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Pradana Soewondo
Department of Internal Medicine
Faculty of Medicine University of Indonesia-
Cipto Mangunkusumo National Referral
Hospital
Jakarta, Indonesia
Overview
Epidemiology diabetes in
Indonesia
Diabetes management
Algorithm Perkeni
Conclusion
Diagnostic Cut Points for IFG, IGT, and
Diabetes
126 mg/dL
100 mg/dL
IFG IFG + IGT
Normal
IGT
Glucose
N = 24.400
> 15 years
2 1
4
4 2
3 1
Objective
To collect information on diabetes management,
diabetes complications, and awareness of self-
control in diabetic population of the country. This
study also evaluated the physician perspectives,
psychological aspects, and quality of life of
diabetic patients.
Patient Demographic and Characteristics
Variable Data
Age (Years)* (n=1719) 58.939.57
793 (43.3) / 1010
Gender** (n=1803) Male/ Female
(55.16)
Age at Onset (Years)* (n=1686) 49.686.8
Duration of Diabetes (Years)* (n=1704) 8.615.97
Type of Diabetes**
Type 1 17 (0.9)
Type 2 1785 (97.5)
Others 2 (0.1)
BMI (Kg/m2)14 * (n=1646) 25.23.6
<23 / 23 (%) 28.7 / 71.3
Duration of Treatment (Years)* (n=1817) 8.57.0
Duration of OADs (Years)* (n=1727) 8.46.8
Duration of Insulin (Years)** (n=1176) 2.83.0
Smoking (Yes)** (n=1831) 178 (9.7)
* Data expressed as Mean SD; ** Data expressed as n (%); Percentage are calculated out of total cohort (n=1832) except for BMI.
Diabetes Management - The DiabCare Indonesia
2008
Diabetes management variable Data, n (%)
Type of Management
Diet -
Insulin monotherapy 317 (17.3)
Insulin and OAD combination 356 (19.4)
OAD monotherapy 1133 (61.9)
Herbal 5 (0.3)
None 20 (1.1)
Type of OAD Therapy
Biguanides 1085(59.3)
Sulphonylureas 1036(56.6)
Meglitinides 8(0.4)
Alpha Glucosidase inhibitors 461(25.2)
Thiazolidinediones 51(2.8)
Other OADs 48 (2.6)
Traditional Herbal medicines 5(0.3)
Double drug fixed dose combination 88 (4.8)
Triple drug fixed dose combination 5 (0.3)
Use of OADs Decreased at Duration of Diabetes 10
Years
Number of patients (%)
92 -- 89.71
90 --
88 -- 86.67 86.86 86.83
86 -- 84.27
84 --
82 --
80 --
77.71
78 --
76 --
74 --
72 --
70
<1 1 and <3 3
Duration ofand <5 5
diabetes and <7 7 and <10
(years)
10 DiabCare Indonesia
2008
Glycemic Control In The Study Population
250
207.7
Glycaemic control level
200.2
200
143.6
150
100
50
0
FPG (mg/dL) PPG(mg/dLl) RPG(mg/dl)
90
81.01
80
67.85 68.78
70
% of patients
60
50 47.22
40
30
20
10
0
ADA AACE/IDF ADA (>7.22) AACE/IDF
(7%) /APDPG /APDPG
HbA1c (%) (6.5%) FPG (mmol/l) (6.1)
Profil Lipid
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17
Pancreatic Islet Dysfunction Leads to Hyperglycemia
in T2DM
Fewer -Cells
-Cells Hypertrophy
Insufficient Excessive
Insulin Glucagon
+
+
Glucose
Glucose HGO
Uptake
Age, lifestyle,
environmental factors
Insulin resistance
330
Glucose
Meal
300
270
240
110
80
150 Depressed/delayed insulin response
120
(U/ml)
Insulin
90
60
30
0
140
Glucagon
130
(g/ml)
Time (minutes)
*Insulin measured in five patients
Adapted from Mller WA et al N Engl J Med 1970;283:109115.
21
Incretins Regulate Glucose Homeostasis
Through Effects on Islet Cell Function
Ingestion of
food Glucose dependent
Insulin Insulin
from beta cells increases
(GLP-1 and GIP) peripheral
glucose
GI tract Release of Pancreas uptake
incretin gut
hormones Beta cells Blood
Alpha cells glucose control
Active
GLP-1 and GIP
Increased insulin
Glucagon and decreased
glucagon
from alpha cells reduce
(GLP-1) hepatic
Glucose dependent glucose output
Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:26532659; Zander M et al Lancet 2002;359:824830; Ahrn B Curr Diab Rep
2003;3:365372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483.
