Overall Mortality in Diabetes Mellitus: Where Do We Stand Today?

Overall Mortality in Diabetes Mellitus:Where Do We Stand Today?

George Dailey, M.D.

Abstract

Life expectancy for a patient with type 2 diabetes remains substantially shorter than an equivalent individualwithout diabetes, largely because of a greater risk of cardiovascular disease. Diabetes is also associated with anincreased incidence of many types of cancer, suggesting that malignancy may also contribute to higher rates ofmortality. Hyperglycemia is one of the key risk factors for diabetes-associated macro- and microvascular disease,and as such, intensive glycemic control is associated with improved outcomes for patients, including a reductionin this risk of death from any cause, when initiated early in the disease course. Recent trials in patients with moreadvanced disease have failed to demonstrate a mortality benefit with intensive glycemic control, although thismay reflect their short observation period. Intensive multifactorial therapy, including lifestyle intervention andcontrol of hyperglycemia, hypertension, lipids, thrombosis, and microalbuminuria, is likely to be the beststrategy against diabetes-associated macrovascular mortality. However, analysis of the Action to Control Car-diovascular Risk in Diabetes (ACCORD) trial indicates that there may be a subpopulation of patients who areunable to achieve glycemic targets with intensive therapy and that aggressive intensification of treatment in thisgroup may increase mortality risk. It remains to be determined whether the relationship between diabetes andmalignancy is causal or whether they share common risk factors. Current recommendations for a healthylifestyle based on good diet, physical exercise, and weight management in order to control diabetes-relatedcomplications are likely to apply in reducing the risk of many forms of cancer and should be advocated for allpatients.

Introduction

It is well established that diabetes is associated with anincreased risk of premature mortality. The latest data from

the National Center for Health Statistics reveal that diabeteswas the seventh leading cause of death in the United States in2007.1 A total of 71,382 death certificates listed diabetes as theunderlying cause, representing nearly 3% of all mortality inthat year. In reality, these figures are likely to be a consider-able underestimate given that individuals with diabetes oftendie of associated complications, such as cardiovascular dis-ease (CVD) and renal disease, which may be recorded on thedeath certificate in preference to diabetes. Estimates based onrelative risk rates reported in the literature indicate thatmortality in the United States attributable to diabetes maybe as high as 8% of all deaths.2 Recent evidence from theFramingham Heart Study cohort (1976–2005) shows that in-dividuals with diabetes have a twofold increase in the risk ofall-cause mortality relative to individuals without diabetes.3

Life expectancy at age 50 years and older for women and menwith diabetes was 8.2 and 7.5 years less, respectively, than for

comparable individuals without diabetes.4 Other population-based studies have reported at least a similar magnitude ofexcess risk.5–7

The major factor in increased mortality associated withdiabetes is the risk of CVD, which is the leading cause of deathin this population. Analysis of the First National Health andNutrition Examination Survey covering the period 1971–1993revealed that more than two-thirds of deaths of people withdiabetes were due to CVD.5 The most recent update of theTayside observational cohort, based in Scotland, UK, fol-lowed a defined group of 10,532 patients newly diagnosedwith type 2 diabetes and 21,056 comparators without diabetesfrom 1993 to 2004.8 Vascular disease was the most frequentcause of death in both groups, but the incidence of such dis-ease was considerably greater in patients with diabetes versusthose without (45% vs. 39%). The study controlled for levels ofdeprivation, which is positively associated with higher ratesof diabetes and mortality. Diabetes was associated with a 50%increase in cardiovascular mortality and 30% increase in all-cause mortality.8 These figures are lower than in previousobservational trials, which is likely to be owing, in part, to the

Scripps Clinic Torrey Pines, La Jolla, California.

