1 diabetes mellitus dr wayne riback senior medical advisor
TRANSCRIPT
1
Diabetes MellitusDiabetes Mellitus
Dr Wayne Riback
Senior Medical Advisor
2
Diabetes is an increasing healthcare epidemic throughout the world
Global projections for the number of people with diabetes
(20–79 age group), 2007–2025 (millions)
South and Central America
Africa
Eastern Mediterraneanand Middle East
Europe
North America
South-East Asia
Western Pacific
28.340.5
+43%
16.232.7
+102%
10.418.7
+80%
24.544.5
+81%
53.264.1
+21%
67.099.4
+48%
46.580.3
+73%
IDF. Diabetes Atlas 3rd Edition – 2006
Worldwide:246 million people in 2007
380 million projected for 2025
3
Diabetes prevalence in the Middle East and Africa is high and increasing
Morocco
Algeria Egypt
Tunisia
SaudiArabia
Iran
Pakistan
IsraelLebanon
SouthAfrica Egypt
2007: 10.1% – 4,3572025: 12.2% – 7,650
Pakistan
2007: 8.3% – 6,9292025: 8.5% – 11,538
Iran
2007: 6% – 2,5652025: 8.4% – 5,115
Saudi Arabia
2007: 13.5% – 1,8552025: 15.7% – 3,610
Lebanon
2007: 7.4% – 1672025: 9.1% – 267Algeria
2007: 7.3% – 1,4752025: 8.9% – 2,528
Morocco
2007: 7.1% – 1,3602025: 9.1% – 2,396
Tunisia
2007: 4.8% – 3172025: 6.2% – 535
Israel
2007: 7.8% – 3372030: 8.5% – 495
South Africa
2007: 4.5% – 1,2132025: 4.4% – 1,279IDF. Diabetes Atlas 3rd Edition –
2006
Prevalence rates and numbers of adults with diabetes (1,000s)
4
How is South Africa performing with respect to DM Practices?
Diabetes Action Now Booklet – Adapted from Wild S. Diabetes care 27: 1047-1053; 2004
5
Patients are uncontrolled with respect to HbA1c
South Africa
HbA1c>7%
HbA1c<7%
0
30
100
% o
f p
atie
nts
30.4
69.4
6
Patients uncontrolled with respect to HbA1c
HbA1c>8.4%
HbA1c<7%
HbA1c 7%- 8.4%
% o
f p
atie
nts
0
30
60
100
South Africa
30.4
31.4
38.2
7
Type 2 DM Patients are not adequately screened for complications
Percentage of patients who have never been screened in the last 12 months
CardioVasculardisease
Eye Nerve Kidney DiabeticFootulcer
Lipid
5
15
25
35
45
South Africa
5.8 8.2 5.9 6.9 5.6 3.1
8
Type 2 DM Patients with complications
Percentage of patients who have diabetes complications
CoronaryArtery
disease
Eye Nerve Kidney DiabeticFootulcer
PVD
5
15
25
35
45
South Africa
14
17
19
4
12
8
9
T2 DM: Only few patients have an HbA1c tested every 6 Months
% o
f p
atie
nts
In the last12 months
Every 6 months
Every3 months
10002030405060708090
100
South Africa
99%
41%
2%
10Jonsson B. Diabetologia 2002;45:S5–S12
The burden of diabetes on healthcare systemsThe burden of diabetes on healthcare systems
CODE-2: cost of type 2 diabetes in Europe
Status of diabetes management
Diabetes accounts for between 5% and 10% of any nation’s health budget
Three times the healthcare resources are being spent on treating diabetes complications compared with that spent on controlling diabetes before the onset of complications
11
Pathogenesis of type 2 diabetes mellitus
12
4:00 16:00 20:00 24:00 4:00
Breakfast Lunch Dinner
8:0012:008:00
Time
Pla
sma
insu
lin
Insulin-glucose profile after mealInsulin-glucose profile after meal
13
Type 2 diabetes mellitus (T2DM) requires progressive therapy
T2DM is a progressive disease characterised by increased insulin resistance and decreasing pancreatic β-cell function1
At diagnosis, patients may have already lost approximately 50% of β-cell function2
An ideal treatment regimen for T2DM should provide: Continuity of care as the disease progresses Flexibility to adapt to individual needs
1. Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995―1015.
2. Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.
14HOMA=homeostasis model assessmentAdapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.