22
GLP-1 and GIP Are Synthesized and Secreted from the
Gut in Response to Food Intake
L-Cell
(ileum)
ProGIP
Proglucagon
K-Cell
(jejunum)
GLP-1 [736 NH2]
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1
Adapted from Drucker DJ. Diabetes Care. 2003; 26: 29292940.
23
GLP-1 Restores Insulin and Glucagon Responses in a
Glucose-Sensitive Manner in Patients with T2DM
250 2.5 25
200 * 20
2.0 *
*
*
*
*
150 1.5 15
*
*
*
*
100 * 1.0 10
*
*
* *
50 0.5 5 * *
*
*
0 0.0 0
30 0 30 60 90 120 150 180 210 240 30 0 30 60 90 120 150 180 210 240 30 0 30 60 90 120 150 180 210 240
Time (Min) Time (Min) Time (Min)
GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus
*P <0.05 GLP-1 Placebo
GLP-1(736 amide) infused at 1.2 pmol/kg/min for 240 minutes.
200
150
100 * * * *
* * * When glucose levels
50
*
approached normal,
insulin levels declined
Glucagon
20
(pmol/L)
Time (minutes)
N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drug schedule was
allowed for one day between the experiments with GLP-1 and placebo.
25
*p<0.05 GLP-1 vs. placebo
Adapted from Nauck MA et al Diabetologia 1993;36:741744.
Decreased Glucose Disposal and Increased HGP
Contribute to Increased FPG in T2DM
2.8
Diagnosis
2.4
4.5
4.0 Excessive
3.5 glucagon-mediated
HGP 3.0
(mg/kg min) glucose output
2.5
2.0
1.5
1.0
50 100 150 200 250 300
FPG (mg/dL)
FPG=fasting plasma glucose; HGP=hepatic glucose production; T2DM=type 2 diabetes mellitus
Adapted from DeFronzo RA. Diabetes. 1988; 37: 667687.
26
Treatment Targets: Deteriorating Islet Cell Function in
the Setting of Insulin Resistance
Insulin resistance
Prediabetes
NGT Diabetes
(IFG/IGT)
Thiazolidinediones
Increase glucose uptake in
skeletal muscle and
decrease lipolysis in
adipose tissue
Sulfonylureas
Increase insulin secretion
from pancreatic -cells
-glucosidase inhibitors
Delay intestinal carbohydrate
Meglitinides absorption
Increase insulin secretion
from pancreatic -cells
DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus
Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213226.
30
Expected HbA1c reduction according to intervention
Intervention Expected in HbA1c (%)
Lifestyle interventions 1 to 2%
Metformin 1 to 2%
Sulfonylureas 1 to 2%
Insulin 1.5 to 3.5%
1
Glinides 1 to 1.5%
Thiazolidinediones 0.5 to 1.4%
-Glucosidase inhibitors 0.5 to 0.8%
GLP-1 agonist 0.5 to 1.0%
Pramlintide 0.5 to 1.0%
DPP-IV inhibitors 0.5 to 0.8%
GHS
GHS
+
monoterapi
Catatan: GHS
1. GHS = gaya hidup sehat +
2. Dinayatakan gagal bila
terapi selama 2-3 bulan
Kombinasi 2 OHO
pada tiap tahap tidak
mencapai target terapi GHS
HbA1c <7% Jalur pilihan alternatif, bila:
3. Bila tidak ada -tidak terdapat insulin +
pemeriksaan HbA1c -diabetisi betul-betul menolak Kombinasi 2 OHO
dapat dipergunakan insulin +
pemeriksaan glukosa -kendali glukosa belum
darah optimal Basal insulin
Rata-2 hasil pemeriksaan
beberapa kali gukosa
darah sehari yang
dikonversikan ke HbA1c GSH
menurut kriteria ADA, +
2010 Insulin intensif*
Kombinasi 3 OHO
GHS GHS
Gaya Hidup +
Sehat
Monoterapi GHS
Penurunan +
berat badan
Met, SU,
Mengatur diit AGI, Glinid, Kombinasi GHS
Latihan TZD,
Jasmani teratur 2 obat +
DPP-IV inh
Met, SU, Kombinasi GHS
AGI, Glinid 3 obat +
Catatan TZD,
1. Dinyatakan gagal bila Met, SU, Kombinasi
DPP-IV inh AGI, Glinid 2 obat
dengan terapi 2-3 bulan
tidak mencapai target TZD, DPP- Met, SU,
HbA1c <7% IV inh
2. Bila tidak ada pemeriksaan
AGI,
HbA1c dapat digunakan Glinid, TZD
pemeriksaan glukosa + GHS
darah. Rata-rata glukosa
darah sehari dikonversikan Basal Insulin +
ke HbA1c menurut kriteria Insulin
ADA 2010 Intensif*
* Insulin intensif : penggunaan insulin basal bersamaan dengan insulin prandial
-Cell Function Continues to Decline Regardless of
Intervention in T2DM
80
-Cell Function (%)*
60
40
20
0
5 4 3 2 1 0 1 2 3 4 5 6
Years Since Diagnosis
T2DM=type 2 diabetes mellitus
*-cell function measured by homeostasis model assessment (HOMA)
Adapted from UKPDS Group. Diabetes. 1995; 44: 12491258.
