Download Diabetes

Diabetes is emerging as the dominant
healthcare epidemic
Source: Diabetes Atlas 3rd Edition. www.eatlas.idf.org. Last accessed 25 January 2007
The Tale of Two Epidemics
AIDS RELATED DEATHS 1990 - 2009
(UNAIDS 2010)
• SA prevalence Diabetes
= 5.5%
• Direct cause of death =
4.3%
• Contributory to 14% IHD,
12% hypertensive, 12%
renal + 10% stroke
deaths
• Glycemic Control: 37% of
patients have HbA levels
< 7.0%
• Metabolic Control: 20%
achieve HbA + BP + Lipid
targets
(SAMJ 2007)
HIV vs DM in SA
•
•
•
•
•
•
•
•
Absolute No (m)
Mortality Rank
Mortality Growth Rate
ARV vs OHA/Ins (%)
VL vs HbA control (%)
Medication vintage
Advocacy 1
Advocacy 2
•
•
•
•
•
•
•
•
6 vs 4
1 vs 6
1 vs 3
37 vs 66
90 vs 30
2010 vs 1947
TAC vs SA Diabetes
Guidelines HIV vs DM
Cost of DM Care
• US 2006: $1 in $7 / $ 200 billion
• OPD: 15% / consultations / laboratory /
medications
• In-Patients: 85% / complications /
investigations / procedures / medications
Poor Glucose Control in SA
•
•
•
•
•
Many patients
Many undiagnosed
Few health personnel
Poorly skilled personnel
Poorly resourced clinics
• Reduced patient contact
time (40 min per year)
• Poor uptake / application
of lab testing (30 % have
regular tests)
• Delay in treatment
change / up-titration
• Sub-optimal medication
Diabetes
“Re-thinking the Failure”
Defining Mental Retardation
“ achieve no result, persist in doing the
same and expect and different outcome”
(Albert Einstein)
UKPDS 35: Higher HbA1c is associated with
increased micro- and macrovascular
complications in T2DM
Each 1% rise in mean HbA1c
was associated with
– 21% risk increase for any
diabetes endpoint
(p<0.0001)
– 21% risk increase for
diabetes-related mortality
(p<0.0001)
– 14% risk increase for
myocardial infarction (MI)
(p<0.0001)
– 37% risk increase for
microvascular complications
(p<0.0001)
140
Any diabetes endpoint
120
Adjusted event rate / 1,000 person years
•
100
80
Microvascular
complications
60
Diabetes-related
morbidity
40
MI
20
0
<6%
67%
78%
89% 910% ≥10%
Mean HbA1c concentration (%)
Stratton IM, et al. BMJ 2000;321:405–12
Diagnosis – Fasting Glucose
• Insulin Resistance
• > 5.6 mmol/l
• Pre-Diabetes
• > 6.0 mmol/l
• Diabetes
• > 7.0 mmol/l
T2 DM and Primary Prevention
Parameter
Success Rate
• Weight Loss
• <5%
• Exercise
• <5%
Type 2 Diabetes and Primary Prevention
ADA CONCENSUS 2007
TREAT PRE-DIABETES (IFG / IGT)
LIFESTYLE
LIFESTYLE + METFORMIN
Age < 60 y
Risk Factors (BP, Lipids, BMI)
HbAic > 6 %
Cost Analysis DPP 10 y FU:
Lifestyle vs Metformin:: +$1500 vs -$30
[ADA 71st 2011]
Effects of intensive glucose
lowering in T2DM
ACCORD
Standard therapy
Intensive therapy
