpride appears
`to have less risk of treatrnent-einerger"t dyslipidaeniia in comparison to olanzapine.
`
`
`
`With incre"
`rig data tron] clinical trip
`but little or no currently published data
`from large retrospective database analyses, there is no evidence at this time to sag--
`gesl that ziprasidone and aripiprazole treatment are associated with an increase in risk
`for diabetes, dyslipidaeniia or other adverse effects on glucose or lipid metabolism.
`
`in general, the rank, order of risk observed for the secondugeneration antips: ‘h
`medications sur sis that the differing weight gain liability of atypical agents con~
`tribntes to the dittering relative risk of insulin resistance dyslipidaernia and hyper”
`
`glycaetnia. Th
`would be consistent with effects observed in nonpi
`'chiatric sani~
`ples, where risk for adverse metabolic changes tends to increase With increasing
`
`adiposity From this perspective, a pc ble increase in risk wonlcl he predicted to
`occur in associat‘ n with any treatment that produces increases in weight and adi-
`posity. However, case reports tentatively suggest that substantial wei ght gain or obe~
`sity may not be a factor in up to one—quarter of cases of new—onset diabetes that
`occur during treatment. Pending further testing from preclinical and clinical stud
`ies, linii ted controlled studies support the hypothesis that clozapine and olanzapine
`may have a direct effect on glucose regulation independent of adiposity. The results
`of studies in this area are relevant to primary and secondary prevention efforts that
`aim to address the multiple factors that contribute to increased prevalence of type 2
`diabetes ntellitus and, cardiovascular disease in populations that tre often treate
`with secoitdugerieration antipsychotic medications,
`
`
`
`Reports of treatinenl~crncrgent adverse events
`such as diabetes rnellitus, diabetic ketoacidosis,
`hyperglycaernia and dyslipitlaenuas in patients
`receiving atypical or second—generation antipsy—
`ehotios have increased in recent years This has led
`to growing concern about a possible link between
`these metabolic el’l’ects and therapy with second—
`generation antipsychotics, and a number of issues
`have been raised:
`
`0 is there an increased risk of diabetes associated
`
`with second-generation antipsyohotie therapy? or
`do these reports simply reflect an increased risk
`of diabetes in patients with schizophrenia?
`
`~ if there is an increased risk of diabetes with scc~
`
`ondgeneration antipsychotics, does this risk dill
`
`
`for between the dill rent agents“?
`~ li‘ there is an increased risk of diabetes with sec~
`
`is it related to
`end—generation antipsychotics,
`their effects on bodyweiglit or adiposity, or
`action through other tilechanistiis?
`9 is there an increased risk of dyslipidaeinia asso—
`ciated with secontiwgencration antipsychotics? if
`so, does this risk vary between the different
`agents? is this also related to adiposity‘!
`
`This comprehensive literature review consid-
`ers the evidence for an association between glucose
`
`(C) Attils Dali] information BV 2005. All rights; reserved.
`
`CNS Drugs 2:305, l9 Suppl l
`
`
`
`10
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`L»)
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`ht ‘cs and letabolic Effects
`--Generation Antip
`Seco
`
`
`and/or lipid dysregulation and the second—genera,—
`‘tion antipsychotics currently available in the US
`and/or Europe: clozapinet olanzapine, risperidone,
`quetiapinc, zotepine, amisulpridc, ziprasidonc and
`aripiprazole. lt includes published reports of data—
`base analyses, chart reviews, clinical trials and case
`studies examining glucose and lipid regulation in
`patients treated with any of the eight atypical
`agents. Detailed below in the search methodology
`section, referenws extending into 2004 were idenu
`tilled by Medline search, as well as review ol‘
`selected meeting abstracts. Searches were per-
`formed for each of the individual antipsychotic
`agents, plus ‘atypical antipsychotics’, combined
`with the following terms: diabetes, glucose,
`ltetoacidosis, hyperglycaemia, triglycerides, hypcru
`triglyceridaernia, hyperlipidaernia, lipidaernia, dys—
`lipidaemia and cholesterol, Data are presented and
`discussed for each of the eight antipsycliotics indiu
`virlnally, with the overall findings reviewed in a
`final discussion section.
