The document discusses new perspectives on oral medications for diabetes, summarizing findings from major clinical trials such as DCCT, UKPDS, ACCORD, and ADVANCE on the benefits of intensive glycemic control in reducing complications as well as risks such as hypoglycemia and increased mortality. While intensive control can slow disease progression, safety must be considered given risks of severe hypoglycemia and potential increased cardiovascular mortality with very tight glycemic control. Lifestyle modifications and certain anti-diabetic agents may help prevent diabetes development and complications with lower risks than intensive insulin therapy.

1. 糖尿病口服藥物新思維
內分泌新陳代謝科
林文玉醫師

2. 視網膜病變的流行率: NHANES III
A1C 2hPG FPG
18
16
14
Retinopathy (%)
12
10
8
6
4
2
0
FPG (mg/dl) 42 87 90 93 96 98 101 104 109 120
2hPG (mg/dl) 34 75 86 94 102 112 120 133 154 195
A1C (%) 3.3 4.9 5.1 5.2 5.4 5.5 5.6 5.7 5.9 6.2
Diabetes Care, 20(7):1183-1997.

3. 血糖是主角嗎?
Diabetes Care 32: 2007-2032, 2009

4. Association of A1c and Fasting Plasma
Glucose levels With Diabetes Retinopathy
Diabetes Care 32: 2007-2032, 2009

5. Glycemic Thresholds for Diabetes- Specific
Retinopathy
Diabetes Care 34:145–150, 2011

6. 從大型臨床研究學到什麼?
• DCCT and EDIC
• UKPDS and extended study
• ACCORD
• ADVANCE
• VADT

7. Complications (DCCT)
15
13
Retinop
11
9
RELATIVE RISK
Neph
7
5 Neurop
3
1
6 7 8 9 10 11 12
Mean A1C
DCCT Research Group, N Engl J Med 1993, 329:977-
986.

8. DCCT: intensive control reduces
complications in type 1 diabetes
Conventional versus intensive insulin
therapy (n = 1,441)
11
0
10 Conventional treatment (n =
730)
9 20
Reduction (%)
HbA1c (%)
8 P < 0.001 39%
7
40
54% 54%
6 Intensive treatment 60%
60
0
(n = 711)
76%
0 1 2 3 4 5 6 7 8 9 10
80
Year of study
*Subdivided to primary and secondary prevention of retinopathy. Age 27 years, HbA1c 8.8%.
Insulin dose (U/kg/d) 0.62 (primary), 0.71 (secondary).
DCCT Research Group. N Engl J Med 1993; 329:977–986.

9. DCCT/EDIC: long-term follow-up and
legacy effect
9 Glucose
Conventional treatment similar BUT
CV events
8
still higher
HbA1C (%)
Intensive treatment
7
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years
DCCT (intervention period) EDIC (observational follow-up)
0.06
Cumulative incidence of
non-fatal MI, stroke or
57% risk reduction in non-fatal MI, stroke or CVD death* Conventional
0.04
treatment
death from CVD
0.02 Intensive
treatment
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years
DCCT (intervention period) EDIC (observational follow-up)
*Intensive vs conventional treatment. DCCT Research Group. N Engl J Med 1993; 329:977–986.
Nathan DM, et al. N Engl J Med 2005; 353:2643–2653.

10. UKPDS
Glucose Control Study Summary
The intensive glucose control policy maintained a lower HbA1c by
mean 0.9 % over a median follow up of 10 years from diagnosis of
type 2 diabetes with reduction in risk of:
12% for any diabetes related endpoint p=0.029
25% for microvascular endpoints p=0.0099
16% for myocardial infarction p=0.052
24% for cataract extraction p=0.046
21% for retinopathy at twelve years p=0.015
33% for albuminuria at twelve years p=0.000054

11. UKPDS: intensive control reduces
complications in type 2 diabetes
9 0
Conventional
Relative risk reduction (%)
6%
–5
Median HbA1C (%)
P = 0.44
8 –10 12%
–15 P = 0.029 16%
Intensive
–20 P = 0.052
7 25%
–25
6.2% = upper limit of normal range P = 0.0099
–30
6
0
0 5 10 15
UKPDS randomized years
Reproduced from UKPDS Study Group. Lancet 1998; 352:837–853.