DIABETES TECHNOLOGY & THERAPEUTICSVolume 13, Supplement 1, 2011ª Mary Ann Liebert, Inc.DOI: 10.1089/dia.2011.0019

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design of the analysis, but may also reflect improvements incare of diabetes over the last decade. There are additional datasuggesting that more stringent control of vascular risk factorsadvocated by management guidelines may have improvedlife expectancy for individuals with diabetes in recent years.Data from a defined cohort of 973 patients with type 2 dia-betes in The Netherlands covering the period 2001–2007 re-ported no reduction in life expectancy compared with thegeneral population, based on Dutch national statistics, butonly in the absence of existing CVD or albuminuria.9 Theauthors asserted that a normal life expectancy may beachievable in the future for patients with type 2 diabetes.

However, questions remain, including the rationale fordata suggesting that intensive glycemic control, which is oneof the cornerstones of current management guidelines, may beassociated with increased mortality.10 The aim of this article isto overview the latest evidence on the influences of mortalityin patients with type 2 diabetes.

The Role of Hyperglycemia in Diabetes-AssociatedCVD and Mortality

The Diabetes Control and Complications Trial (DCCT) wasthe first large-scale randomized, controlled trial to conclu-sively demonstrate that intensive glycemic control could re-duce the risk of microvascular complications in patients withtype 1 diabetes compared with conventional therapy.11 Pa-tients in the intensive treatment arm showed a dramatic re-duction in the incidence of diabetes-associated microvascularcomplications. There was no significant difference in the riskof macrovascular disease, although intensive therapy did re-duce the development of hypercholesterolemia by 34% rela-tive to conventional therapy, indicating an improvement inpatients’ risk profiles.

The DCCT cohort was followed up on an annual basis foranother 11 years after the end of intervention as part of theEpidemiology of Diabetes Interventions and Complications(EDIC) study.12,13 At the end of the DCCT, mean A1c levelswere approximately 2% lower in the intensive treatment armversus the conventional arm (EDIC population: 7.2% vs. 9.1%;P< 0.001).12 This difference in A1c narrowed over the fol-lowing 8 years of follow-up, stabilizing at approximately 8%for both groups (P¼ 0.83). Despite this convergence, follow-up at 11 years post-closure of the DCCT (17 years of totalfollow-up) revealed a significantly lower risk of macro-vascular complications with initial intensive versus conven-tional therapy.13 A total of 144 cardiovascular events occurredin 83 patients over this period, with a rate of 0.38 events per1,000 patient-years in the intensive arm and 0.80 events per1,000 patient-years in the conventional treatment arm(P¼ 0.007). Overall, intensive treatment was associated with a42% relative reduction in risk of a first cardiovascular event(P¼ 0.02) and a 57% reduction in risk of nonfatal myocardialinfarction, stroke, or death from CVD (P¼ 0.02).

The United Kingdom Prospective Diabetes Study (UKPDS)is the equivalent landmark trial for patients with type 2 dia-betes. A total of 4,209 patients with newly diagnosed type 2diabetes were randomized to receive conventional treatmentor intensive therapy with a sulfonylurea, insulin, or, foroverweight patients, a metformin-based regimen.14,15 In theanalysis of patients treated with a sulfonylurea and/or insu-lin, median A1c levels over 10 years of treatment were sig-

nificantly lower with intensive versus conventional therapy(7.0% vs. 7.9%).14 This difference was associated with a sig-nificant reduction in the relative risk for intensively treatedpatients of 25% for any microvascular end point (P¼ 0.0099),including a 21% reduction in the incidence of retinopathy(P¼ 0.015) and a 33% reduction in microalbuminuria(P< 0.0001). The relative risk of nonfatal myocardial infarc-tion was 21% lower with intensive therapy, albeit with bor-derline statistical significance (P¼ 0.057). There was nosignificant difference in mortality rates, although there was atrend in favor of the intensive group, with a 10% relative riskreduction for diabetes-related death and 6% for all-causemortality.