9.0
8.5
HbA1c (%)
8.1%
8.0
7.5%
7.5
7.0
6.4%
6.5
6.0
0
0
1
2
3
Years
Gerstein et al. N Engl J Med 2008;358:2545–59
4
5
6
Effects of intensive glucose
lowering in T2DM
ACCORD
Patients with events (%)
Standard therapy
Intensive therapy
25
First occurrence of non-fatal MI,
non-fatal stroke or CV death
25
Death from any cause
20
HR (CI) 0.90 (0.78, 1.04)
p=0.16
20
HR (CI) 1.22 (1.01, 1.46)
p=0.04
15
15
10
10
5
5
0
0
0
1
2
3
Years
4
Gerstein et al. N Engl J Med 2008;358:2545–59
5
6
0
1
2
3
Years
4
5
6
Side-effects of intensive
glucose lowering
ACCORD
Hypothesis:
Standard
therapy
Intensive
therapy
Hypoglycaemia*
261 (5.1)
830 (16.2)
<0.001
713 (14.1)
1399 (27.8)
<0.001
p-value
N (%)
Weight gain >10kg
N (%)
Drug interaction
70% of non-insulin-treated and 60% of
insulin-treated patients were taking three or
more oral antidiabetic drugs at study end
*hypoglycaemia defined as requiring any assistance
Gerstein et al. N Engl J Med 2008;358:2545–59
Potential mechanisms of
hypoglycaemia-induced mortality
 Cardiac arrhythmias due to abnormal cardiac
repolarisation in high-risk patients (IHD,
cardiac autonomic neuropathy)
 Increased thrombotic tendency/decreased
thrombolysis
 Cardiovascular changes induced by
catecholamines
• Increased heart rate
• Silent myocardial ischaemia
• Angina and myocardial infarction
GLP 1 Mimetics
The Virtuous Therapeutic Cycle
GLUCOSE CONTROL
HbA = 7 %
WEIGHT LOSS
NO HYPOGLYCEMIA
Diabetes Therapy - Safety
•
•
•
•
Hypoglycemia
Weight gain
CVS mortality
Cancer
Strategic Rx
ADVERSE
AE / PE
Wt Gain
POSITIVE
Hypo’s
Wt Loss
Met
(3) no
no
yes=no
BPLipids
etc
yes=no
SU
(0) yes
yes
no
no
Pio
(2) yes
no
no
yes
DPP (3) no
no
yes>no
yes>no
GLP1 (4) no
no
yes
yes
OHA and CV Protection
• Metformin (UKPDS)
• MI reduction 39% (vs
insulin / chlor / gliben
• Rosi / TZD (RECORD) • MI increased (OR 1.43)
• Tolbu / SU (UGDP)
• CV mortality increased
by 30%
SU vs Met
SU
(Schramm T et al, Eur Heart J, April 2011)
Glimiperide
Increase AllIncrease MI, All
Cause Mortality CVD, Stroke
32 %
21 %
Glibenclamide
19 %
12 %
Glipizide
27 %
17 %
Tolbutamide
28 %
27 %
[Conclusion: Metformin = protective? vs some SU bad?]
DM and Cancer
• Medications for DM can affect cancer risk
and outcome - ? Insulin ? Pioglitazone
• Metformin reduces cancer risk
• Sulfonylurea: probably no effect
• GLP-1 agonists: currently unknown but
seemingly safe
GLP-1 and DPP-41
DPP-4
His
Plasma t½ = 1–2 min (IV)
Ala Glu Gly Thr Phe Thr Ser Asp
7
Val
9
CL = 5–10 L/min
Ser
Lys Ala
Ala Gln Gly Glu Leu
Tyr
Ser
Glu
36
Phe
Ile
Ala Trp Leu Val Lys Gly Ala
CL=clearance rate; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; IV=intravenously.
