TREATING TYPE 2 DIABETES: A MATTER

OF PROOF

Prof Jean Claude MBANYA MD, PhD, FRCP (UK)

Doctor Honoris Causa, University of Oslo, Norway

Coordinator Doctoral School of Life Sciences, Health and

Environment

Professor of Medicine and Endocrinology

Faculty of Medicine and Biomedical Sciences

University of Yaoundé 1, Yaoundé, Cameroon

Speaker for Servier

Conflicts of Interests

Global burden of DM in 2013 (6th Ed IDF Diabetes Atlas)

Metabolic observations in natural hx of DM: CVD risks

Perspectives on early morbi-mortality trials: Anything

gained in the treatment of diabetes?

Comparison of the results of the various recent trials

as sources of evidence for the treatment of diabetes

Evidence based treatment algorithms

Conclusion

Overview of presentation

Type 2 Diabetes: Global Burden

2013 IDF Diabetes Atlas - Sixth edition

A huge and growing problem

2013 IDF Diabetes Atlas - Sixth edition

Top 10 countries

2013 IDF Diabetes Atlas

- Sixth edition

Insulin Sensitivity

Insulin Secretion

Associated Risk Factors • Hypertension

• Dyslipidemia

Atherogenesis

Microvascular Complications

Type 2 Diabetes Age (years)

Fasting Blood Glucose

“ Cardio-Metabolic Risk”

Proposed Metabolic Observations in the Natural History of Type

2 Diabetes

Euglycemia

Vascular Wall

Abnormalities

Metabolic Observations in Natural History

of Type 2 Diabetes

Rela

tive

Ris

k o

f M

I o

r S

tro

ke

0

1

2

3

4

5

6

7

Nondiabetic

Throughout

2.4

>15 Yr

Before Dx

10-14.9 Yr

Before Dx

3.64

<10 Yr

Before Dx

Diabetic

Throughout

5.02

3.19

1.0

Hu FB, et al. Diabetes Care. 2002;25:1129-1134.

Non-Diabetic Diabetes

Cardiovascular Risk in Pre-Diabetes

Patients

(%)

Norhammar A et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective studyLancet. 2002;359:2140-2144.

Almost 70% of Patients with First MI

Have IGT or Undiagnosed Diabetes

N = 181 consecutive patients admitted to CCU

0

10

30

50

70

Undiagnosed diabetes 31

35 Impaired glucose

tolerance (IGT)

Glucose Tolerance Test Results

Diagnosis of Patients with First Cardiovascular Event

Global cardiometabolic risk

Cause of death Hazard ratio 95% CI

Coronary heart disease 3.2 2.9–3.5

Other Cardiovascular Disease 2.3 1.8–2.9

All Cardiovascular Disease 3.0 2.8–3.3

All causes 2.5 2.4–2.7

Stroke 2.8 2.0–3.7

Stamler et al, MRFIT Group. Diabetes Care 1993;16:434-443

Risks associated with diabetes

Perspectives on recent morbi-mortality

trials: Anything gained in the

treatment of diabetes?

Evidence Base for Treatment Options

Metformin

SU AGI

DPP 4

Insulin Second line

Third line AGI GLP -1 Insulin

Fourth line DPP 4 GLP -1 Insulin

Possible Combinations = 6 x 5 x 4 = 120

TZD DPP 4

First line

Not taking into account different agents within a class

GLP -1

TZD

TZD

Blood glucose and vascular risk in diabetes

Evidence in 2000

UK Prospective Diabetes Study Lancet 1998

1%

-18%

-13%

-16%

-17%

-28%

Cardiovascular disease

Peripheral arterial disease

Stroke

Fatal coronary heart disease

Coronary heart disease

Reduced Risk*

EVERY 1% reduction in HbA1c

Number of patients

Number of studies

7435 10

6684 6

3042 5

5962 3

3748 3

*p<0.0001

Meta-Analysis: Glycosylated Hemoglobin

and Cardiovascular Disease in Diabetes mellitus

Selvin et al. Ann. Intern. Med. 2004;141:421

Recommended Guidelines : reduction of HbA1c < 7.0%

UKPDS: HbA1c and vascular disease

Stratton et al. BMJ 2000.

Blood glucose and vascular risk in diabetes

Evidence in 2000

Stratton et al. BMJ 2000.