An analysis of the UKPDS data from 10 years after the endof the interventional period (total follow-up >20 years) pro-vided further insight.16 In this analysis, the relative risk ofnonfatal myocardial infarction in the intensive treatmentgroup was 15% lower and statistically significant (P¼ 0.01).The relative risk of death related to diabetes was 17% lowerwith intensive therapy (P¼ 0.01), and the risk of all-causemortality was 13% lower (P¼ 0.007). The benefit against mi-crovascular complications was also maintained over the ex-tended follow-up period. Outcomes for the 342 overweightpatients treated with metformin-based intensive therapy fol-lowed a similar pattern and were even greater in magnitude.These benefits were achieved despite the fact that the differ-ence in A1c levels apparent at the end of intervention was lostwithin 1 year and were comparable over the remaining periodof follow-up. This is analogous with the experience with type1 diabetes patients in the EDIC study and demonstrates againthe ‘‘legacy effect,’’ where the benefits of glycemic controlpersist long after intervention. Moreover, this also suggeststhat longer periods of observation than the approximately 5-year follow-up of the recent trials described below may beneeded to see benefits on cardiovascular end points.

Is There a Link Between Hypoglycemia and Mortalityin Patients with Diabetes?

Following the findings of the original UKPDS, severallarge-scale prospective trials were initiated to evaluate thebenefits of intensive glycemic control against macrovasculardisease in higher-risk populations (Table 1).

In the Action to Control Cardiovascular Risk in Diabetes(ACCORD) trial, 10,251 patients with type 2 diabetes andat high risk of CVD were randomized to intensive therapy(A1c, <6.0%) or to standard therapy (A1c, 7.0–7.9%).10 TheACCORD population had a mean age of 62 years and a meanduration of diabetes of 10 years, with 35% already treatedwith insulin at baseline. Median baseline A1c levels were 8.1%and stabilized on study at 6.4% and 7.5% after 1 year of in-tensive or conventional therapy, respectively. At the interimanalysis point (mean follow-up, 3.5 years), comparison of theintensive and conventional arms also revealed a significantlyhigher rate of death from any cause (5.0% vs. 4.0%; P¼ 0.04)and death from CVD (2.6% vs. 1.8%; P¼ 0.02) with intensivetherapy, and the monitoring board prematurely terminatedintensive treatment and switched all patients to the controlarm. This was the first demonstration in a large-scale clinicaltrial that linked very aggressive blood glucose control with anincreased risk of mortality in type 2 diabetes and caused muchconsternation. However, evidence from two additional trials

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published in the same year failed to support this ACCORDfinding.

The Action in Diabetes and Vascular Disease: Preterax andDiamicron Modified Release Controlled Evaluation (AD-VANCE) study was a second large-scale randomized trialcomparing the impact of intensive glucose control withstandard therapy.17 As in the ACCORD study, the AD-VANCE population were relatively old (mean age, 66 years)and were at high risk of CVD. However, compared with theACCORD cohort, patients in the ADVANCE study had amean duration of diabetes that was 2 years shorter (mean, 8years), lower baseline A1c (median, 7.2%), and almost no useof insulin at enrollment. At median follow-up of 5 years,median A1c levels were 6.4% and 7.0% in the intensive andstandard treatment arms, respectively. Intensive treatmentwas associated with a significant 14% reduction in the risk of

microvascular events (P¼ 0.01), but the rate of macrovascularevents was comparable between the two groups (P¼ 0.32). Incontrast to the ACCORD study, intensive therapy was notassociated with increased cardiovascular or all-cause mor-tality.