12. UKPDS: long-term follow-up and legacy effect
Intervention
ends
UKPDS UKPDS
Active Follow-up 0
10
9 –5
Conventional 9%
Median HbA1c (%)
–10 P = 0.040
Relative risk reduction (%)
13%
8 Biochemical
15%
data no longer P = 0.007
collected
–15
P = 0.014
7 Intensive
–20
24%
6 –25 P = 0.001
0 5 10 15 5 10 –30
1977 1997 2007
Years from randomization
Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247.
Holman RR, et al. N Engl J Med 2008; 359:1577–1589.

13. Legacy Effect
Differences in glycosylated hemoglobin (HbA1c) levels
between intensively and conventionally treated patients
disappeared within 1 year of the trial’s end.
Nevertheless, outcomes continued to favor the intensively
treated group: During post-trial follow-up, the significant
relative reduction in microvascular disease persisted, and
significant reductions in myocardial infarction and all-cause
mortality emerged in the intensive-control group.

14. The Action to Control Cardiovascular risk
in Diabetes study group ( ACCOD trial )

15. ACCORD Results

17. Outcomes: Summary of ACCORD, ADVANCE and
VADT
*ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial halted intensive glucose group (2/6/08)
† significant difference between intensive and standard group
ACCORD Study Group, NEJM 2008, 358:2545-2559.
ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572.
VADT Study Results ADA Scientific Session San Francisco, 2008
In Press, Diabetes Obesity and Metabolism, 2008

18. Adverse Outcomes:
ACCORD, ADVANCE and VADT
ACCORD Study Group, NEJM 2008, 358:2545-2559.
ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572.
VADT Study Results ADA Scientific Session San Francisco, 2008
In Press, Diabetes Obesity and Metabolism, 2008

19. Intervention Works...but at a
Price: DCCT and UKPDS
Severe Hypoglycemia
100 DCCT (Type 1) UKPDS (Type 2)
Major Episodes
5
80
Major Episodes Incidence (%)
Rate/100 Patient Years
4
60
Intensive 3
Intensive
40
2
20 1
Conventional Conventional
0
0
5 6 7 8 9 10 11 12 13 14 0 3 6 9 12 15
HbA1c (%) During Study Years from Randomization
DCCT Research Group, Diabetes. 1997;46:271-286 UKPDS Group (33), Lancet. 352: 837-853, 1998

20. Asymptomatic Episodes of
Hypoglycemia May Go Unreported
100
75 • In a cohort of patients with
62.5
55.7 diabetes, more than 50% had
Patients, %
46.6 asymptomatic (unrecognized)
50
hypoglycemia, as identified by
continuous glucose monitoring.
25
• Other researchers have
n=70 n=40 n=30
0 reported similar findings
All patients Type 1 Type 2
with diabetes diabetes
diabetes
Patients With ≥1 Unrecognized Hypoglycemic Event, %
1. Chico A et al. Diabetes Care. 2003;26(4):1153–1157. Permission pending.
2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494.
3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.

21. Why was mortality increased in
intensive treatment group in ACCORD?
• Not certain
• Speed of HbA1c reduction ( 1.4 % vs. 0.6% in 4 months)
• Drug combinations
• Unidentified hypoglycemia
• Weight gain
• Hypoglycemia unawareness (associated cardiac autonomic
neuropathy)
Analysis proves that the increased mortality rates are not related to
1. Specific OAD ( Rosiiglitazone, SU , Insulin etc)
2. Changes in other medications( Statins, Aspirin etc)
Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD,
ADVANCE, and VA Diabetes Trials Diabetes Care January 2009 vol. 32 no. 1 187-192