UKPDS Guidelines

10-year post-trial monitoring from 1997 to 2007 of UKPDS Study†

† Data from sulfonylurea–insulin group shown

* P≤0.05; ** P≤0.01; *** P≤0.001;

Trial end (1997)

Post-trial follow up (2007)

-25

-20

-15

-10

-5

0

Microvascular disease

Myocardial Infraction

Any diabetes-related endpoint

Death from any cause

Rela

tive R

isk

Red

ucti

on

(%

)

1. UKPDS 33 Study Group. Lancet. 1998;352:837-853; 2. Holman RR, et al. N Engl J Med. 2008;359:1577-1589.

3. Chalmers J and Cooper ME. N Engl J Med. 2008; 359: 1618–1620.

Early glycemic control provides lasting

protection: The legacy effect

Blood glucose lowering in diabetes

Unresolved issues 2000

Among patients with diabetes…

Does blood glucose-lowering therapy:

Produce additional micro-vascular benefits when

haemoglobin A1c is reduced to 6.5% or lower?

Produce macro-vascular benefits when haemoglobin

A1c is reduced to 6.5% or lower?

HbA1c - How low should we go?

Clinical trials to prevent cardiovascular

disease in patients with T2D

FINAL TREATMENT REGIMENS

VADT (Veterans Diabetes

Trial)

ACCORD (Action to Control

Cardiovascular Risk in Diabetes

Trial)

ADVANCE (Action in

Diabetes and Vascular Disease)

1. N Engl J Med. 358(2008)2545-59

2. N Engl J Med. 360(2009)129-39

ACCORD1 VADT2

Number 10,251 1,791

Primary CVD

endpoint 10% (p=0.16) 13% (p=0.12)

Mortality

(overall) 22% (p=0.04) 6.5% (p=NS)

CV mortality 39% (p=0.02) 25% (p=NS)

Reduction of CV disease risk in type 2 diabetes:

lessons learned from ACCORD and VADT trials

Lessons from ACCORD1 and VADT2

Intensive glucose control :

1. ACCORD Study Group. N Engl J Med. 358(2008)2545-2559.

2. VADT Investigators. N Engl J Med. 360(2009)129-139.

Does not reduce cardiovascular disease

mortality in type 2 diabetes

May increase risk of coronary heart disease,

especially in patients with pre-existing

coronary heart disease

SNIIRAM (French national healthinsurance

information system )

%22 1.491.060 Type 2 Diabetic Patients 155.535 pioglitazone treated patients 175 bladder cancer reported

Dose depended / total dose > 28.000 mg %75 Treatment duration depended > 24 months % 36

Neumann et al. Diabetologia Feb 2012

Secondary prevention of macrovascular events in patients with type 2 diabetes in Proactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial Table 9: Reports of heart failure The Lancet Vol 366 Oct 8, 2005 *Not adjudicated ⱡ Adjudicated cause of death

Pioglitazone (n=2605) Plasebo (n=2633) p

Number of events

Number of patients

Number of events

Number of patients

Any report of heart failure*

417 281 (11%) 302 198 (8%) <0.0001

Heart failure not needing hospital admission*

160 132 (5%) 117 90 (3%) 0.003

Heart failure needing hospital admission*

209 149 (6%) 153 108 (4%) 0.007

Fatal heart failureⱡ

25 25 (1%) 22 22 (1%) 0.634

Increased Risk Of Heart Failure by Pioglitazone in Proactive Trial

Cardiovascular disease and heart failure in

pioglitazone treated patients: meta-analysis

Lincoff AM et al JAMA. 2007 ;298 (10) : 1180-1188

Food and Drug Administration Guidance

As a result of concerns regarding the association of

antidiabetic agents with adverse CV outcomes;

The FDA released a guidance in December 2008 titled,

“Diabetes Mellitus – Evaluating Cardiovascular Risk in New

Antidiabetic Therapies to Treat Type 2 Diabetes.”

This guidance outlines requirements for CV safety

assessment before and after approval of all new antidiabetic

therapies. Specifically, sponsors must rule out an upper 95%

CI of the hazard ratio (HR) of 1.8 before approval and 1.3

after approval. In most cases, these upper CI boundaries

would be associated with HRs of 1.0 or less.