A third trial, the Veterans Affairs Diabetes Trial (VADT),randomized 1791 military veterans with type 2 diabetes to anintensive glycemic control (A1c, <6.0%) or standard glycemiccontrol regimen.18 Other CVD risk factors were treated ag-gressively and equally in both groups. Enrolled patients wereuncontrolled on insulin or maximal-dose oral agents and re-presented a poorly controlled population with median base-line A1c of 9.4%. Mean age was 60 years, and the duration ofdiabetes was longer than in the ACCORD and ADVANCEstudies, at 11.5 years. Median A1c levels of 6.9% and8.5% were achieved in the intensive and standard arms,

Table 1. Comparison of Mortality in Subjects with Type 2 Diabetes in Large-Scale Trials

Baseline End of follow-up

Study, treatmentgroups (n)

Age(years)

Duration ofdiabetes (years)

Median A1C(%) A1C (%)

Hypoglycemiarequiring assistance

All-causemortality

UKPDS (insulin–sulfonylurea group)14

Conventional(n¼ 1,138)

53.4 All newlydiagnosed

7.05 7.0a 18.9

Intensive (n¼ 2,729) 53.2 7.09 7.9a NR 17.9 (P¼ 0.44)

UKPDS 10-year follow-up (insulin–sulfonylurea group)16

Conventional(n¼ 880)

63 8.5 30.3

Intensive(n¼ 2,118)

63 NR 7.9 No significantdifference

NR 26.8 (P¼ 0.007)

UKPDS (metformin group)15


53 All newlydiagnosed

7.1 8.0a 0.7% 20.6

Intensive(n¼ 342)

53 7.3 7.4a 0% 18.5 (P¼ 0.011)

UKPDS (metformin group)16


63 8.9 No significantdifference

NR 33.1

Intensive(n¼ 279)

64 NR 8.4 25.9 (P¼ 0.002)

ACCORD10

Standard(n¼ 5,123)

62.2 10 8.1 7.5 5.1% 4.0


62.2 10 8.1 6.4 16.2% (P< 0.001) 5.0 (P¼ 0.04)

ADVANCE17

Standard(n¼ 5,569)

66 8.0 7.2 7.0 1.5% 9.6


66 7.9 7.2 6.4 2.7% (P< 0.001) 8.9 (P¼ 0.28)

VADT18

Standard(n¼ 899)

60.3 11.5 9.4 8.4 3b 10.6

Intensive(n¼ 892)

60.5 11.5 9.4 6.9 9b (P< 0.001) 11.4 (P¼ 0.62)

All values are mean (SD) unless stated otherwise.aMedian over duration of follow-up period.bEvents with impaired consciousness per 100 patient-years.ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and

Diamicron Modified Release Controlled Evaluation; NR, not reported; UKPDS, United Kingdom Prospective Diabetes Study; VADT,Veterans Affairs Diabetes Trial.

COMBATING CARDIOVASCULAR DISEASE AND CANCER S-67

respectively, within the first 3 months of the study andmaintained for the duration of the median 5.6 years of follow-up. There was no significant difference between the twogroups in any one of the macrovascular events that formedthe composite primary outcome. There was also no significantdifference in the rate of microvascular events between the twogroups and no difference in the rate of death from any cause(P¼ 0.62).

Based on the outcomes of these three trials and the contrastwith the UKPDS, it appears that glycemic control may bemore effective when initiated early in the course of diseasebefore the underlying mechanisms that mediate vascularcomplications are established. The benefits of intensive gly-cemic control are also likely to be more evident with longerfollow-up of more than 10 years, given that the power ofACCORD, ADVANCE, and VADT was limited in this re-spect. Several meta-analyses of the major trials assessingglycemic control in type 2 diabetes have been performed withdata included from the UKPDS, ACCORD, ADVANCE, andVADT studies and others.19–21 Based on similar data sources,the analyses are consistent in showing a significant reductionin CVD with intensive versus conventional therapy and, inparticular, a reduction in myocardial infarction. In the anal-ysis by Ray et al.,20 intensive glycemic control resulted in a17% reduction in rates of nonfatal myocardial infarction and a15% reduction in coronary heart disease events; these benefitswere achieved with no significant increase in the rate of all-cause mortality.