`
`1. Background: Ghostly, insulin
`Resistance, Diabetes and
`Dyslipidoemios
`
`l.l Overweight and Obesity
`
`Overweight and obesity are increasing proh~
`lems in the US and throughout the Western world
`and have significant health implications. hi the US,
`data from the Third National Health and Nutrition
`
`Examination Survey (Ni-IANES lll) conducted in
`ESE—1994 showed that 53% of people aged 20
`years and above were either overweight (body
`mass index [Eh/ll] 250—29,“) kg/ini) or obese (Eh/ll
`2:30 ltg/rnz). The prevalence of overweight was
`higher for men than for woinen (39.9% vs 25.7%),
`whereas obesity prevalence was higher among
`women than men (25.5% vs “99%). in the most
`recent \lHA\LԤ data For 19997772000,
`the preva—
`lence of Overweight and obesity combined. had
`risen to 64%. Trends in obesity prevalence over the
`last 40 years showed little change From lean to
`l980,
`then a marked increase to the present day
`(men ”80. 13%; l99l, Ell/7:0; 1999—2000, 289%;
`
`women 1980. 17%; Will, 26%; 1999—2000., 34%).
`The increasing prevalence of overweight has also
`been observed in children and adolescents, in chil-
`
`dren (ft—l l years), the proportion overweight (BM l
`>95th percentile) increased from 4% in l965 to
`l3% in 1999, while for adolescents (lZ—lg years),
`the percentage rose from 5% in l970 to l4% in
`E999.
`
`Findings are similar in European countries.
`Data, from the international Obesity Taslt Force
`(lUl‘lli and the European Association for the Study
`of Obesity (EASG) published in 2802 showed that
`407.50% of men and 254002 of women were over—
`
`weight, and that “in-20% of men and ill-"25% of
`women were obese.m in each country overweight
`was more prevalent among men than woinen7 while
`obesity rates were almost always higher for women
`than 111611, The prevalence of obesity has also
`shown a. marked increase in recent years, with the
`majority 0t European countries showing a ill-"50975
`increase in rates over the last 10 years. Prevalence
`of overweight in children and adolescents has also
`increased. Surveys conducted over the last 10 years
`typically show that 10—20% children aged around
`it) years are overweight, although in some coun-
`tries prevalence rates were over 30%.“
`Overweight and obesity are associated with
`increased rates of mortality and n‘torbidity.
`Mortality rates increase for both men and women
`throughout the range of moderate and severe over-
`weightm Among obese individuals,
`the risk of
`death from all causes is 50----l0(l‘;7£> greater than for
`those of normal weight (BMl 20725 log/n11); most
`of the increased risk is due to cardirnrascular caus—
`
`es?J Estimates put the number of deaths attributa—
`ble to obesity in the US at 300 000 per year.m
`Overweight and obesity are known to increase
`the risk for a number of diseases.
`including dia—
`betes, cardiovascular disease (eg. coronary heart
`disease ECHD] and cerebrovascnlar disease),
`hypertension and certain cancersfi” in addition,
`they are associated. with abnormal metabolic
`changes such as insulin resistance and dyslipi—
`daeniia, which are themselves risk factors for car--
`diovascular disease (CVD) and diabetes. The con-
`siderable overall impact of overweight and obesity
`
`(C) Artils Dali] information BV 2005. All rig
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`on health is therefore not surprising, with CVD
`representing the major cause of mortality in the
`developed world: in 2000, heart disease accounted
`for almost: 30% of all deaths in the US)“
`
`Increasing adiposi ty is directly associated with
`increases in morbidity and mortality from C‘s/Ba in
`addition to indirect effects through adiposityn'clatu
`ed increases in knot/“n CVl') risk factors? such as
`hyperglycaeniia, dyslipidaemia and hypertension.