Adapted from White et al. (2011) American Heat journal Vol. 162, No 4

Recent FDA guidelines impose statistical hurdles for approval of anti-diabetic

agents. The figure illustrates five hypothetical examples of possible hazard

ratios (HRs) and the upper limit of the 95% confidence interval. The

regulatory consequences of each outcome also are indicated.

O. Mosenzon and I. Raz (2012) 14 (Supplement B), B22-B29.

Food and Drug Administration Guidance

Morbi-mortality trials

MACE HR 0.71 [0.59 – 0.86]

Perception of “protective” effects

DPP4i and CVD : meta-analysis “hints”

Monami et al. Diabetes, Obesity Metab 15(2013)112-20

Worldwide Orientation Plan 2013-2014

SAVOR EXAMINE

Primary end-point composite of cardiovascular death, nonfatal

myocardial infarction, or nonfatal ischemic stroke

Design Multicenter, double blind and randomized

Treatment Saxagliptin vs placebo

in addition to existing

antihyperglycemic therapy

Alogliptin vs placebo

in addition to existing

antihyperglycemic therapy

Patients 16 492 5 380

Follow-up 2.1 years 18 months

Study protocol

SAVOR EXAMINE

Primary end-point composite of cardiovascular death, nonfatal

myocardial infarction, or nonfatal ischemic stroke

Design Multicenter, double blind and randomized

Treatment Saxagliptin vs placebo

in addition to existing

antihyperglycemic therapy

Alogliptin vs placebo

in addition to existing

antihyperglycemic therapy

Patients 16 492 5 380

SAVOR EXAMINE

Primary end-point composite of cardiovascular death, nonfatal

myocardial infarction, or nonfatal ischemic stroke

Design Multicenter, double blind and randomized

Treatment Saxagliptin vs placebo

in addition to existing

antihyperglycemic therapy

Alogliptin vs placebo

in addition to existing

antihyperglycemic therapy

SAVOR EXAMINE

Primary end-point composite of cardiovascular death, nonfatal

myocardial infarction, or nonfatal ischemic stroke

Design Multicenter, double blind and randomized

SAVOR EXAMINE

Primary end-point composite of cardiovascular death, nonfatal

myocardial infarction, or nonfatal ischemic stroke

Worldwide Orientation Plan 2013-2014

SAVOR EXAMINE Median age (yr) 65 61

Duration of diabetes (yr) 10.3 7.3

HbA1c 8.0% 8.0%

Established CVD

Hypertension

Prior MI

Prior HF

81%

38%

13%

83%

88%

28%

eGFR (ml/min) 72 71

Baseline patient characteristics

Composite of cardiovascular death,

myocardial infarction, or ischemic stroke

Scirica et al. NEJM 369(2013)1317-26

White et al. NEJM 369(2013)1327-35

Composite of cardiovascular death,

myocardial infarction, or ischemic stroke

Placebo

(N=8,212)

Saxagliptin

(N=8,280) HR

P-value for

superiority

CV Death 2.9 3.2 1.03 (0.87-1.22) 0.72

MI 3.4 3.2 0.95 (0.80-1.12) 0.52

Ischemic Stroke 1.7 1.9 1.11 (0.88-1.39) 0.38

Hosp for Cor. Revasc 5.6 5.2 0.91 (0.80-1.04) 0.18

Hosp for Unstab Angina 1.0 1.2 1.19 (0.89-1.60) 0.24

Hosp for Heart Failure 2.8 3.5 1.27 (1.07-1.51) 0.007

All-Cause Mortality 4.2 4.9 1.11 (0.96-1.27) 0.15

2-year KM rate (%)

Individual Endpoints

Significantly more patients in

saxagliptin group than placebo

were hospitalized for heart

failure

Scirica et al. NEJM 369(2013)1317-26

Hospitalization for Heart Failure

Need to consider that increase in heart

failure hospitalization is a real signal

Physicians should be reluctant to give to patients with heart failure

Sattar EASD Barcelona 26-Sept 2013

25.0

38.4 40.0

36.2

25.9 27.5

30.0 27.9

0

10

20

30

40

50

Rand 1 year 2 year EoT

Saxagliptin Placebo

8.0

7.6 7.5

7.7

8.0 7.9

7.8 7.9

6

7

8

9

Rand 1 year 2 year EoT

HbA

1c (

%)