34
ADOPT Study: Progression of Hyperglycemia in T2DM
7.6
Glycated Hemoglobin (%)
7.2
6.8
0
0 1 2 3 4 5
Years
Glinides
Use with caution in elderly, and in renal and hepatic impairment, watch
SUs
for hypoglycemia
Meglitinides Use with caution in elderly, and in renal and hepatic impairment
TZDs
Contraindicated in severe liver disease, congestive heart failure,
monitor liver enzymes
SUs1
Hypoglycemia, weight gain, hyperinsulinemia a
Meglitinides1
Weight gain, edema, CHF, bone fractures (pioglitazone,
TZDs1-3 rosiglitazone)
Myocardial ischemic events (rosiglitazone)
Diabetes Care 2004; 27: 2628-2635; 5DeFronzo RA, et al. Diabetes Care 2005; 28: 1092-1100; 6Kendall DM, et al. Diabetes Care 2005; 28: 1083-1091;
7Kolterman OG, et al. Am J Health-Syst Pharm 2005; 62: 173-181; 8Byetta US Prescribing Information.
38
Weight Gain is a Common Side Effect of Diabetes
Treatments
-3.80.5
Metformin13
-0.41.7
SUs14
0.94.6
TZDs46
0.33.0
Meglitinides4,7,8
-0.31.9
Metformin + SU13
0.82.1
Metformin + TZD5,6,9
-5 -4 -3 -2 -1 0 1 2 3 4 5
OAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione
1. Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2004. 2. Glucovance [package insert]. Princeton, NJ: Bristol-Meyers
Squibb Company; 2004. 3. Metaglip [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2002. 4. Malone M. Ann Pharmacother. 2005; 39:
20462055. 5. Actos [package insert]. Indianapolis, Ind: Eli Lilly and Company; 2004. 6. Avandia [package insert]. Research Triangle Park, NC:
GlaxoSmithKline; 2005. 7. Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004. 8. Prandin [package insert].
Princeton, NJ: Novo Nordisk, Inc; 2004. 9. Avandamet [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.
39
Hypoglycemia is Common with SUs
25
Incidence of Hypoglycemia (%)
21.3%
20
15.3%
15 14%
11%
10
5%
5 2.9%*
0
Glyburide1 Chlorpropamide2 Glibenclamide3 Glimepiride3 Gliclazide4 Glipizide5
Sulfonylureas
Insulin
T2DM
Incretin
Further impaired
response Hyperglycemia
islet function
diminished
Glucagon
DPP-4 inhibitor
Insulin
Incretin
Improved islet Improved
activity
function glycemic control
prolonged
Glucagon
DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus
Adapted from Unger RH. Metabolism. 1974; 23: 581593. Ahrn B. Curr Enzyme Inhib. 2005; 1: 6573.
44
45
Trend of OAD usage in Indonesia 2010 -2011
SAXA 5 mg Placebo
A1C, %* FPG, mg/dL PPG, mg/dL
n= 103 92 105 92 84 71
Baseline Mean 8.0 7.9 171 172 278 283
0.6 3030
0.19 2020 6.1
0.4
6.1
00
0.0
-10-10 -6.0
-8.7
-0.2 -20-20 -8.7
-0.4 -30-30 -6.0
-0.6
-40
-40
-50 -43.3
-0.8 -0.46 -50
-60
-1.0 -60 -43.3
-70
-1.2 -70-80
0.4 10 1.2
0.13
0.2 0
0 -10
-0.2 -20
-0.4 -30 -22.0
-18.0
-0.6 -40
-0.8 -50
-0.69
-1 -60
-1.2 -70
-58.2
-80
*P<.0001 vs placebo + MET.
