defining cure for diabetes

8/2/2019 Defining Cure for Diabetes

1/3

How Do We Define Cure of Diabetes?

JOHN B. BUSE, MD, PHD1

SONIA CAPRIO, MD2

WILLIAM T. CEFALU, MD3

ANTONIO CERIELLO, MD4

STEFANO DEL PRATO, MD5

SILVIO E. INZUCCHI, MD6

SUE MCLAUGHLIN, BS, RD, CDE, CPT7

GORDON L. PHILLIPS II, MD8

R. PAUL ROBERTSON, MD9

FRANCESCO RUBINO, MD10

RICHARD KAHN, PHD11

M. SUE KIRKMAN, MD11

The mission of the American Diabetes

Association is to prevent and curediabetes and to improve the lives of

all people affected by diabetes. Increas-ingly, scientific and medical articles (1)and commentaries (2) about diabetes in-terventions use the terms remission andcure as possible outcomes. Several ap-proved or experimental treatments fortype 1 and type 2 diabetes (e.g., pancreas

or islet transplants, immunomodulation,bariatric/metabolic surgery) are of cura-tive intent or have been portrayed in themedia as a possible cure. However, defin-ing remission or cure of diabetes is not asstraightforward as it may seem. Unlikedichotomous diseases such as many ma-lignancies, diabetes is defined by hyper-glycemia, which exists on a continuumand may be impacted over a short timeframe by everyday treatment or events(medications, diet, activity, intercurrentillness). The distinction between success-ful treatment and cure is blurred in thecase of diabetes. Presumably improved ornormalized glycemia must be part of thedefinition of remission or cure. Glycemicmeasures below diagnostic cut points fordiabetes can occur with ongoing medica-tions (e.g., antihyperglycemic drugs, im-munosuppressive medications after atransplant), major efforts at lifestylechange, a history of bariatric/metabolicsurgery, or ongoing procedures (such as re-peated replacements of endoluminal de-

vices). Do we use the terms remission orcure for all patients with normal glycemicmeasures, regardless of how this isachieved?

A consensus group comprised of ex-perts in pediatric and adult endocrinol-ogy, diabetes education, transplantation,metabolism, bariatric/metabolic surgery,and (for another perspective) hematolo-gy-oncology met in June 2009 to discuss

these issues. The group considered a widevariety of questions, including whether itis ever accurate to say that a chronic ill-ness is cured;what the definitions of man-agement, remission, or cure might be;whether goals of managing comorbidconditions revert to those of patientswithout diabetes if someone is cured;and whether screening for diabetes com-plications needs to continue in thecured patient. Since littleor no scientificor actuarial evidence exists to inform thegroups discussions, consensus was diffi-cult to attain in a number of areas. Theopinions and recommendations ex-pressed herein are those of the authorsand not the official position of the Amer-ican Diabetes Association.

Medically, cure may be defined as res-toration to good health, while remission isdefined as abatement or disappearance ofthe signs and symptoms of a disease (3).Implicit in the latter is the possibility ofrecurrence of the disease. Many cliniciansconsider true cure to be limited to acute

diseases. Infectious diseases could be seenas a model: acute bacterial pneumoniacan be cured with antibiotics, but HIV in-fection, currently, can at best be stated to

be in remission or converted to a chronicdisease. The consensus group consideredthe history of childhood acute lymphoblas-tic leukemia, which evolved from a uni-formly fatal disease to one that could be putinto remission to one that can now often beconsidered cured (4). Conversely, chronicmyelocytic leukemia is now considered tobe in prolonged remission, but not cured,with therapies such as imatinib.

For a chronic illness such as diabetes,it may be more accurate to use the termremission than cure. Current or potentialfuture therapies for type 1 or type 2 dia-

betes will likely always leave patients atrisk for relapse, given underlying patho-physiologic abnormalities and/or geneticpredisposition. However, terminologysuch as prolonged remission is probablyless satisfactory to patients than use of themore hopeful and definitive term cureafter some period of time has elapsed. Ad-ditionally, if cure means remission thatlasts for a lifetime, then by definition apatient could never be considered curedwhile still alive. Hence, it may make senseoperationally to consider prolonged remis-

sion of diabetes essentially equivalent tocure. This is analogous to certain cancers,where cureis defined as complete remissionof sufficient duration that the future risk ofrecurrence is felt to be very low.

Abnormal glucose metabolism lead-ing to hyperglycemia defines the diseasediabetes, yet hyperglycemia exists on acontinuum and the diagnosis of the dis-ease occurs at levels sufficiently high to beassociated with the diabetes-specific com-plication retinopathy. Should absence ofthe disease diabetes be defined as glucosevalues considered within the normalrange, sub-diabetic but not necessarilynormal glucose values, or the completeabsence of underlying abnormal physiol-ogy such as insulin resistance or -celldysfunction or loss?