22. Increased Mortality, Myocardial Infarction, and
Hypoglycemia With Intensive Therapy:
ACCORD Trial
Mortality (% per year)
≥1 severe hypoglycemia
(n = 705)
3.1
No hypoglycemia
1.2
(n = 9,546)
a
Defined by requirement for medical or paramedical intervention, with
documented glucose <50 mg/dL and relief by parenteral or oral glucose
or by glucagon.
1 Bloomgarden ZT. Diabetes Care. 2008;31(9):1913–1919. 2. Dluhy RG, McMahon GT. N Engl J Med. 2008;358:2630–2633.

24. Gl

26. Type 2 Diabetes Prevention
• Finnish Diabetes Prevention Study (DPS): randomized 522 overweight
(average BMI 31 kg/m2) middle-aged individuals, weight loss 5% and exercise with
at least 30 minutes per day of combined aerobic activity and resistance training; At
the 3-year follow-up, the group reduced their cumulative risk by 58% compared to
the control subjects.
• Diabetes Prevention Program (DPP): randomized 3,234 overweight
participants with IGT and elevated fasting glucose from 22 sites in the USA to one
of three interventions: intensive lifestyle intervention (ILS), metformin, or placebo.
58% ( ILS ), 31% ( Metformin )
• Study to Prevent Non-Insulin-Dependent Diabetes (STOP-NIDDM) : 25%
reduction in incidence
• Diabetes Reduction Assessment with Ramipril and Rosiglitazone
Medication (DREAM) trial: 62% reduction
• China Da Qing Diabetes Prevention Study: 43.8% in the diet group, 41.1% in
the exercise group, and 46% in the diet-plus-exercise group .

27. Whether lower HbA1c relates to lower
mortality rate in cases of IGT, or HBA1C less
than 6.5%, by lifestyle modification or non-
insulin secretagogue anti-diabetic agents?
Unknown

28. Summary
• DM development is preventable via life style modification or
anti-diabetic agents such as Metformin, TZD and Acarbose.
• Intensive glycemic control slows down progress of diabetic
complications, microvascular and probably macrovascular.
• Intensive glycemic control has patient risk hypoglycemia, and
risk higher CV mortality.
• Severe hypoglycemia increased CV mortality 3.1X than
otherwise.
• Insulin sensitizer, acarbose, or DDP-IV inhibitor causing rare
hypoglycemia, benefit patient with early DM, even HbA1c <
6.5% ?
• Safety is a dominant issue in the following era.

29. Weight gain
DM in itself:
1. Physical inactivity
2. Hyperinsulinemia
3. Delay satiety and easily hungry ( polyphagia )
Hypoglycemic agents related:
1. Hyperinsulinemia ( SU, glitinide, insulin )
2. Hypoglycemia with preventive intake ( insulin, SU, glinide )
3. Fluid water retention ( TZD, distal convoluted tubule, ENAC;
insulin )
4. Adipogenesis, and transdifferentiation from myocyte ( TZD ).
PNAS Vol. 92, pp. 9856-9860, October 1995 Cell Biology

30. UKPDS 33: intensive therapy was associated
with weight gain
10.0 Insulin
Chlorpropamide
Glibenclamide
Mean change in weight (kg)
7.5
Conventional
5.0
2.5
0
0 3 6 9 12 15
Years from randomisation
Dashed lines indicate patients followed for 10 years
Solid lines indicate all patients assigned to regimen
Adapted from: Lancet 1998;352:837–53