Saxagliptin Placebo

* * *

*p<0.001

* * *

Mean HbA1c (%) HbA1c <7.0%

Glycemic Indices Over Time

Scirica et al. NEJM 369(2013)1317-26

Worldwide Orientation Plan 2013-2014

Glycemic Indices Over Time

White et al. NEJM 369(2013)1327-35

Worldwide Orientation Plan 2013-2014

SAVOR EXAMINE

HbA1c (at the end of the trial)

-0.3% -0.36%

Glycemic control

HbA1c efficacy

Hypoglycemia

15.3% 14.2%

2.1% 0.6%

13.4% 12.5%

1.7% 0.5%

Any Minor Major RequiringHospitalization

Saxagliptin Placebo

p=0.33 p=0.047

p=0.002 p<0.001

Major – required assistance to actively intervene

Minor – symptoms, but recovered by themselves w/in 30 min, or glucose level <54 mg/dl

(%)

0

5

10

15

Significantly more

patients in saxagliptin

group than placebo

reported at least one HE

Should we be surprised that only

non-inferiority was achieved ?

Limited efficacy on glycemic control (-0.30% /-0.36%)

Short duration (1.5 to 2.1 yrs)

Not designed to assess impact on micro-vascular events

Very minimal effects on hypertension or dyslipidemia

No cardiovascular protection

observed with DPP4 inhibitors

Big trials get closer to truth – provide robust evidence on

speculated matters, good or bad – trials helpful

Mechanistic or observational studies can only ever be

hypothesis generating

Results reaffirm understanding that lowering glucose in short

term yields more micro than macro gain:

Better ways to CVD: statins to lower cholesterol ?

Blood pressure and smoking reduction

CVD mortality rates : battle being won

• Ferguson & Sattar (2013) DOM

Lessons learned from trials

Conclusion : DPP-4 inhibitors

No cardiovascular protection

hospitalization for heart failure

Limited glycemic efficacy

Increased risk of hypoglycemia

Rationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28.

ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.

Intensive BP-control

Perindopril-Indapamide

Intensive HbA1c

control with Gliclazide

Standard HbA1c

control

Standard BP-control

PLACEBO

Intensive HbA1c

control with Gliclazide

Standard HbA1c

control

(same glycemic control)

11 140 patients

2x2 factorial randomized trial (2 arms, 4 subgroups)

– Blood pressure-lowering arm: Perindopril-Indapamide or

placebo on top of current therapy, including other BP-lowering drugs.

– Glucose-lowering arm: Gliclazide MR-based intensive therapy

targeting an HbA1c ≤ 6.5% versus standard glucose control.

ADVANCE study: Action in Diabetes and Vascular disease

preterAx and diamicroN mr Controlled Evaluation

ADVANCE: positive trend for reducing cardiovascular death

CONTROL Group; Turnbull FM, Abraira C, Anderson RJ, et al. Diabetologia. 2009;52:2288-2298.

ADVANCE trial: strict weight neutrality

whatever the BMI

The ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. N Engl J Med. 2008;358(24):2560-2572.

Perkovic et al. Kidney Int 83(2013) 517–24

Renal Protection

65%

ESRD

Intensive glucose control based on

gliclazide MR improves kidney outcomes

ADVANCE: Summary Renal Protection

Perkovic V et al; ADVANCE Collaborative Group. Kidney Int. 2013;83(3):517-523.

ADVANCE results for different stages of renal disease in the intensive arm based on gliclazide MR.

SAVOR ADVANCE

Antidiabetic agents:

Metformin

Sulfonylureas

DPP-4 inh.

TZDs

Insulin

69%

40%

99%

5%

44%

74%

93%

0%

17%

40%

Cardiovascular agents:

Statin

RAS blocking

-blockers

Aspirin

81%

82%

63%

78%

46%

89% any BP lowering drug

Worldwide Orientation Plan 2013-2014

Concomitant treatment at

end of the study

Scirica et al. NEJM 369(2013)1317-26

ADVANCE trial shows the low risk of

hypoglycemia

1. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, et al. N Engl J Med. 2008;358(24):2545-2559. 2. UKPDS Group (33).

Lancet. 1998;352:837-853. 3. The ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. N Engl J Med. 2008;358(24):2560-2572.