The group modeled its consensus defi-nitions somewhat on terminology thatexists for certain malignancies, withhyperglycemia analogous to tumor load.Cancer may initially be put into remission,either partial (substantial reduction in tu-mor load) or complete (no evidence oftumor). Eventually, the duration of a

From the 1Division of Endocrinology, Department of Medicine, University of North Carolina School ofMedicine,Chapel Hill,North Carolina; the 2Department of Pediatrics,Yale University Schoolof Medicine,New Haven, Connecticut; 3Pennington Biomedical Research Center, Louisiana State University System,Baton Rouge, Louisiana; the 4University of Warwick, Warwick Medical School, Coventry, U.K.; the5Department of Endocrinology & Metabolism, Section of Metabolic Diseases and Diabetes, Universityof Pisa, Pisa, Italy; the 6Section of Endocrinology, Department of Medicine, Yale University School ofMedicine, New Haven, Connecticut; 7Nebraska Medical Center, Omaha, Nebraska; the 8Division ofHematology/Oncology,Department of Medicine, and theWilmotCancer Center, University of RochesterSchool of Medicine, Rochester, New York; 9Pacific Northwest Diabetes Research Institute and Universityof Washington, Seattle, Washington; the 10Section of Metabolic Surgery, Department of Surgery, WeillCornell Medical College-New York Presbyterian Hospital, New York, New York; and the 11AmericanDiabetes Association, Alexandria, Virginia.

Corresponding author: M. Sue Kirkman, [email protected]: 10.2337/dc09-9036 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t s

C O N S E N S U S S T A T E M E N T

care.diabetesjournals.org DIABETES CARE, VOLUME 32, NUMBER 11, NOVEMBER 2009 2133


2/3

complete remission is felt to be sufficientsuch that the risk of recurrenceis likely tobelow, and such a prolonged remission mightoperationally be considered a cure. How-ever, unlike tumor size in people with can-cer, glucose levels in people with diabetesmay fluctuate greatly from day to day. In apatient with type 2 diabetes, for example,

improved or normal glycemia that occursafter only a few days of a stringent dietshould certainly not be considered remis-sion. Otherwise, patients could be in andout of remission constantly. The minimumduration of improved or normal glycemiathat must occur before being labeled remis-sion was the subject of great debate, and inthe end the group consensus was to be con-servative. Additionally, although glycemicmeasures just below the diabetic cut pointscould be defined as absence of the diseasediabetes, the group considered impaired

glucose homeostasis a sign of minimal re-sidual disease and hence only a partial re-mission. The group was unable to reach aconsensus on the incremental value of oralglucose tolerance testing, beyond the moreconvenient A1C and FPG tests, in definingremission.

The authors agreed upon the follow-ing definitions, which are the same fortype 1 and type 2 diabetes: Remission isdefined as achieving glycemia below thediabetic range in the absence of activepharmacologic (anti-hyperglycemic med-

ications, immunosuppressive medica-tions) or surgical (ongoing proceduressuch as repeated replacements of endolu-minal devices) therapy. A remission canbe characterized as partial or complete.

Partial remission is sub-diabetic hyper-glycemia (A1C not diagnostic of diabetes[6.5%], fasting glucose 100125 mg/dl[5.66.9 mmol/l]) of at least 1 years dura-tion in the absence of active pharmacologictherapy or ongoing procedures.

Complete remission is a return to nor-mal measures of glucose metabolism (A1Cin the normal range, fasting glucose 100mg/dl [5.6 mmol/l]) of at least 1 years du-ration in the absence of active pharmaco-logic therapy or ongoing procedures.

Remission of type 2 diabetes could beattained, for example, after bariatric/metabolic surgery or with lifestyle effortssuch as weight loss and exercise. Nondi-abetic glycemia resulting from ongoingmedications or repeated procedures(such as in the dynamic phase of bandadjustment after laparoscopic gastricbanding) would not meet the definition ofremission, as these interventions are con-

sidered treatment. Remission can be con-sidered an outcome of devices (e.g., gastricbanding, endoluminal devices) only afterthe patient has achieved a steady state andno longer requires repeated adjustmentsand/or replacements of the device. For type1 diabetes, remission could potentially be

attained after immune modulating or islet-replacement therapies that do not requireongoing immunosuppression but not withtransplants that require ongoing immuno-suppression or future therapies such as animplanted artificial pancreas.