1. DeFronzo R et al. Diabetes Care. 2009;32:1649-1655.
2. AstraZeneca. Data on file, Study CV181014.
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48
Saxagliptin + Metformin helps more patients achieve target
HbA1c compared to placebo plus metformin1
50
P<0.0001
Patients reaching HbA1c <7% at week 24 (%)
44%
40
30
20
17%
10
0
Metformin + Metformin +
Placebo Onglyza 5 mg
1. DeFronzo RA, et al. Diabetes Care. 2009;32(9):1649-55.
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49
Saxagliptin + Thiazolidinedione Provides Significant
Reductions in A1C, FPG, and PPG at Week 24
SAXA 5 mg + TZD Placebo + TZD
A1C, %* FPG, mg/dL PPG, mg/dL*
n= 183 180 185 181 134 127
Baseline Mean 8.4 8.2 160 162 303 291
0 10
0
-0.2
-10 -2.8
-0.4 -20
-17.3
-0.3 -30 -14.6
-0.6
-40
-0.8 -50
-60
-1
-0.9
-70
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50
Saxagliptin + TZD results in significant increases in the
percentage of patients reaching HbA1c <7.0%1
50
Patients reaching HbA1c <7% at week 24 (%)
P<0.0013 41.8%
40
30
25.6%
20
10
0
Glitazone + Glitazone +
Placebo Onglyza 5 mg
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51
Saxagliptin + Sulfonylurea Provides Significant
Reductions in A1C, FPG, and PPG at Week 24
SAXA 5 mg + SU Placebo + SU
A1C, %* FPG, mg/dL PPG, mg/dL*
n= 250 264 252 265 202 206
Baseline Mean 8.5 8.4 175 174 315 323
20 7.6
0.7 8.0
0.4 10
0.08 0.7
0 -10
-9.7
-20 -9.7
-0.2
-30
-0.4
-40 -34.0
-0.6 -34.2
-50
-0.8 -60
-0.64
-1 -70
-1.2 -80
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52
Saxagliptin + sulfonylurea results in significant increases in
the percentage of patients reaching HbA1c <7.0%1
50
Patients reaching HbA1c <7% at week 24 (%)
40
30
P<0.0001
22.8%
20
10 9.1%
0
Up-titrated glibenclamide + Glibenclamide +
Placebo Onglyza 5 mg
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53
Low Incidence of Hypoglycemia
With Saxagliptin 5 mg
Confirmed
0.5 0.6 0 0 0.8 0.7
hypoglycemia
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54
Combination Therapy With Saxagliptin 5 mg
Was Weight Neutral
Add-on to MET1 Add-on to TZD2 Add-on to SU3
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55
Adverse Reactions Occurring in 5% of
Patients: Pooled Data From Clinical Trials
% of Patients
SAXA 5 mg Placebo
Add-on therapy and monotherapy* N=882 N=799
Upper respiratory tract infection 7.7 7.6
Urinary tract infection 6.8 6.1
Headache 6.5 5.9
Metformin in drug-nave N=320 N=328
Headache 7.5 5.2
Nasopharyngitis 6.9 4.0
* Data pooled from 5 placebo-controlled trials: 2 monotherapy trials and 1 add-on combination therapy trial with each of the following: metformin,
thiazolidinedione, or glyburide; table shows 24-week data regardless of glycemic rescue.; data from a 24-week, active-controlled trial of
saxagliptin plus metformin verus placebo plus metformin in treatment-nave patients.
OnglyzaTM [package insert]. Princeton, NJ: Bristol-Myers Squibb Company & Wilmington, DE: AstraZeneca Pharmaceuticals LP; July 2009.
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58
Saxagliptin + Metformin vs Glipizide +
Metformin: 52-Week Noninferiority Trial
SAXA 5 mg + MET SU + MET
A1C, %* FPG, mg/dL PPG, mg/dL
n= 293 293 424 426 18 17
Baseline Mean 7.5 7.5 162 161 285 280
0.0 20
10
-0.2 0
-10
-0.4 -20 -9.5
-15.6
-30
-0.6 -40
-50
-60
-0.8
-0.74 -70 -28.5
-0.80
-80
-1.0
*Per-protocol analysis set (primary analysis); Full analysis set, LOCF; -90 -49.2
Full analysis set, LOCF, oral glucose tolerance test subset.
Gke B, et al. Presented at: 70th Annual Meeting of the American Diabetes Association; June 25-29, 2010. Orlando, FL. Abstract 578-P.
AstraZeneca. Data on file, Study D1680C00001.
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59
Saxagliptin + Metformin vs Sulfonylurea +
Metformin: Difference in Hypoglycemia
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60
Saxagliptin + Metformin vs Sulfonylurea +
Metformin: Difference in Weight Gain
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61
Conclusions
There is a need for a large proportion of
patients to be adjusted to more intensive
pharmacotherapy
Traditional oral treatments of T2DM do not
address the key driver of T2DM: the sensitivity
the -cell and -cell to glucose
Saxagliptin - DDP-4 inhibitor as monotherapy
or add on, provided statistically and clinically
important reductions in glyceamia parameters
(HbA1c, FPG, PPG) with lower incidence of
Hypoglycemia.