`Recent studies have suggested, for exan‘iple, that
`even modest increases in Bit/ll increase the risk ol‘
`
`CED. in the Nurses" Health Study, for example, the
`relative
`risk
`ol’ CED at BlVll
`levels of
`
`25----28.9 leg/tn2 and 229 leg/nuZ was 2—fold and 3~
`told greater,
`respectively;
`than at BMl below
`2i leg/mi. ‘Wcight gain of 5—8kg increased the risk
`of CHD by 25% compared with individuals with
`stable weight}bi A study in British men showed, a
`ltlft’i; increase in the risk of coronary events with
`each 1—point increase in BMl at lib/ll levels above
`22 kg/rnhr’l
`Overweight and obesity are linked to an
`increased risk of other cardiovascular events.
`
`Several studies, including the Framingham Heart
`Study, have shown that overweight and obesity are
`independent risk factors for congestive heart failure
`(CHF). CHF is a frequent complication and a major
`cause of death in severe obesity}sl The Framingham
`Heart Study also suggests that overweight inereas~
`es the risk for stroke independent of the etl'ects of
`hypertension and diabetes. More recent studies
`have shown an association between overweight and
`ischaeinie, but not haemorrhagic, stroke, with risk
`
`increasing with increasing Blvll."' ‘Ul
`In addition to the direct association between
`
`increasing adiposity and increases in morbidity and
`inortality front C VIE-related events. increasing adi-
`posity is associated with increases in other known
`risk factors for CVD, such as hyperglyeaeniia, dys-
`lipidaeinia and hypertension. Overweight and olive—
`sity are well established risk factors [or diabetes,
`with increased rates of diabetes associated. with
`
`increasing adiposity in both men and women.
`Recent studies have reported increases in the risk
`of diabetes beginning at BMl values as low as 22
`
`log/nil.g 1"
`in one study, each unit
`it kgi’mz)
`
`increase in BMI over 22 log/mZ increased the risk
`of diabetes by about 215%?“ Nutrierous studies
`have
`similarly demonstrated the association
`between blood pressure and BMl or weight.
`NHANES lll data showed increasing rates of hi gh
`blood pressure with increasing BMI in both men
`and women?“ Obesity and weight gain are also
`associated with dyslipidactniae another established
`
`risk factor for CVD,
`14‘ Obesity, overweight and
`excess abdominal fat are predictive of increased
`levels of total cholesterol, low—density lipoprotein
`(LDL) cholesterol and triglycerides and reduced
`levels of high-density lipoprotein (HDL) choles—
`terolgl“ in a recent US population survey; both over—
`weight and obese individuals showed, an increased
`risk of elevated cholesterol levels compared with
`
`normal individuals.
`The changes in cholesterol
`levels seen in overweight and obese individuals
`result in a high, LDL to HDL cholesterol ratio,
`increasing the risk of atherogenesis
`
`l .2 Adiposity and the Effect ot Fol Distribution
`
`The distribution of fat (adipose tissue) within
`the body is recognised as a key factor influencing
`the effect ol’ increasing weigl‘n on health“ Several
`studies have demonstrated a link between abdomi-
`
`nal adiposity and overall n‘iortality, with visceral
`adipesity particularly related to an increased risk of
`disease. Visceral adiposity is associated with an
`increased risk for dyslipidaeniia and glucose intol—
`eranee.“SJ The changes in lipid parameters observed
`with visceral adiposity increase the risk for CW).
`The association between visceral adiposity and
`increased insulin resistance is a key factor con—
`tributing to increased risk for glucose intolerance
`and dyslipidaeniia. Differences in visceral adiposi-
`ty accounted for much of the variation in insulin
`resistance seen between individuals in a study of
`
`A Frican Americans with type
`2 diabetes.
`Tl
`Reductions in visceral adiposity in non—diabetic
`obese individuals were the best predictor of
`improved insulin sensitivity in a weight loss inter—
`vention study!“ Other aspects of regional adiposi--
`Ly may also have an effect on insulin resistance in
`the lower extremities, intramuscular adipose tissue
`
`
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`is strongly correlated with insulin resistance,
`wheie1s subcutaneous adiposity is only] weakly
`associated?”
`
`Recent research has begun to address the
`pathophysiological mechanisms that link adiposity
`to insulin resistance (reviewed by Goldsteinm).
`Adipose tissue secretes an umber of factors, incl udu
`ing tree Fatty acids (FF/t). peptides and cytokines,
`which can adversely affect insulin action and may
`have a detrimental effect on beta cell function.