31. RESULTS— Individuals trying to lose weight had a 23% lower mortality rate (hazard rate
ratio [HRR] 0.77, 95% CI 0.61– 0.99) than those who reported not trying to lose weight. This
association was as strong for those who failed to lose weight (0.72, 0.55– 0.96) as for those
who succeeded in losing weight (0.83, 0.63–1.08). Trying to lose weight was beneficial for
overweight (BMI 25–30 kg/m2) individuals (0.62, 0.46–0.83) but not for obese (BMI 30)
individuals (1.17, 0.72–1.92). Overall weight loss, without regard to intent, was associated
with an increase of 22% (1.22, 0.99 –1.50) in the mortality rate. This increase was largely
explained by unintentional weight loss, which was associated with a 58% (1.58, 1.08 –2.31)
higher mortality rate.
Diabetes care 27:657-662, 2004

32. Satiety
• Decline of beta-cell function: impaired secretion of insulin and
hIAPP ( Amylin).
• Impaired secretion of CCK-8
• Impaired GLP-1 secretion
• Lower level of PYY
• Rapid gastric emptying in spite of solid and liquid meals, in early
type II diabetic patients.
• Non-suppressible ghrelin level after feeding

34. Does ghrelin explain accelerated gastric
emptying in the early stages of type 2 DM?
Am J Physiol Regul Integr Comp Physiol 294: R1807–R1812, 2008.

35. Regulation of gastric emptying
DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008

36. Melanocortin System and Regulation of Appetite
And Body Weight
NTS
(-)

37. Central Melanocortin System and
AgRP/NPY
• This system is involved in body weight regulation through its role in appetite and energy
expenditure via leptin, grhelin and Agouti related protein. It receives inputs from hormone,
nutrients and afferent neural inputs, and is unique in its composition of fibers which express
both agonists and antagonists of melanocortin receptors.
• The melanocortin receptors, MC3-R and MC4-R, are directly positive linked to metabolism
and to lowering body weight. These receptors are activated by the peptide hormone α-MSH
(melanocyte-stimulating hormone) and antagonized by the agouti-related protein.
• Agouti-related protein also called Agouti-related peptide (AgRP) is a neuropeptide produced
in the brain by the AgRP/NPY neuron. It is only synthesised in NPY containing cell bodies
located in the ventromedial part of the arcuate nucleus in the hypothalamus. AgRP is co-
expressed with Neuropeptide Y and works by increasing appetite and decreasing metabolism
and energy expenditure ( increased weight ). It is one of the most potent and long-lasting of
appetite stimulators

38. Ominous Octet
Beta cell, fat, muscle, liver, gut, alfa cell, kidney, brain
Ralph A. DeFronzo Diabetes, Vol. 58, April 2009

39. Increased renal glucose reabsorption
 In animal models of both type 1 and type 2 diabetes, the maximal renal
tubular reabsorptive capacity, or Tm, for glucose is increased. In humans
with type 1 diabetes, Mogensen et al. have shown that the Tm for
glucose is increased.
 Cultured human proximal renal tubular cells from type 2 diabetic
patients demonstrate markedly increased levels of SGLT2 mRNA and
protein and a fourfold increase in the uptake of -methyl-D-
glucopyranoside (AMG), a nonmetabolizeable glucose analog
 Thus, an adaptive response by the kidney to conserve glucose, which is
essential to meet the energy demands of the body, especially the brain
and other neural tissues, which have an obligate need for
glucose, becomes maladaptive in the diabetic patient
Ralph A. DeFronzo Diabetes, Vol. 58, April 2009

40. Cerebral insulin resistance
After glucose ingestion, two hypothalamic areas with consistent
inhibition were noted: the lower posterior hypothalamus, which
contains the ventromedial nuclei, and the upper posterior
hypothalamus, which contains the paraventricular nuclei. In both
of these hypothalamic areas, which are key centers for appetite
regulation, the magnitude of the inhibitory response following
glucose ingestion was reduced in obese, insulin-resistant, normal
glucose tolerant subjects, and there was a delay in the time taken
to reach the maximum inhibitory response, even though the
plasma insulin response was markedly increased in the obese
group.
Ralph A. DeFronzo Diabetes, Vol. 58, April 2009

41. Pathogenesis of type 2 DM:
Implication for Therapy
 Effective treatment of type 2 diabetes requires multiple
drugs used in combination to correct multiple
pathophysiological defects.
 Treatment should be based on known pathogenic
abnormalities and not simply on reduction of A1C.
 Therapy must be started early in the natural history of type 2
diabetes to prevent progressive beta-cell failure.