Insight into the benefits of early initiation of intensive ther-apy on macrovascular outcomes and mortality is likely to comefrom the ongoing ‘‘Outcome Reduction with an Initial GlargineIntervention’’ (ORIGIN) trial. The study has enrolled 12,612subjects with evidence of CVD and with either impaired fastingglucose, impaired glucose tolerance, or newly detected or es-tablished diabetes (on zero or one oral antidiabetes agent).22

Using a 2�2 factorial design, patients were randomized toinitiate insulin glargine targeting an fasting plasma glucose of�95 mg/dL (5.5 mmol/L) or standard glycemic care and too-3fatty acid supplements or placebo. The primary end points arethe rate of cardiovascular events and cardiovascular mortality,respectively. To date, the risk of hypoglycemia appears to below;23 efficacy data are expected next year.

Evidence in support of the ACCORD finding on mortalitycomes from a recent retrospective, registry-based cohortstudy, by Currie et al.,24 who utilized data from a UK-basedprimary care database derived from patient records. Eligiblepatients had a diagnosis of type 2 diabetes, a case history of atleast 6 months, and a documented history specifying escala-tion of their diabetes treatment. The primary outcome mea-sure was all-cause mortality assessed according to post-indexA1c, which was defined as the mean of all observations re-corded after the first prescription of intensified diabetestherapy. The analysis revealed a U-shaped relationship be-tween mortality and post-index A1c levels, with an increasedunadjusted mortality rate at the highest and lowest A1c levels.The lowest mortality rate occurred at an intermediate A1clevel of approximately 7.5%. However, the design of thisstudy has been criticized, with the principal problem beingthe definition of A1c as a fixed variable rather than one thatcan change over time. Critics have also pointed out thatstudies in other fields have noted spurious U-shaped rela-tionships between various biomarkers and mortality due to

an association between extreme levels at either end of thespectrum and underlying disease.25 For example, a U-shapedrelationship was observed for cholesterol levels and mortality,which was influenced by a minority of critically ill patientswith very low cholesterol levels; yet, clinical use of statins tolower cholesterol levels is not associated with increasedmortality risk.

Despite numerous post hoc analyses, the reason for theexcess mortality in the intensive arm of the ACCORD trialremains elusive. Several explanations have been proposed,including an excessively rapid reduction in A1c, increasedsevere hypoglycemia, weight gain, and high doses of certainantidiabetes agents or combinations of agents. In examiningthe first of these hypotheses, an epidemiological analysis ofthe interim data revealed that a moderate or large reduction inA1c over the first year of treatment was associated withsimilar rates of mortality in both the intensive and conven-tional treatment arms, whereas higher mortality rates wereseen with intensive treatment when little or no reduction inA1c occurred26 (Fig. 1). This observation is at odds with the‘‘rapid A1c reduction’’ theory. The glycemic measure moststrongly associated with mortality in the analysis was averageA1c over the study period: a 1% increase in average A1c wasassociated with a 20% increase in the risk of death. This leavesthe question as to why there was an excess of deaths in theintensive treatment arm despite mean A1c levels being sig-nificantly lower throughout the observed period. This may bepartly explained by the fact that the correlation betweenhigher A1c and death was greater in the intensive versus theconventional treatment arm. Plotting the risk of all-causemortality against average A1c showed a linear increase in riskfrom 6% to >9% with intensive treatment (Fig. 2). In contrast,the conventional therapy plot showed a U-shaped relation-ship and a markedly lower risk of death relative to the in-tensive arm at average A1c levels >7% (Fig. 2). Therefore, itseems that patients in both groups who failed to achieve anotable reduction in A1c were at greater risk of death thanthose with an average A1c below 7%, but this increased riskwas exaggerated in the intensive treatment arm.