Decreasing -cell function as part of the progression of T2DM
Normal -cell
function by HOMA (%)
Time (years)
0
20
40
60
80
100
―10 ―8 ―6 ―4 ―2 0 2 4 6
Time of diagnosis?
Pancreatic function~50% of normal
15
Multiple factors may drive progressive decline of b-cell function
-cell(genetic background)
Hyperglycaemia(glucose toxicity)
Proteinglycation
Amyloiddeposition
Insulin resistance
“lipotoxicity”elevated FFA,TG
16
Both FBG and PPBG contribute to overall hyperglycaemia
FBG=fasting blood glucose; IGT=impaired glucose tolerance; PPBG=postprandial blood glucose.
Adapted from Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995―1015.
19.416.713.911.18.35.52.8
Plasmaglucose (mmol/l)
Years
350300250200150100
50
Insulin level
Insulin resistance250
200
150
100
50
0
Relative-cell
function (%)
FBGPPBG
Plasmaglucose (mg/dl)
Onset of diabetes
Clinicalfeatures
Uncontrolled hyperglycaemia
Risk for diabetes complications with uncontrolled hyperglycaemia
-cell failure
–10–5 0 5 10 15 20 25 30
Obesity IGT T2DM
17
Contribution of fasting hyperglycaemia to overall glycaemia increases with worsening diabetes
ADA=American Diabetes Association; OHA=oral hypoglycaemic agent; PG=plasma glucose.Adapted from Monnier L, et al. Diabetes Care 2003;26:881―5.
290 patients with T2DM treated with diet or OHAsBaseline (normal) PG defined as 6.1 mmol/ l (110 mg/ dl) ―threshold defined by ADA as the upper limit of normal PG at fasting or preprandial times
100
0
50
Rela
tive
con
trib
utio
n (%
)
<7.3 7.3―8.4 8.5―9.2 9.3―10.2 >10.2 HbA1c (%) quintiles
70%
30%
Fasting
18Comparison of 24-hour plasma glucose levels in healthy subjects vs patients with diabetes (p<0.001).Adapted from Hirsch I et al Clin Diab 2005;23:78-86
24-hour plasma glucose profile in T2DM and healthy subjects
Time of day (hours)
400
300
200
100
006:00 06:0010:00 14:00 18:00 22:00 02:00
Pla
sma g
luco
se (
mg/d
l)
Healthy subjectsMeal Meal Meal
20
15
10
5
0
Pla
sma g
luco
se (m
mol/l)
T2DM
19
1. ADA. Diabetes Care 2006;29(suppl 1):S4–S42.2. ADA. Diabetes Care 2006;29(suppl 1):S43–8.3. ADA/EASD Consensus Algorithm - Nathan DM, et al. Diabetologia 2006;49:1711–214. AACE. Endocr Pract 2002;8(suppl 1):40–82.5. IDF. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation, 2005.
http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf.
<7.8**1
(<140)
<5.52
(<100)<6.0
(<110)6.0
(110)3.97.2
(70130) FBG, mmol/l(mg/dl)
<8.0**(<145)
7.8**(140)
<10.0**(<180)
PPBG, mmol/l(mg/dl)
<6.56.5<7.0†HbA1c* (%)
IDF5AACE4
ADA/EASD1&3
Normal
<6.01
Guidelines provide HbA1c, FBG and PPBG targets
*DCCT referenced assays: normal range 4–6%; **1–2 hours postprandial; †ADA/EASD guidelines recommend HbA1c levels as close to normal (<6%) as possible without significant hypoglycaemia1,5
AACE=American Association of Clinical Endocrinologists; ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; IDF=International Diabetes Federation
Targets for Diabetic Patients
SEMSDA
<7.0(<130)
<8.0(<145)
<7.0
20
SEMSDA Guidelines 2009
21
22
0
50
100
150
200
250
-10 -5 0 5 10 15 20 25 30
50100150200250300350
Years of Diabetes
Insulin Resistance
Insulin Level
Fasting Glucose
Beta cell dysfunction
Post Meal Glucose
At risk for DM
©2000 International Diabetes Center. All rights reserved
Glu
cose (
mg
/dL)
% o
f N
orm
al Fu
ncti
on
Adapted from: UKPDS 33: Lancet 1998; 352, 837-853 DeFronzo RA. Diabetes. 37:667, 1988. Saltiel J. Diabetes. 45:1661-1669, 1996. Robertson RP. Diabetes. 43:1085, 1994.
Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777.
Lifestyle changes Insulin
Metformin(insulin sensitisers)
Secretagogue
Risk for diabetes complications
T2DM is a progressive condition
23
InsulinInsulin
The most powerful agent we have
to control glucose
24
Balancing Good Glycemic Control with a Low Risk Balancing Good Glycemic Control with a Low Risk of Hypoglycemia…of Hypoglycemia…
Hypoglycemia
Glycemic control
25
Imagine consulting room on Monday with Imagine consulting room on Monday with the following:the following:
59 years old male working as a financial manager – sedentary work most of the times during the week – works long hours. Over week-ends he enjoys hikingType 2 diabetes diagnosed 12 years agoHe has hypertension, dyslipidaemia.
26
Current medication:
Glimepiride 4 mg/day Metformin 1g bd Irbesartan 300
mg/day Rosuvastatin 10
mg/day Disprin CV 1/day
Case study (continued)Case study (continued)
27
Body mass index = 30 Waist circumference =
104.5 cm BP = 120/74 mm Hg No diabetes complications
HbA1c = 8.9% FBG of 9-10 mmol/l PPBG up to 15 mmol/l
Case study (continued)Case study (continued)
28
What will be prescribed?What will be prescribed?
More than 200 combinations of insulin and oral agents are possible: Intensified insulin – basal-bolus or MDI Basal-plus Conventional – premix Basal-oral
Basal – Glargine, Detemir, NPH Bolus – Glulisine, Lispro, Aspart, Human
Regular, Premix- Regular or Rapidacting bolus
component Different % combinations
29
0
20
40
60
<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2
Postprandial
Fasting
Rel
ativ
e co
ntr
ibu
tio
n
of
FB
G v
s P
PB
G (
%)
HbA1c (%)
Adapted from Monnier L, et al. Diabetes Care 2003;26:881–5.
Relative contribution of FBG and PPBG to Relative contribution of FBG and PPBG to HbAHbA1c1c
The relative contribution of PPBG is predominant in subjects with moderate diabetes, whereas the contribution of FBG increases as diabetes worsens
30Comparison of 24-hour glucose levels in control subjects versus patients with diabetes (p<0.001).Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―1239.Copyright © 2007 Massachusetts Medical Society. All rights reserved.
Time of day (hours)
400
300
200
100
006.00 06.0010.00 14.00 18.00 22.00 02.00
Plas
ma
gluc
ose
(mg/
dl)
Normal
Meal Meal Meal
20
15
10
5
0
Plasma glucose (m
mol/l)
Treating fasting hyperglycaemia lowers Treating fasting hyperglycaemia lowers the entire 24-h plasma glucose profilethe entire 24-h plasma glucose profile
Hyperglycaemia due to an increase in fasting glucoseT2DM
32
Case studyCase study
Max OAD HbA1c = 8.9% FBG of 9-10 mmol/l PPBG up to 15 mmol/l Hb
33
More physiologic insulin More physiologic insulin replacement replacement
==Basal – Bolus/ Basal-PlusBasal – Bolus/ Basal-Plus
34
FBG <6mM but HbA1c >7.0% (>6.5%)introduce Glulisine before meal with max BG
excursion >7.8mM (>10mM)
4
8
12
8 1812 22.00 hrs
Glu
cose
(mm
ol/l
)
Breakfast DinnerLunch
0
Snack
glargine
OHAs+
glargine
Metformin no change (2g/d)Glimepiride, gliclazide SR no change, Glibenclamide, gliclazide no change, reduce or stop pre-dinner doseMeglitinides need to stop pre-dinner dose
*Start Glulisine 4 units based on SMBG if PPBG >/=7.8 mM Titrate upwards by 2 units every 5-7 days to achieve PPBG <7.8mM
Glulisine*
Type 2 DMType 2 DM RRx x StrategiesStrategies : ‘Basal-Plus’ : ‘Basal-Plus’ therapytherapy
35
Insulin treatment options in type 2 diabetesInsulin treatment options in type 2 diabetes
Basal insulin therapy
Long-acting insulin
+/- oral agents
Prandial / Intensified
Insulin Therapy
Short acting insulin or rapid insulin analog prandially +
long-acting insulin
ConventionalInsulin Therapy
2-3 injections
mix of regular insulin / rapid-acting insulin analog and long-acting insulin