42. In Clinical Aspects
“Ideal oral drug”
• Targeting underlying pathogenesis, including lowering insulin
resistance ( Metfromin, TZD ), recovering beta-cell function
( SU, glinide, DPP-4i ) and reducing hepatic glucose production
( Metformin ).
• Safe, minimal hypoglycemia ( Metformin, TZD, AGI, DPP-
4i,, SGLT-2i )
• No weight gain ( Metfromin, AGI, DPP-4i, SGLT-2i)
• Satiety promotion ( ? AGI, DPP-4i,Metformin )
• Weight losing ( MC4R agonist ? Metformin, DPP 4i, AGI, SGLT-
2i )
• Beta-cell neogenesis ( ? TZD, DPP 4i )
• Reduced CV risk ( Metformin, AGI, DPP 4i )

43. Incretin-based therapy是不是糖尿病用藥的”藍海” ?

44. IN-CRET-IN
INtestine seCRETion INsulin
Definition: gut derived factors that increase glucose
stimulated insulin secretion
Two hormones: (1) glucagon-like peptide-1 (GLP-1)
(2) glucose-dependent insulinotropic polypeptide
(GIP)
Source :Creutzfeldt Diabetologia 28: 5645 1985

45. Incretin effect on insulin secretion
80 Control subjects (n=8) 80 People with Type 2 diabetes (n=14)
60 60
Insulin (mU/l)
Insulin (mU/l)
40 Incretin 40
effect
20 20
0 0
0 60 120 180 0 60 120 180
Time (min) Time (min)
Oral glucose load
Intravenous glucose infusion
Nauck et al. Diabetologia. 1986

46. What is GLP-1?
Increased insulin response Key observations
80 • A 31 amino acid peptide
• Cleaved from proglucagon in
60 L-cells in the GI-tract (and neurons in
IR-insulin (mU/l)
hindbrain/hypothalamus)
Incretin
effect • Secreted in response to meal ingestion
40 (direct luminal and indirect neuronal
stimulation)
* *
20 * * * • Member of incretin family (GIP, GLP-1 and
* *
others)
0 • GLP-1 has following effects:
–10 –5 60 120 180 • Glucose-dependently stimulates insulin
Time (min) secretion and decreases glucagon secretion
Insulin response to oral glucose load (50 g/400 • Delays gastric emptying
ml, ●) and during isoglycaemic i.v. glucose infusion
(●)
• Decreases food intake and induces satiety
• Stimulates -cell function and preserves or
increases -cell mass in animal models
Nauck et al. Diabetologia 1986;29: 46–52, *p ≤ 0.05.

47. Effects of GLP-1 on Insulin and Glucagon
Shown to Be Glucose Dependent in Type 2 Diabetes
15.0 Placebo
(mmol/L) GLP-1 infusion
12.5
Glucose
10.0 *
7.5 * *
* *
5.0 * *
Infusion
With hyperglycemia
GLP-1 stimulated insulin
250
(pmol/L)
and suppressed glucagon.
Insulin
200
150
100 * * *
50 * * * * When glucose levels
*
approached normal,
insulin levels declined
Glucagon
(pmol/L)
20
15 and glucagon was no
10 * * * * longer suppressed.
5
0 60 120 180 240
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.
*p<0.05 GLP-1 vs. placebo
Adapted from Nauck MA et al Diabetologia 1993;36:741–744.
11

48. Why not GIP ?

49. Because of its short half-life, native GLP-1 has
limited clinical value
DPP-IV
i.v. bolus GLP-1 (15 nmol/l)
His Ala Glu Gly Thr Phe Thr Ser Asp 1000 Healthy individuals
Intact GLP-1 (pmol/l)
Val Type 2 diabetes
7 9
Ser
500
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Glu
Phe 37
0
Ile Ala Trp Leu Val Lys Gly Arg Gly
–5 5 15 25 35 45
Time (min)
Enzymatic cleavage t½ = 1.5–2.1 minutes
High clearance (i.v. bolus 2.5–25.0 nmol/l)
(4–9 l/min)
Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88: 220–224.