The rates of hypoglycemia requiring medical or any assis-tance were significantly higher with intensive versus con-ventional treatment in the ACCORD study,10 leading to theproposal that hypoglycemia may be responsible for the excessmortality in the intensive arm. In both treatment arms, pa-tients who experienced an episode of severe, symptomatichypoglycemia had a greater risk of death compared withthose patients who had not experienced hypoglycemia.27

However, among all patients who experienced a severe,symptomatic hypoglycemia episode, the risk of death waslower for patients in the intensive rather than the standardarm. This suggests that increased mortality in the intensivetreatment arm cannot be attributed only to hypoglycemia. Infact, across both treatment groups, a 1% increase in patients’average A1c over the study period was associated with a 76%and 30% increase in the risk of severe hypoglycemia for theintensive and conventional treatment groups, respectively.28

Echoing the results of the mortality analysis, patients with thesmallest reduction from baseline in A1c were at greatest riskof severe hypoglycemia.28

Combining these two lines of evidence from the ACCORDtrial indicates that there may be a subpopulation of vulnerablepatients who are unable to reduce their A1c level below 7%

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and that intensive therapy in this subgroup can increase therisk of mortality. This suggests that physicians who encounterpatients with persistently high A1c levels should be cautiousin intensifying treatment. Further study is required in order toidentify and characterize subgroups with differing mortalityrisk so that treatment can be tailored appropriately.

Multifactorial Therapy to Reduce the Riskof Diabetes-Associated Mortality

It is well recognized that hyperglycemia represents onlyone of several potential risk factors for CVD and that controlof all these factors may be necessary for optimal management.The Steno-2 study was a single-center, randomized, open-label, parallel-group trial that evaluated multifactorial ther-apy in 160 individuals with type 2 diabetes (mean duration, 6years) and persistent microalbumiuria.29,30 Eighty patientswere randomized to receive conventional treatment for mul-tiple CVD risk factors according to the Danish standard ofcare at the time of the study initiation in 1992.30 The remaining80 patients were randomized to intensive multifactorialtherapy comprising lifestyle intervention and polypharmacy,

with specific targets for controlling hyperglycemia (A1c<6.5%), hypertension, lipids, thrombosis, and micro-albuminuria. The behavioral, clinical, and biochemical char-acteristics of the two study groups were comparable atbaseline but had diverged considerably in favor of the inten-sive group after a mean follow-up of 7.8 years. These differ-ences were reflected in the risk of CVD, which, for patientswho received intensive treatment, was more than 50% lowercompared with conventional therapy (hazard ratio [HR], 0.47[95% confidence intervals [CI]: 0.24–0.73]). The risks of ne-phropathy, retinopathy, and neuropathy were also signifi-cantly lower. Rates of hypoglycemia were comparablebetween the groups.

A follow-up analysis of the Steno-2 study was conducted5.5 years after the end of intervention, by which time thecharacteristics of the two groups had converged, primarilybecause of intensified therapy in the original conventionaltherapy group. Over the entire 13.3-year period of follow-up,24 deaths (30%) in the intensive group and 40 deaths (50%)in the conventional group had occurred, which translatedinto a 46% reduction in mortality with intensive therapy(HR, 0.54 [95% CI: 0.32–0.89]; P¼ 0.02).29 Intensive therapy

FIG. 1. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study: adjusted mortality rates by treatmentstrategy.26 Curves display all-cause mortality rates by treatment for the whole period of follow-up, over a range of decreasesin A1c from baseline in the first year of treatment (as a percentage of A1c). The calculations used a Poisson regression modelwith data from selected characteristics of participants and sites at baseline, severe hypoglycemia and weight change as time-varying covariates, and the randomization assignments in other ACCORD trials, plus assignment to the standard or intensiveglycemic treatment strategies. The bold solid line represents the intensive treatment group, the bold dashed line representsthe standard group, and the finer lines represent the 95% confidence intervals for each group. Adapted from Riddle et al.26 ª2010. Reproduced with permission of the American Diabetes Association.


was also associated with a lower risk of death from cardio-vascular causes (HR, 0.43 [95% CI: 0.19–0.94]; P¼ 0.04) and ofcardiovascular events (HR, 0.41 [95% CI: 0.25–0.67];P< 0.001).29