Basal Plus therapy
long-acting insulin
+ rapid acting analog with 1-2 meals
+/- oral agents
36
Insulins
Class of insulin ProductAction onset
Action duration
Peak/max
Human Insulins
Shortacting ActrapidHumulin R
30 min 8 hrs 2.5-5hrs
Intermediate-acting: Isophane Zinc suspension
Humulin NProtaphaneHumulin L
1.5hr
2.5 hrs
16hrs
20hrs
4-12hrs
7-15hrs
Biphasic/Premixed Actraphane (30/70)Humulin 30/70Mixtard 20/80
30 min 24 hrs 2-12 hrs
Inhaled Insulins Exubera*
Analogue insulins
Ultra shortacting Humalog NovorapidGlulisine*
10-20 min
3-5 hrs 1-3 hrs
Intermediate-acting Detemir 14 hours (hypoglycaemic effect
6-8 hours
Biphasic/premixed Humalog mix 25Novomix 30
10-20 min
15-18 hrs 1-4hrs
Longacting Lantus (Glargine) 1 hr 24 hrs No peak
37
Onset and Duration of Insulin PreparationsOnset and Duration of Insulin Preparations
Gummerson, Irene. Insulin analogues revisited, Hospital Pharmacist, April 2003, vol. 10, p.165 - 172
38
The Ideal Basal Insulin …The Ideal Basal Insulin …
Mimics normal pancreatic basal insulin secretion
Long-lasting effect Smooth peakless profile Reproducible and predictable effects Reduced nocturnal hypoglycemia Once-daily administration for convenience Pharmacodynamic effects similar to insulin
pump
39
Basal/Bolus Treatment Program with Basal/Bolus Treatment Program with Rapid-Acting and Long-Acting AnalogsRapid-Acting and Long-Acting Analogs
Time 4:00 16:00 20:00 24:00 4:00
Breakfast Lunch Dinner
8:0012:008:00
Glargine
Aspartor
Lispro
Aspartor
Lispro
Aspartor
LisproPlasma insulin (U/mL)
75
50
25
0
Verbal communication from Bode, BW. Atlanta, Ga; Feb. 2003.
40
Current Strategies for Improving the Therapeutic Potential of GLP-1
Agents that mimic the actions of GLP-1 (incretin mimetics) DPP-IV–resistant GLP-1 derivatives (dipeptidyl
peptidase) Examples: GLP-1 analogues, albumin bound GLP-1
Novel peptides that mimic some of the glucoregulatory actions of GLP-1 Exenatide- Victoza (NovoNordisk)- Syncria (GSK – Phase II)
Agents that prolong the activity of endogenous GLP-1 DPP-IV Inhibitors
Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940.; Baggio LL, et al. Diabetes. 2004;53:2492-2500.
41
GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins
Promotes satiety and reduces appetite
Beta cells:Enhances glucose-dependent insulin
secretion
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
Liver: ↓ Glucagon reduces
hepatic glucose output
Alpha cells:↓ Postprandial
glucagon secretion
Stomach: Helps regulate
gastric emptying
GLP-1 secreted upon the ingestion of food
42
GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins
Promotes satiety and reduces appetite
Beta cells:Enhances glucose-dependent insulin
secretion
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
Liver: ↓ Glucagon reduces
hepatic glucose output
Alpha cells:↓ Postprandial
glucagon secretion
Stomach: Helps regulate
gastric emptying
GLP-1 secreted upon the ingestion of food
43
The Incretin Effect Demonstrates the Response to Oral vs IV Glucose
Mean ± SE; N = 6; *P .05; 01-02 = glucose infusion time.Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492-498. Copyright 1986, The Endocrine Society.
Ve
no
us
Pla
sm
a G
luc
os
e (
mm
ol/
L)
Time (min)
C-p
ep
tid
e (
nm
ol/
L)
11
5.5
001 60 120 180 01 60 120 180
0.0
0.5
1.0
1.5
2.0
Time (min)02
02
Incretin Effect
Oral Glucose IV Glucose
**
*
*
**
*
44
The Incretin Effect Is Reduced in Patients With Type 2 Diabetes
0
20
40
60
80
Ins
uli
n (
mU
/L)
0 30 60 90 120 150 180
Time (min)
** *
** **
0
20
40
60
80
0 30 60 90 120 150 180
Time (min)
**
*
*P ≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29:46-52. Reprinted with permission from Springer-Verlag © 1986.
Patients With Type 2 DiabetesControl Subjects
Intravenous Glucose
Oral Glucose