50. GLP-1 enhancement
GLP-1 secretion is impaired in Type 2
diabetes
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues Block DPP-4, the
with longer half-life: enzyme that
• exenatide degrades GLP-1:
• liraglutide • Sitagliptin
• Vildagliptin
• Linagliptin
Injectables
Oral agents
Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

51. DPP-4 Inhibitor – mechanism of action
Glucose-dependent
insulin secretion
ß-cells
Food intake Increases glucose utilisation
by muscle and adipose tissue
Pancreas
α-cells
Glucose-dependent Decreases hepatic glucose release
glucagon suppression improving overall glucose control
Inactive
Active DPP2-4 GLP1-1 (9-36)
Intestine
GLP1-1 (7-36) amide
2 amino acids
DPP-4 cleaved from
inhibitor amino terminus
Source: Adapted from Drucker DJ. Expert Opin Invest Drugs. 2003;12(1):87–100; Ahrén B. Curr Diab Rep.2003;3:365–372
51

52. Sitagliptin Consistently and Significantly Lowers A1C With
Once-Daily Dosing in Monotherapy
18-Week study 24-Week study Japanese study
Change vs
-0.6% -0.79% -1.05%
placebo*
(P<.001) (P<.001) 8.4 (P<.001)
8.4 8.4
8.0
8.0 8.0
A1C (%)
A1C (%)
A1C (%)
7.6
7.6 7.6
7.2
Placebo (n=74) Placebo (n=244) Placebo (n=75)
7.2 Sitagliptin 100 mg (n=168) 7.2 6.8
Sitagliptin 100 mg (n=229) Sitagliptin 100 mg (n=75)
0 6 12 18 0 5 10 15 20 25 0 4 8 12
Time (wk) Time (wk) Time (wk)
*Between group difference in LS means.
Nonaka K et al; A201. Abstracts presented at: 66th Scientific Sessions of ADA; June 9-13, 2006; Washington, DC. 52

53. Sitagliptin Lowers Post-meal Glucose
Excursion and Enhances Insulin Secretion
P<0.05 for between group difference
Japanese Monotherapy Study 70
Placebo Sitagliptin 100 mg qd
60
Baseline Baseline
Plasma Insulin (µU/mL)
Week 12 Week 12 50
40
320
Plasma Glucose (mg/dL)
30
11.7
mg/dL
20
280
10
-69.2
240 mg/dL
0
0 0.5 1.0 2.0 0 0.5 1.0 2.0
0.5
Insulinogenic Index (µU/mg)
Placebo Time (hr)
200 0.4 Sitagliptin 100 mg qd
0.3
160 Placebo Sitagliptin 100 mg qd
0.2
120 0.1
0 0.5 1. 2.0 0 0. 1. 2.0
0 5 0 0
Time (hr)
P<0.001 for difference in change from baseilne in 2-hr PPG Week 0 Week 12
Between group difference (P<0.001)
Insulinogenic index = ∆ I30 / ∆ G30
Nonaka K et al. A201. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC. 53

54. Sitagliptin Improved Markers of Beta-Cell
Function: 24-Week Monotherapy Study
Proinsulin/insulin ratio HOMA-β
0.48 75
p< 0.001* p< 0.001*
0.46 70
0.44 65
0.42 60
0.4 55
0.38 50
0.36 45
0.34 40
0.32 35
0.3 30
Placebo Sitagliptin Placebo Sitagliptin
Red = baseline ∆ from baseline vs = 13.2 +/- 3.3
∆ from baseline vs pbo = 0.078 Yellow = Week 24
(95% CI -0.114, -0.023) pbo (95% CI 3.9, 21.9)
* P value for change from baseline compared to placebo
Aschner P et al. PN021; Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC. 54

