www.who.int/chp

Expanding Priorities—Confronting Chronic Disease in Countries with Low Income

Gerard Anderson and Edward Chu argue that international health organizations need to greatly expand their efforts to

prevent and treat noncommunicable chronic diseases.

January 18, 2007

Obesity and Diabetes in the Developing World — A Growing Challenge

January 18, 2007

Propelling an upsurge in cases of diabetes and hypertension is the growing prevalence of overweight and obesity. Drs. Parvez Hossain, Bisher Kawar, and Meguid El Nahas write that preventing obesity,

diabetes, and hypertension will require fundamental social and political changes.

88

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Dr. Enrique Mendoza

12/04/2312/04/23

Dr. Enrique Mendoza

Figure 1—Disorders of glycemia: etiologic types and stages. Even after presenting in ketoacidosis, these ∗patients can briefly return to normoglycemia without requiring continuous therapy (i.e., “honeymoon” remission); in rare instances, patients in these categories (e.g., Vacor toxicity, type 1 diabetes presenting ∗∗in pregnancy) may require insulin for survival.

12/04/2312/04/23

Dr. Enrique Mendoza

©1999, Medical Age Publishing, Division of Snyder Healthcare Communications Worldwide, Stamford, Connecticut. All rights reserved.

DCCT

Intensive Insulin Treatment in Type 1 Diabetes

The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986, with permission.

Med

ian

Hb

A1c

(%)

11

10

9

8

7

6

50 1 2 3 4 5 6 7 8 9 10

Study Year

Conventional therapy

Intensive therapy

Normalrange

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Dr. Enrique Mendoza

©1999, Medical Age Publishing, Division of Snyder Healthcare Communications Worldwide, Stamford, Connecticut. All rights reserved.

DCCT

Microvascular Risk Reduction With Intensive Treatment

Data from the Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986.

Reduction inComplication Relative Risk

Retinopathy 63%

Nephropathy 54%

Neuropathy 60%

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Dr. Enrique Mendoza

©1999, Medical Age Publishing, Division of Snyder Healthcare Communications Worldwide, Stamford, Connecticut. All rights reserved.

DCCT

Relationship of HbA1c to Risk of Microvascular Complications

Skyler. Endocrinol Metab Clin. 1996;25:243-254, with permission.

Rel

ativ

e R

isk

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

HbA1c (%)

15

13

11

9

7

5

3

1

6 7 8 9 10 11 12

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Dr. Enrique Mendoza

©1999, Medical Age Publishing, Division of Snyder Healthcare Communications Worldwide, Stamford, Connecticut. All rights reserved.

UKPDS

Blood Glucose Control Study:Aims

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

• To determine whether improved glycemic control will prevent clinical complications

• To determine whether treatment with a sulfonylurea, insulin, or metformin has specific advantages or disadvantages

12/04/2312/04/23

Dr. Enrique Mendoza

©1999, Medical Age Publishing, Division of Snyder Healthcare Communications Worldwide, Stamford, Connecticut. All rights reserved.

UKPDS

Effect of Treatment on HbA1c

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853, with permission.

Conventional(10-y cohort)

9

8

7

6

00 3 6

6.2% upper limit of normal range

ADA goal

ADA action

9 12 15Time From Randomization (y)

Intensive(all patients)

Conventional(all patients)

Intensive(10-y cohort)

Med

ian

Hb

A1c

(%)

12/04/2312/04/23

Dr. Enrique Mendoza

©1999, Medical Age Publishing, Division of Snyder Healthcare Communications Worldwide, Stamford, Connecticut. All rights reserved.

UKPDS

Risk Reduction of Microvascular Complications

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853, with permission.

% o

f P

atie

nts

Wit

h a

n E

ven

t

Intensive policy group25% overall risk reductionP=.0099

ConventionalIntensive

0 3 6

0

10

20

30

9 12 15Time From Randomization (y)

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Dr. Enrique Mendoza

Volume 359:1577-1589 October 9, 2008 Number 15

10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes

Rury R. Holman, F.R.C.P., Sanjoy K. Paul, Ph.D., M. Angelyn Bethel, M.D., David R. Matthews, F.R.C.P., and H. Andrew W. Neil, F.R.C.P.

Volume 359:1577-1589 October 9, 2008 Number 15

10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes

Rury R. Holman, F.R.C.P., Sanjoy K. Paul, Ph.D., M. Angelyn Bethel, M.D., David R. Matthews, F.R.C.P., and H. Andrew W. Neil, F.R.C.P.

Background During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes.

Methods Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories.

Results Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea–insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002).