Prolonged remission is complete re-mission that lasts for more than 5 yearsand might operationally be considered acure. The 5-year period was chosen arbi-trarily, since there are no actuarial dataindicating the likelihood of relapse overvarious periods of time from the onset of

normoglycemia. It is recognized that therisk of relapse likely remains higher forpeople with diabetes in remission than forage-, sex-, BMI-, and ethnicity-matchedindividuals who have never had diabetes.

In addition to hyperglycemia, diabe-tes is characterized by specific (microvas-cular) or nonspecific (cardiovascular)complications. Diabetes managementincludes treating cardiovascular risk fac-tors, such as hypertension and dyslipide-mia, often to more stringent goals thanthose for patients who do not have diabe-tes. People with diabetes also need regular

screenings for the microvascular compli-cations of the disease, such as retinopathyand nephropathy. If a patient is in remis-sion from diabetes, do they still requirediabetes-specific treatment goals andscreening protocols, and if so, for howlong? The consensus group considered

both issues to be a function of risk overtime. For cardiovascular disease, the veryhigh risk that diabetes imparts is unlikelyto be modified quickly, if ever, by amelio-ration of hyperglycemia, particularly ifthe usual coexisting risk factors are stillpresent. For diabetes-specific complica-tions such as retinopathy, risk for inci-dent complications is likely to declinesignificantly with prolonged normogly-cemia, while established complicationswould likely need ongoing monitoringindefinitely.

In a partial or complete remission ofless than 5 years duration, the goals fortreatment of comorbidities (hyperten-sion, dyslipidemia) should remain thesame as for those with diabetes (e.g.,blood pressure goal 130/80 mmHg).

Whe n complete remission exce eds 5years, goals appropriate for a patientwithout diabetes could be considered,as long as the patient remained withoutrecurrence of diabetes and without car-diovascular events.

In a partial or complete remission ofless than 5 years duration, the patient

Table 1Summary of consensus definitions and recommendations

DefinitionsPartial remission

Hyperglycemia below diagnostic thresholds for diabetesAt least 1 years duration

No active pharmacologic therapy or ongoing proceduresComplete remission

Normal glycemic measuresAt least 1 years duration

No active pharmacologic therapy or ongoing proceduresProlonged remission

Complete remission of at least 5 years duration

RecommendationsTreatment goals for comorbid conditions

Same as those for patients with diabetes for patients with partial or complete remissionof less than 5 years duration

With prolonged remission, could consider goals appropriate for patients withoutdiabetes, as long as there is no recurrence of diabetes and no cardiovascular disease

Screening for microvascular complicationsSame protocols as those for patients with diabetes for patients with partial or complete

remission of less than 5 years durationWith prolonged remission, could consider screening at reduced frequency depending on

the status of each complicationWith prolonged remission, only consider stopping screening for a particular

complication completely if there is no history of that complication

How do we define cure of diabetes?

2134 DIABETES CARE, VOLUME 32, NUMBER 11, NOVEMBER 2009 care.diabetesjournals.org


3/3

should receive screening for the compli-cations of diabetes at the same fre-quency as when diabetes was present.Once a complete remission exceeds 5years, complication screening might oc-cur at a reduced frequency (dependingon the status of each complication).Completely stopping screening for a

particular complication should be con-sidered only if there is no history of thatcomplication.

These definitions and consensus rec-ommendations, summarized in Table 1,are based on what the consensus groupfelt to be reasonable given the therapies oftoday. The authors hope that this article

will engender active discussion in thefield. As new therapies of curative intentemerge for type 1 and type 2 diabetes andactuarial and scientific evidence regard-ing prognosis builds, these issues willsurely require further deliberation.

Acknowledgments F.R. is a consultant forCovidien and Ethicon, is on speaker bureausfor NGM Biotech and GI Dynamics, and re-ceives research grant support from Roche andCovidien. The group acknowledges the pres-ence of inevitable potential intellectual conflictsof interest related to their scientific and medicalinterests. No other potential conflicts of interestrelevant to this article were reported.

References

1. Dixon JB,OBrien PE,Playfair J, ChapmanL, Schachter LM, Skinner S, Proietto J,Bailey M, Anderson M. Adjustable gastricbanding and conventional therapy fortype 2 diabetes: a randomized controlledtrial. JAMA 2008;299:316323

2. Saudek CD. Can diabetes be cured? Po-

tential biological and mechanical ap-proaches. JAMA 2009;301:15881590

3. Medial terminology [website]. Availableat www.medicalterms.com. Accessed 5August 2009

4. Barnes E. Between remission and cure:patients, practitioners and the transfor-mation of leukaemia in the late twentiethcentury. Chronic Illness 2007;3:253264

Buse and Associates

care.diabetesjournals.org DIABETES CARE, VOLUME 32, NUMBER 11, NOVEMBER 2009 2135

defining cure for diabetes

Documents