Prof JC Mbanya Treating Diabetes a Matter of Evidence - Accra
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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
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Speaker for Servier
Conflicts of Interests
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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
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Type 2 Diabetes: Global Burden
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2013 IDF Diabetes Atlas - Sixth edition
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A huge and growing problem
2013 IDF Diabetes Atlas - Sixth edition
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Top 10 countries
2013 IDF Diabetes Atlas
- Sixth edition
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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
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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
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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
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Global cardiometabolic risk
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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
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Perspectives on recent morbi-mortality
trials: Anything gained in the
treatment of diabetes?
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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
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Blood glucose and vascular risk in diabetes
Evidence in 2000
UK Prospective Diabetes Study Lancet 1998
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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
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Recommended Guidelines : reduction of HbA1c < 7.0%
UKPDS: HbA1c and vascular disease
Stratton et al. BMJ 2000.
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Blood glucose and vascular risk in diabetes
Evidence in 2000
Stratton et al. BMJ 2000.
UKPDS Guidelines
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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
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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?
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HbA1c - How low should we go?
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Clinical trials to prevent cardiovascular
disease in patients with T2D
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FINAL TREATMENT REGIMENS
VADT (Veterans Diabetes
Trial)
ACCORD (Action to Control
Cardiovascular Risk in Diabetes
Trial)
ADVANCE (Action in
Diabetes and Vascular Disease)
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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
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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
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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
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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
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Cardiovascular disease and heart failure in
pioglitazone treated patients: meta-analysis
Lincoff AM et al JAMA. 2007 ;298 (10) : 1180-1188
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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
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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
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Morbi-mortality trials
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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
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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
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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
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Composite of cardiovascular death,
myocardial infarction, or ischemic stroke
Scirica et al. NEJM 369(2013)1317-26
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White et al. NEJM 369(2013)1327-35
Composite of cardiovascular death,
myocardial infarction, or ischemic stroke
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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
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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
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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
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Worldwide Orientation Plan 2013-2014
Glycemic Indices Over Time
White et al. NEJM 369(2013)1327-35
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Worldwide Orientation Plan 2013-2014
SAVOR EXAMINE
HbA1c (at the end of the trial)
-0.3% -0.36%
Glycemic control
HbA1c efficacy
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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
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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
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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
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Conclusion : DPP-4 inhibitors
No cardiovascular protection
hospitalization for heart failure
Limited glycemic efficacy
Increased risk of hypoglycemia
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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
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ADVANCE: positive trend for reducing cardiovascular death
CONTROL Group; Turnbull FM, Abraira C, Anderson RJ, et al. Diabetologia. 2009;52:2288-2298.
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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.
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Perkovic et al. Kidney Int 83(2013) 517–24
Renal Protection
65%
ESRD
Intensive glucose control based on
gliclazide MR improves kidney outcomes
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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.
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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
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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.
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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
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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
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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
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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
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The incidence of mild and severe hypoglycemia in patients
with T2D treated with SUs.
Diabetes Metabolism Research and Review – September 2013
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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)
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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
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ADA/EASD Guidelines. Diabetes Care 32(2009)193-203
Summary of glucose-lowering interventions
HbA1c efficacy
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ADA/EASD Recommendations 2012
Inzucchi SE et al. Diabetes Care.2012;35(6):1364-1379.
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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).
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ADVANCE-ON results: 2014
EASD Sept 19, 2014:
Evidence of CV protection
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Glucose control targets
Personalized Targets
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Changing Times – Need Social Engineering
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• 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!
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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
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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
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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.
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BP reduction in type 2 diabetes
UKPDS – ADVANCE - ACCORD
SBP
UKPDS ADV ACCORD
Limited
benefit
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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
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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 !
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ADVANCE
Effects of blood pressure and blood glucose interventions
are independent and addititive
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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
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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
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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
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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
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“You might as
well fall flat on
your face, as
lean over too far
backwards”
James Thurber.
Fl. 1945
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“Everything should be made as
simple as possible, but not simpler”
Albert Einstein
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And if you have been
listening…
Thank You