The ACCORD study also evaluated the impact of intensivecontrol of hypertension or dyslipidemia on cardiovascularoutcomes and mortality. Of the 10,251 patients randomized tointensive or standard glycemic control, 5,518 were also ran-domly assigned (in a 2�2 factorial design) to either simvas-tatin plus fenofibrate or simvastatin plus placebo (theACCORD lipid trial),31 and the remaining 4,733 participantswere also randomly assigned to either intensive (<120 mmHg) or standard (<140 mm Hg) blood pressure control (theACCORD blood pressure trial).32 As in the original study, theprimary outcome for both subtrials was the composite of firstoccurrence of nonfatal myocardial infarction, nonfatal stroke,or death from cardiovascular causes. With a mean follow-upof 4.7 years, both studies failed to show any significant benefitin either the primary or secondary outcomes, with the ex-ception of a reduced risk of any and nonfatal stroke withintensive versus standard blood pressure control.31,32 Mor-tality rates were comparable between the two groups in bothtrials. As in the case of glycemic control, the benefits of con-trolling hypertension and dyslipidemia may take several

years to become apparent or may be less evident in patients athigher risk who are likely to have more established risk fac-tors that are not easily reversible.

The Potential Role of Cancer in the Mortalityof Patients with Type 2 Diabetes

Epidemiological evidence suggests that diabetes maybe associated with an increased incidence of many cancers,indicating that death due to malignancy could be an addi-tional reason for higher rates of mortality with diabetes.Diabetes is a recognized risk factor for a range of cancers,including bladder, breast, colorectal, endometrial, liver, andpancreatic cancer and non-Hodgkin’s lymphoma.33 However,it is not known whether these associations are causal orwhether they are due to the fact that both diabetes and cancershare several common risk factors, including obesity, lowphysical activity, poor diet, high alcohol consumption, andsmoking.

Mortality rates in obesity, diabetes, and cancer populationsare high, with both obesity and type 2 diabetes being inde-pendently associated with an increased risk of cancer-relatedmortality.34–41 Evidence from a large, prospective U.S. cohortshows diabetes is an independent predictor of mortality from

FIG. 2. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study: risk of all-cause mortality (adjustedlog[hazard ratio]) by treatment strategy.26 Spline curves displaying the risk of all-cause mortality with the two treatmentstrategies over the range of average A1c from 6% to 9% relative to standard therapy at an A1c of 6%. The curves represent thelinear part of the proportional hazards models derived from values for intervals of average A1c. The bold solid line representsthe intensive treatment strategy group, the bold dashed line represents the standard group, and the finer lines represent the95% confidence intervals for each group. Adapted from Riddle et al.26 ª 2010. Reproduced with permission of the AmericanDiabetes Association.

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cancer of the colon, pancreas, and breast in women and of theliver and bladder in men.34 There is also evidence to suggestthat diabetes may significantly increase mortality in patientswith cancer. Meta-analyses of data from selected cancer sitesdemonstrate that preexisting diabetes increases the risk oflong-term mortality in patients with endometrial, breast, andcolorectal cancer.37,42,43 Mortality risk also increases in post-operative cancer patients with diabetes.44

Several plausible biological mechanisms have been putforward for the link between diabetes and cancer, includingthe effects of hyperglycemia, hyperinsulinemia, and inflam-mation. The Warburg effect is based on the observation thatcancer cells produce energy primarily by glycolysis, whichcreates a high requirement for glucose. Thus, hyperglycemiamay facilitate the proliferation of malignant cells. Elevatedfasting serum glucose levels have been shown to be an inde-pendent risk factor for certain cancers, and the risk increaseswith increased glucose levels, as does cancer-related mortal-ity.45 A prospective cohort study of more than 60,000 Swedishindividuals identified a significant increase in cancer risk forpatients in the highest quartile for fasting and postload plas-ma glucose.46 However, there is no conclusive clinical evi-dence to suggest that good glycemic control reduces the riskof cancer. A recent meta-analysis of large-scale randomizedcontrolled trials in patients with type 2 diabetes, includingthe UKPDS, ACCORD, ADVANCE, and VADT, failed tofind a relationship between reduced blood glucose levels andimprovements in the risk of cancer incidence or mortalitydue to cancer.47 There is a suggestion from a meta-analysis ofepidemiological trials that metformin-treated patients mayhave a lower risk of some malignancies versus other treat-ment types, although the risk of selection bias in non-randomized trials means that prospective data fromrandomized controlled trials are required to confirm this ob-servation.48 There has also been a suggested link between theuse of insulin analogs and malignancy in epidemiologicalstudies, although other studies show no such evidence.49–53