`
`Secretion of these factors is influenced by overall
`adiposity and by fat distribution, with visceral adi-
`posity appearing more pathogenic. increased vis—
`ceral adiposity is associated with increased release
`of FFA front adipose tissue. Prolonged exposure to
`elevated FFA levels can directly reduce the
`response of skeletal muscle and liver to insulin
`action through activity on insulin receptor sig-
`nalling pathways. Elevated FFA levels also appear
`to compromise pancreatic beta cell function, reduc—
`ing insulin secretion.
`
`l.3 Diabetes Mollllur — (:1 Growing Health
`Problem
`
`Diabetes is a growing health prohlenL both in
`the US and worldwide. According to latest
`American Diabetes Association (ADA) estimates
`thased on 2002 census data). there are l3 million
`individuals with diagnosed diabetes in the US —
`4.5% of the population?“ Other estimates put the
`prevalence of diagnosed diabetes in the US at more
`than 7%.”
`
`W’HO data indicate that diabetes prevalence
`ranges from about 2% to over 6% in western
`European countries?“ Population studies have also
`revealed large numbers of individuals with undiag-
`nosed diabetes. in NHANES lll. 2.7% of the stir—
`
`veyed population had undiagnosed diabetes, based
`on blood glucose analysis (Le. fasting plasma glu—
`cose 2126 trig/(.llnlii—i This compares with 5.1%
`with diagnosed diabetes. Undiagnosed diabetes is
`also widespread in Europe. Data from l3 studies
`performed in nine European countries showed that
`inure than hall of diabetes was undiagnosed in
`individuals younger than 50 years.” The ADA
`
`estimates that up to one—third of individuals with
`diabetes are undiagnosed. This represents an addi—
`tional 5.2 million people in the US with die dis-
`ease, giving an overall total of l8.2’ million indi—
`viduals with diabetes
`6.3% of the US popula—
`tion!” in addition, large numbers of individuals in
`the US have ‘pre—diabetes’. That
`is,
`they have
`blood glucose levels that are above normal. but do
`not meet the diagnostic criteria for diabetes (see
`below). According to the ADA, an estimated 4i
`million people in the US have ‘pre~diabetes’.l“l
`Diabetes is associated with increased mortali-
`
`ty compared with the general population. Analysis
`of Nl—lANES l data showed that overall age—adjust—
`ed mortality in individuals with diabetes was
`approximately twice that in the nonudiabctic popu—
`lation.” Mortality rates were observed to increase
`with age, although the relative risk of death in dia-
`betic individuals compared with non—diabetic indi—
`viduals decreased from 3.6 in those aged 25-44
`years to l5 in those aged 6511174 years. Median life
`expectancy for individuals with diabetes was 8
`years lower for those aged 55-64 years and 4 years
`lower for those aged 65—74 years compared with
`non-diabetic adults. The relative risls: of death was
`
`higher in diabetic individuals than non—diabetic
`individuals for all major causes of death, except
`in al i gn ant n eo pl asn‘i s. [:5]
`Diabetes is also associated with increased
`
`individuals with the disease are at
`morbidity.
`increased risk of morbidity due to CVD, hyperten—
`sion and stroke.
`in general. diabetes and pre—dia—
`betes (see below) increase the risk of niacrovascu—
`lar disease (i.e. atherosclerosis), including CVD—
`related events (eg. myocardial
`infarction and
`stroke) and peripheral vascular disease—related
`events tog. amputations). Diabetes is also associat-
`ed with mierovascular disease. including nepllropa—
`thy (kidney or renal disease), retinopathy and nett-
`ropathy. ll: is the leading cause of treated, end—stage
`renal disease and new cases of blindness among
`adults aged 20~74 years. The healthcare burden
`associated with diabetes is apparent from the high
`economic
`costs
`associated with
`treatment.
`
`Estimated direct costs exceeded $US9l billion in
`2002, and medical expenditure was approximately
`
`(C) Aviills Dotti information BV 2005. All rights; reserved.
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`2.4 times higher for individuals with diabetes than
`those w