Gliclazide 60 MR, demonstrated low risk of

hypoglycemia

1. Al Sifri S et al. Int J Clin Pract. 2011;65(11):1132-1140.

2. Aravind SR et al. Curr Med Res Opin. 2012;28:1289-1296.

Gliclazide 60 MR Gliclazide 60 MR

SAVOR ADVANCE

Major hypoglycemia* 2.1% (177 patients) 2.7% (150 patients)

*required assistance - active intervention

SAVOR EXAMINE ADVANCE

HbA1c (at the end of the trial)

-0.3% -0.36% -1%

Hypoglycemia

SAVOR1 ADVANCE2

Number 16,492 11,140

Primary CVD endpoint 0% (p=0.99) 6% (p=0.12)

Myocardial infarction 5% (p=0.52) 2% (p=0.28)

Stroke 11% (p=0.15) 2% (p=0.78)

CV mortality 3% (p=0.72) 12% (p=0.12)

Mortality (all cause) 11% (p=0.15) 7% (p=0.28)

Hospitalization for

heart failure 27% (p=0.007) 5% (p=0.45)

Conclusions from ADVANCE and SAVOR trials

Reduction of CV disease risk in type 2 diabetes:

1-Scirica et al. NEJM 369(2013)1317-26

2-Patel et al, NEJM 358(2008)260-72

Systematic review and meta-analysis

25 studies (randomized, controlled, ≥12

weeks)

6 500 T2D patients treated with SU

The incidence of mild and severe hypoglycemia in patients

with T2D treated with Sus.

Diabetes Metabolism Research and Review – September 2013

The incidence of mild and severe hypoglycemia in patients

with T2D treated with SUs.

Diabetes Metabolism Research and Review – September 2013

Safety and Efficacy of Gliclazide as Treatment for T2D PLOS one – February 2014

Systematic review and meta-analysis

19 studies (randomized, controlled, ≥12

weeks)

6 238 T2D patients treated, comparing

gliclazide to :

other SUs/meglitinides (8 studies)

metformin (4 studies)

pioglitazone (4 studies)

DPP-4 inhibitors (2 studies)

an a-glucosidase inhibitor (2 studies)

Safety and Efficacy of Gliclazide as Treatment for T2D PLOS one – February 2014

“compared to other glucose lowering agents gliclazide was more effective” in lowering

HbA1c from baseline with weighted difference of -0.13% (-0.21% vs other SUs)

“The number of severe hypoglycemic episodes was extremely low”

Reduction of HbA 1c

ADA/EASD Guidelines. Diabetes Care 32(2009)193-203

Summary of glucose-lowering interventions

HbA1c efficacy

ADA/EASD Recommendations 2012

Inzucchi SE et al. Diabetes Care.2012;35(6):1364-1379.

Essential Medicines 18th edition

WHO Model List - 2013 18.5 Insulins and other medicines used for diabetes

Gliclazide*

Oral solid dosage form (controlled release tablets): 30

mg; 60 mg; 80 mg.

Glucagon Injection: 1 mg/ml.

Insulin injection (soluble) Injection: 40 IU/ml in 10‐ml vial;

100 IU/ml in 10‐ml vial.

intermediate‐acting insulin Injection: 40 IU/ml in 10‐ml vial;

100 IU/ml in 10‐ml vial (as

compound insulin zinc suspension or isophane insulin).

Metformin Tablet: 500 mg (hydrochloride).

ADVANCE-ON results: 2014

EASD Sept 19, 2014:

Evidence of CV protection

Glucose control targets

Personalized Targets

Changing Times – Need Social Engineering

• Unifying mechanism for tissue damage fits well with microvascular disease

• Data from major studies have shown that hyperglycemia is not the major

determinant of diabetic macrovascular disease.

• Across HbA1c range from 5.5 --- 9.5%:

- Microvascular risk increases ~10-fold

- Macrovascular risk increases ~ 2-fold

• If not hyperglycemia, what ?

Extrapolation to Diabetic Macrovascular Disease

Most people die in bed.

-- Don’t blame THE BED!