The ongoing ORIGIN study, with more than 12,000 patients,will be the largest prospective study to date examining ma-lignancy risk with insulin analog therapy as a secondary endpoint.

Hyperinsulinemia is a second possible mechanism bywhich diabetes may influence cancer risk. The human insulinreceptor (IR) is expressed as two isoforms, IR-A (short form)and IR-B (long form).54,55 There is considerable evidence thatIR-A, which binds to insulin and insulin-like growth factor-2,may play a critical role in the development of breast cancer56

and other malignancies.57,58 Activation of both the IR andinsulin-like growth factor-1 receptors also results in up-regulation of a variety of intracellular processes, in partthrough shared intracellular signaling pathways for meta-bolic and mitogenic processes, the latter of which can result inthe proliferation of cancers.59

Further study is required in order to determine more pre-cise mechanisms for the increased cancer risk in patients withdiabetes before optimal strategies for management and pre-vention of the risk can be formulated. Current recommenda-tions for a healthy lifestyle based on good diet, physicalexercise, and weight management in order to control diabetes-related complications are likely to apply in reducing the riskof many forms of cancer and should be implemented for allpatients.

Conclusions

Diabetes remains a condition associated with an increasedrisk of mortality with macrovascular disease responsible for alarge proportion of the excess risk. The follow-up of theUKPDS 10 years post-cessation of intervention suggests thatestablishing glycemic control early in the disease course withintensive treatment can significantly improve outcomes, in-cluding a reduced risk of all-cause mortality.14 Control ofadditional risk factors, including lipid profiles and hyper-tension, with multifactorial treatment regimens is likely toconfer additional benefits.29 Acting early after diagnosis isimportant based on the fact that the improved outcomespersist many years after initial intervention and even if gly-cemic control is subsequently lost.12,13,16 However, the ques-tion of whether an intensive treatment strategy reduces therisk of macrovascular disease and mortality in populationswith more advanced disease remains to be answered. Thelarge-scale trials conducted in high-risk patients to date havenot been of sufficient duration to address this question fully.Further study is required in this area, particularly given thatthe reasons for the excess mortality in the intensive arm of theACCORD trial remain a puzzle. There is a possibility thatthere is a subset of patients with type 2 diabetes at high risk ofvascular disease for whom intensive treatment may be life-threatening, and further study is needed to confirm or dis-count this hypothesis. The link among diabetes, cancer, andmortality is another area of increasing interest. Evidence todate is based largely on epidemiological trials, and well-controlled, prospective trials are needed. Strategies to tacklemortality due to vascular disease are now well established,and further study is required to identify mechanisms, riskfactors, and strategies to combat the risk of malignancy indiabetes populations. Considerable progress has been madein mitigating the increased risk of mortality associated withtype 2 diabetes, but we have further to go if we are to achievethe ultimate aim of a normal life expectancy.

Acknowledgments

Editorial support for this article was provided by HuwJones, Ph.D., of Medicus International and was funded bysanofi-aventis.

Author Disclosure Statement

G.D. reports receiving consulting fees from sanofi-aventisand Merck, grant support from Medtronic, and honorariafrom sanofi-aventis and Merck.

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Address correspondence to:George Dailey, M.D.

Scripps Clinic Torrey Pines10666 Torrey Pines Road

La Jolla, CA 92037

E-mail: [email protected]

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Documents

Overall Mortality in Diabetes Mellitus: Where Do We Stand Today?