1. Vilsbøll T et al. J Clin Endocrinol Metab. 2003;88(1):220–224
NH2
Incretin Therapy
DPP 4
•
•
•
•
Sitagliptin ^
Vildagliptin*
Alogliptin
Saxagliptin
GLP1
•
•
•
•
•
[*Available / ^ Imminent in SA]
Exenatide*
Liraglutide ^
Exenatide LAR
Albuglutide
Taspoglutide
Incretin - GLP 1 Therapy
• Stimulates insulin
secretion
• Insulin secretion is
glucose dependent
• Inhibits glucagon
secretion
• Increases beta cell mass
• Delays gastric emptying
• Inhibits appetite
• Secretogogue
• No hypoglycemia
• Reduces meal-related
glucose peaks
• Maintains beta cell
reserve
• Reduces meal-related
peaks; reduces weight
• Reduces weight
Liraglutide in combination with metformin
presents a low risk of hypoglycaemia
Minor hypos/patient/year
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Liraglutide
1.2 mg
Liraglutide
1.8 mg
Placebo
Glimepiride
• Minor hypoglycaemic events are at the placebo level (LEAD 2, above)
• There is a small but increased risk of minor hypoglycaemia when
combined with SUs (1.0 events per subject every second year; LEAD 1)
Nauck et al, Diabetes Care, published online 10.23 37/dc08-1355 (LEAD 2) and Marre et al. Diabetes
2008;57(Suppl. 1):A4 (LEAD 1).
A quarter of patients lose an average of 7.7
kg with liraglutide
Weight change (kg)
2
1
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
≤Q1
Q1-Q2
Q2-Q3
>Q3
Q3-Q4
Liraglutide 1.8 mg + met
0–Q1: mean weight change for the 25% of subjects who had the largest weight loss
Q1–Q2: mean weight change for the 25–50% weight loss quartile
Q2–Q3: mean weight change for the 50–75% weight loss quartile
Q3–Q4: mean weight change for the 75–100% weight loss quartile, that is, the 25% who had the
smallest weight loss
Nauck et al, Diabetes Care, published online 10.23 37/dc08-1355 (LEAD 2).
Sustained weight reduction over
52 weeks with liraglutide
***p<0.0001 for change from baseline
52
***
***
•
Waist circumference
was reduced from
baseline by 3.0 cm
with liraglutide 1.8 mg
•
Waist circumference
increased by 0.4 cm
with glimepiride
(p<0.0001)
Glimepiride 8 mg/day
Liraglutide 1.2 mg/day
Liraglutide 1.8 mg/day
Garber et al, The Lancet, early online publication, 25 Sept 2008 (LEAD 3).
Liraglutide reduces visceral
body fat
Visceral vs. subcutaneous fat
CT scan
3
+1.1 kg
(+0.4%)
2
1
0
-1
-2
-3
-4
-1.6*
(-1.1%*)
-2.4*
(-1.2%*)
Liraglutide 1.2 mg + met
Change in percentage fat (%)
Change in body fat, kg (%)
Change in body fat
DEXA scan
10
Visceral
Subcutaneous
+3.4
5
0
5
-10
-4.8
-15
-7.8*
-8.5*
-20
-25
-16.4
-17.1
Liraglutide 1.8 mg + met
• Two thirds of weight lost was fat tissue (liraglutide 1.8 mg)
Data are mean±SEM; *p<0.05 vs. glim+met; n=160.
LEAD 2 substudy, originally presented as Jendle et al. Diabetes 2008;57(Suppl. 1):A32.
Glimepiride + met
Liraglutide improves beta-cell function as
measured by HOMA-B and
proinsulin:insulin ratio
Baseline
56.4%
70.6%
45.5%
56.3%
0.48
0.45
0.45
0.42
HOMA (%)
p=0.0033
Liraglutide Liraglutide
1.8 mg
1.2 mg
Change in proinsulin:insulin
p=0.0313
RosiPlacebo
glitazone
Marre et al. Diabetes 2008;57(Suppl. 1):A4 (LEAD 1). Data are mean±2SE.
Liraglutide Liraglutide
RosiPlacebo
1.8 mg
1.2 mg
glitazone
Diabetes Care – Future?
1)
2)
3)
4)
5)
6)
Pre-Diabetes
CVD Protection
Cancer
Hypoglycemia
Weight
Disease Modifying
•
•
•
•
•
•
Metformin
Metformin, TZD, GLP1
Metformin
Metformin, TZD, GLP1
Metformin, GLP1
GLP1