Conclusions Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837

Volume 359:1618-1620      October 9, 2008      Number 15

John Chalmers, M.D., Ph.D., and Mark E. Cooper, M.D., Ph.D.

UKPDS and the Legacy Effect

The United Kingdom Prospective Diabetes Study (UKPDS) continues to produce important evidence concerning the evolution of type 2 diabetes and its management. Two studies published in this issue of the Journal provide some answers to two questions of fundamental importance to patients with diabetes and to physicians alike. In one article, Holman et al. (UKPDS 80)1 provide data that confirm a so-called legacy effect associated with intensive glucose control in patients with type 2 diabetes, long after the cessation of randomized intervention. This finding provides a fitting parallel to the observations of the Diabetes Control and Complications Trial/Epidemiology of Diabetes…

Volume 358:580-591 February 7, 2008 Number 6

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes

Peter Gæde, M.D., D.M.Sc., Henrik Lund-Andersen, M.D., D.M.Sc., Hans-Henrik Parving, M.D., D.M.Sc., and Oluf Pedersen, M.D., D.M.Sc.

Background Intensified multifactorial intervention — with tight glucose regulation and the use of renin–angiotensin system blockers, aspirin, and lipid-lowering agents — has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria. We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes

Methods In the Steno-2 Study, we randomly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy; the mean treatment period was 7.8 years. Patients were subsequently followed observationally for a mean of 5.5 years, until December 31, 2006. The primary end point at 13.3 years of follow-up was the time to death from any cause.

Results Twenty-four patients in the intensive-therapy group died, as compared with 40 in the conventional-therapy group (hazard ratio, 0.54; 95% confidence interval [CI], 0.32 to 0.89; P=0.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% CI, 0.19 to 0.94; P=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001). One patient in the intensive-therapy group had progression to end-stage renal disease, as compared with six patients in the conventional-therapy group (P=0.04). Fewer patients in the intensive-therapy group required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; P=0.02). Few major side effects were reported.

Conclusions In at-risk patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes.

Treatment Options

Lifestyle interventions

The major environmental factors that increase the risk of type 2 diabetes are overnutrition and a sedentary lifestyle, with consequent overweight and obesity (39,40). Not surprisingly, interventions that reverse or improve these factors have been demonstrated to have a beneficial effect on control of glycemia in established type 2 diabetes (41). Unfortunately, the high rate of weight regain has limited the role of lifestyle interventions as an effective means of controlling glycemia in the long term. The most convincing long-term data indicating that weight loss effectively lowers glycemia have been generated in the follow-up of type 2 diabetic patients who have had bariatric surgery. In this setting, with a mean sustained weight loss of 20 kg, diabetes is virtually eliminated (42– 45).

FACTORES DE RIESGO

Pharmacological agents

The consensus report concluded that “Although still limited, early evidence suggests that metformin is associated

with a lower risk of cancer and that

exogenous insulin is associated with an increased cancer risk. Further research is needed to clarify these issues and evaluate if insulin glargine is more

strongly associated with cancer risk compared with other insulins.”

Emerging evidence suggests that metformin has a range of biological mechanisms that reduce tumour growth beyond its ability to increase

insulin sensitivity. The enhanced binding of insulin glargine to IGF-I receptors is a theoretical concern, but might not translate to an actual increase in cancer risk.

SummaryThe guidelines and treatment algorithm presented here emphasize the following:● Achievement and maintenance of near

normoglycaemia (A1C 7.0%)● Initial therapy with lifestyle intervention

and metformin● Rapid addition of medications, and

transition to new regimens, when targetglycemic goals are not achieved or sustained

● Early addition of insulin therapy in patientswho do not meet target goals

A1C 6.5 – 7.5%**

Monotherapy

MET +

GLP-1 or DPP4 1

TZD 2

Glinide or SU 5

TZD + GLP-1 or DPP4 1

MET + Colesevelam

AGI 3

2 - 3 Mos.***

2 - 3 Mos.***

2 - 3 Mos.***

Dual Therapy

MET +

GLP-1 or DPP4 1

+

TZD 2

Glinide or SU 4,7

A1C > 9.0%

No Symptoms

Drug Naive Under Treatment

INSULIN

± Other

Agent(s) 6

Symptoms

INSULIN

± Other

Agent(s) 6

INSULIN

± Other

Agent(s) 6

Triple Therapy

AACE/ACE Algorithm for Glycemic Control Committee

Cochairpersons:Helena W. Rodbard, MD, FACP, MACEPaul S. Jellinger, MD, MACE

Zachary T. Bloomgarden, MD, FACEJaime A. Davidson, MD, FACP, MACEDaniel Einhorn, MD, FACP, FACEAlan J. Garber, MD, PhD, FACEJames R. Gavin III, MD, PhDGeorge Grunberger, MD, FACP, FACEYehuda Handelsman, MD, FACP, FACEEdward S. Horton, MD, FACEHarold Lebovitz, MD, FACEPhilip Levy, MD, MACEEtie S. Moghissi, MD, FACP, FACEStanley S. Schwartz, MD, FACE