55. GLP-1R expression in mouse
cardiac and vascular tissue
Polycloal Anti-GLP-1R Ab Pre-absorption Mesenteric arerty
Anti-SM (red )
Anti-GLP-1 (green )
Nuclear stain ( blue )
In media SM
Endocardium
Circulation. 2008;117:2340-2350

56. Extracellular signal-regulated kinases
Endocrine Review, April 2012, 33(2): 187-215

57. Linagliptin significantly lowers albuminuria vs.
placebo in pooled phase III study data
Albuminuria: 24 weeks treatment
Effect of linagliptin on albuminuria in humans
• Early marker for renal
damage Adjusted mean change in albuminuria (24 weeks)
• Marker for endothelial Placebo Lina
dysfunction
• Cardiovascular risk factor
-4%
• Lowering of albuminuria
might be associated with
-29%
kidney & CV protection p < 0.05
-33%
n 59 168
-29% in albuminuria vs. placebo
after 24wks treatment*
* This was achieved on the background of ACE/ARB, n=2472
Poster: 953-P, American Diabetes Association 72nd Scientific Sessions, June 8–12, 2012, Philadelphia, USA.

58. DDP-4 inhibitors Control
Risk Ratio (95% CI),
Adverse events Incretin
Mean % (95% CI) Mean % (95% CI)
Achieving Control Achieving Control
vs. Control
Hypoglycemia
All DDP4 inhibitors vs comparator 0.97(0.50-1.86) 1.6 (0.7-3.2) 1.4 (0.6-3.4)
Sitagliptin vs comparator 0.92 (0.30-2.87) 1.8 (0.9-3.3) 1.5 (0.2-8.5)
Vildagliptin vs comparator 0.84 (0.50-1.19) 1.4 (0.4-4.8 1.2 (0.3-5.7)
Nausea
All DDP4 inhibitors vs comparator 0.89 (0.58-1.36) 2.7 (2.1-3.4) 3.1 (2.0-4.7)
Sitagliptin vs comparator 1.46 (0.88-2.43) 2.1 (1.4-3.0) 1.4 (0.7-2.4)
Vildagliptin vs comparator 0.57 (0.37-0.88) 3.4 (2.6-4.6) 5.2 (3.6-7.4)
Vomiting
All DDP4 inhibitors vs comparator 0.69 (0.42-1.15) 1.3 (0.8-2.2) 1.5 (0.9-2.6)
Sitagliptin vs comparator 0.86 (0.45-1.65) 1.1 (0.6-2.0) 1.2 (0.8-1.9)
Vildagliptin vs comparator 0.49 (0.21-1.1.11) NR NR
Diarrhea
All DDP4 inhibitors vs comparator 0.80 (0.42-1.54) 3.8 (2.8-5.1) 4.0 (1.8-4.6)
Sitagliptin vs comparator 1.21 (0.81-1.80) 3.6 (2.5-5.1) 2.8 (1.8-4.6)
Vildagliptin vs comparator 0.34 (0.14-0.80) 4.0 (2.0-8.0) 9.9 (2.7-30.7)
DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval
Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis.
JAMA. 2007;298:194-206.