Traditional CVD Risk Factors in Diabetes

Adapted from Beckman et al. JAMA 2002;287:2570-2581; Dokken BB. Diabetes Spectrum 21:160-5, 2008

Atherosclerosis

Coagulation/

Platelet

Aggregation

Hypertension

Dyslipidemia

Hyperglycemia

Insulin

Resistance

Non-Traditional Risk Factors Inflammation:

• CRP,SAA

• MMP-9,

•ICAM, VCAM

• PAI-1, Lp(a)

• Sialic acid

• Oxidative stress

• ROS

Non-Traditional Risk Factors Endothelial:

• Arginine, NO

• Endothelin

• ADMA

• EPC

• Homocysteine

Adipokines

• Hypoadiponectinemia

• Other

Steno-2: Major Articles

Lancet 1999; 353: 617-22 New Engl J Med 2003; 348: 383-93 New Engl J Med 2008; 358: 580-91

Steno-2 Trial: multiple risk factor intervention in T2DM

Steno-2 Study: Treating the Whole Patient

A1C

<6.5%

Pati

en

ts (

%)

20

30

40

50

60

70

10

80

Cholesterol

<175 mg/dL

Triglycerides

<150 mg/dL

Systolic BP

<130 mm Hg

Diastolic BP

<80 mm Hg

P=0.06

P<0.001

P=0.19

P=0.001

P=0.21

Intensive

therapy (n=80)

Conventional

therapy (n=80)

0

Gaede P and al. N Engl J Med. 2003;348(5):383-393.

BP reduction in type 2 diabetes

UKPDS – ADVANCE - ACCORD

SBP

UKPDS ADV ACCORD

Limited

benefit

Joint effects of blood pressure and glucose lowering in ADVANCE

An

nu

al e

ve

nt ra

te %

Standard

Intensive

Placebo

Perindopril/

indapamide

2.01

1.94

1.75

1.65 1.5

1.7

1.9

2.1

2.3

RRR 18%, P=0.04

Total mortality

Standard Placebo

1.14

1.02

0.89

0.87 0.7

0.9

1.1

1.3

CV death

RRR 24%, P=0.04

Standard Placebo

1.02

0.82 0.84

0.68 0.6

0.8

1.0

1.2

0.82

RRR 33%, P=0.005

New /worsening nephropathy

Adapted from Zoungas S et al. Diab Care 2009; 32: 2068-2074.

Perindopril/

indapamide

Perindopril/

indapamide

Intensive Intensive

Targets and thresholds in T2D

ADVANCE : Achieved SBP of 135/75 mmHg,

clearly beneficial

ACCORD : Achieved SBP of 119/62 mmHg,

more limited benefits and no harm

If recommending thresholds and targets, it is silly

to abandon guideline of 130/80mmHg because

119/62 does not work better (reductio ad absurdum)

A target BP 130/80 mmHg still appropriate in T2D!

ADVANCE demonstrated benefits of routine BP lowering

in all patients with T2D, regardless of baseline BP.

Without threshold or target !

ADVANCE

Effects of blood pressure and blood glucose interventions

are independent and addititive

Conclusions

Intensive glucose lowering with traditional therapy in some

groups of patients with established Type 2 diabetes and tight

glycaemic control:

– Can achieve and maintain HbA1c values of ca. 6.5% safely

– Has no significant effect on macrovascular disease over 5y

– Reduces the onset of diabetic nephropathy

Intensive glucose lowering towards HbA1c levels of 6% +

multiple therapies with aggressive use of insulin may be

hazardous

What do we change in clinical practice?

• Evidence is strongly in favour of intensive treatment

for glycaemia early in T2DM

• Evidence suggests that in those with established

CVD that a rapid lowering of glycaemia to aggressive

targets may cause excess mortality.

• Rosiglitazone needs further evidence for its safety in

established T2DM

• DPPIV-I need to be used with caution with good

patient follow up because of hospitalization for heart

failure and low impact on A1C

• Gliclazide MR use may be appropriate for preventing

microvascular disease (nephropathy) and lowers

glucose at an appropriate rate

Glycemic Control in Type 2 Diabetes: Time for an Evidence-Based About-Face?

“..clinicians should avoid glycemic

control interventions that overwhelm

the patients’ capacity to cope

clinically, psychologically, and

financially.”

Montori and Fernandez-Balsells, Ann Int Med 2009

Some cautions • There will be those who say that

glucose lowering is not cost effective

• There will be those who say that the target of 7.5% is adequate, without saying for whom

• There will be those who say that we should just lower cholesterol and blood pressure

• There will be those who will become famous for saying almost anything, but loudly

“You might as

well fall flat on

your face, as

lean over too far

backwards”

James Thurber.

Fl. 1945

“Everything should be made as

simple as possible, but not simpler”

Albert Einstein

And if you have been

listening…

Thank You