* May not be appropriate for all patients** For patients with diabetes and A1C < 6.5%,

pharmacologic Rx may be considered*** If A1C goal not achieved safely

† Preferred initial agent

1 DPP4 if PPG and FPG or GLP-1 if PPG

2 TZD if metabolic syndrome and/or

nonalcoholic fatty liver disease (NAFLD)

3 AGI if PPG

4 Glinide if PPG or SU if FPG

5 Low-dose secretagogue recommended

6 a) Discontinue insulin secretagoguewith multidose insulin

b) Can use pramlintide with prandial insulin

7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4

8 If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution

9 If A1C > 8.5%, in patients on Dual Therapy,insulin should be considered

MET +

GLP-1

or DPP4 1 ± SU 7

TZD 2

GLP-1

or DPP4 1 ± TZD 2

A1C 7.6 – 9.0%

Dual Therapy 8

2 - 3 Mos.***

2 - 3 Mos.***

Triple Therapy 9

INSULIN

± Other

Agent(s) 6

MET +

GLP-1 or DPP4 1

or TZD 2

SU or Glinide 4,5

MET +

GLP-1

or DPP4 1+ TZD 2

GLP-1

or DPP4 1 + SU 7

TZD 2

MET † DPP4 1 GLP-1 TZD 2 AGI 3

Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

A1C 6.5 – 7.5%**

Monotherapy

MET +

GLP-1 or DPP4 1

TZD 2

Glinide or SU 5

TZD + GLP-1 or DPP4 1

MET +Colesevelam

AGI 3

2 - 3 Mos.***

Dual Therapy

MET +GLP-1 or DPP4 1

+

TZD 2

Glinide or SU 4,7

INSULIN

± Other Agent(s) 6

Triple Therapy

MET † DPP4 1 GLP-1 TZD 2 AGI 3

2 - 3 Mos.***

2 - 3 Mos.***

*** If A1C goal not achieved safely

† Preferred initial agent

1 DPP4 if PPG and FPG or GLP-1if PPG

2 TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD)

3 AGI if PPG

4 Glinide if PPG or SU if FPG

5 Low-dose secretagogue recommended

6 a) Discontinue insulin secretagogue with multidose insulin

b) Can use pramlintide with prandial insulin

7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4

Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

LIFESTYLE MODIFICATION AACE/ACE DIABETES ALGORITHM FOR

GLYCEMIC CONTROL

MET +

GLP-1or DPP4 1

+ TZD 2

GLP-1or DPP4 1 + SU 7

TZD 2

A1C 7.6 – 9.0%LIFESTYLE MODIFICATION AACE/ACE DIABETES ALGORITHM FOR

GLYCEMIC CONTROL

Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

Dual Therapy 8

MET +

GLP-1 or DPP4 1

or TZD 2

SU or Glinide 4,5

2 - 3 Mos.***

Triple Therapy 9

2 - 3 Mos.***

INSULIN

± Other Agent(s) 6

*** If A1C goal not achieved safely

† Preferred initial agent

1 DPP4 if PPG and FPG or GLP-1if PPG

2 TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD)

4 Glinide if PPG or SU if FPG

5 Low-dose secretagogue recommended

6 a) Discontinue insulin secretagogue with multidose insulin

b) Can use pramlintide with prandial insulin

7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4

8 If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution

9 If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered

No Symptoms

Drug Naive Under Treatment

Symptoms

MET +

GLP-1 or DPP4 1

± SU 7

TZD 2

GLP-1 or DPP4 1 ± TZD 2

A1C > 9.0%LIFESTYLE MODIFICATION AACE/ACE DIABETES ALGORITHM FOR

GLYCEMIC CONTROL

Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

INSULIN

± Other Agent(s) 6

INSULIN

± Other Agent(s) 6

1 DPP4 if PPG and FPG or GLP-1if PPG

2 TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD)

6 a) Discontinue insulin secretagogue with multidose insulin

b) Can use pramlintide with prandial insulin

7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4

Rosiglitazone and IHD Risk

Pioglitazone and IHD Risk

Pioglitazone vs Rosiglitazone and

IHD Risk

Thiazolidinediones and Heart Failure

Risk

Recommendations to Reduce Vascular Disease in Patients

with Type 2 Diabetes Mellitus