59. Adverse events in patients with type 2 diabetes treated
with DDP-4 inhibitors (Sitagliptin and Viltagliptin)*
DDP-4 inhibitors Control
Adverse events Risk Ratio (95% CI),
Mean % (95% CI) Mean % (95% CI)
Incretin
Achieving Control Achieving Control
vs. Control
Abdominal pain
All DDP4 inhibitors vs comparator 0.73 (0.36-1.45) 2.4 (1.8-3.2) 3.2 (1.7-5.7)
Sitagliptin vs comparator 0.92 (0.47-1.80) 2.5 (1.8-3.3) 2.6 (1.7-3.9)
Vildagliptin vs comparator 0.32 (0.16-0.66) NR NR
Couph
All DDP4 inhibitors vs comparator 1.07 (0.65-1.78) 2.9 (2.1-4.0) 2.4 (1.7-3.5)
Sitagliptin vs comparator 0.95 (0.54-1.78) 2.5 (1.7-3.5) 2.6 (1.8-3.9)
Vildagliptin vs comparator 1.86 (0.57-6.11) 4.8 (2.6-8.6) 1.7 (0.7-4.1)
Influenza
All DDP4 inhibitors vs comparator 0.87 (0.64-1.19) 4.1 (3.3-5.1) 4.4 (3.4-5.8)
Sitagliptin vs comparator 0.95 (0.65-1.39) 4.0 (3.1-5.1) 5.3 (3.7-7.4)
Vildagliptin vs comparator 0.73 (0.42-1.27) 4.2 (2.5-7.1) 6.1 (5.0-7.4)
Nasopharyngitis
All DDP4 inhibitors vs comparator 1.17 (0.98-1.40) 6.4 (5.1-7.8) 4.5 (3.0-6.7)
Sitagliptin vs comparator 1.38 (1.06-1.81) 5.3 (3.5-7.9) 7.3 (6.0-8.9)
Vildagliptin vs comparator 1.02 (0.80-1.29) 7.3 (5.8-9.3) 6.4 (4.9-8.4)
DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval
* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.

60. Adverse events in patients with type 2 diabetes
treated with DDP-4 inhibitors (Sitagliptin and Viltagliptin)*
DDP-4 inhibitors Control
Adverse events Risk Ratio (95% CI),
Mean % (95% CI) Mean % (95% CI)
Incretin
Achieving Control Achieving Control
vs. Control
Upper respiratory tract infection
All DDP4 inhibitors vs comparator 0.99 (0.81-1.21) 6.3 (5.1-7.7) 6.4 (4.9-8.4)
Sitagliptin vs comparator 1.09 (0.84-1.43) 5.7 (4.0-8.0) 4.7 (2.8-8.0)
Vildagliptin vs comparator 0.88 (0.65-1.18) 6.8 (5.3-8.6) 8.0 (6.5-9.8)
Sinusitis
All DDP4 inhibitors vs comparator 0.61 (0.34-1.12) 2.0 (1.3-3.1) 3.4 (2.4-4.8)
Sitagliptin vs comparator 0.81 (0.41-1.58) 2.2 (1.4-3.4) 2.5 (1.6-3.9)
Vildagliptin vs comparator 0.20 (0.05-0.78) 1.2 (0.3-4.1) 5.4 (3.1-9.2)
Urinary tract infection
All DDP4 inhibitors vs comparator 1.52 (1.04-2.21) 3.2 (2.3-4.5) 2.4 (1.8-3.2)
Sitagliptin vs comparator 1.42 (0.95-2.11) 3.1 (2.1-4.6) 2.6 (1.9-3.5)
Vildagliptin vs comparator 2.72 (0.85-8.68) 3.6 (1.5-8.3) 1.3 (0.5-3.3)
Headache
All DDP4 inhibitors vs comparator 1.38 (1.10-1.72) 5.1 (4.1-6.4) 3.9 (3.1-4.8)
Sitagliptin vs comparator 1.24 (0.82-1.87) 3.6 (2.9-4.5) 3.1 (1.9-4.9)
Vildagliptin vs comparator 1.47 (1.12-1.94) 6.3 (5.0-8.0) 4.4 (3.4-5.6)
DPP4: dipeptidyl peptidase 4 ; Comparator :placebo ororal hypoglycemic agent or insulin; CI :confidence interval
* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.

61. Sitagliptin or sitagliptin/metformin
(marketed as Januvia and Janumet)
Acute pancreatitis warning
 In 2009, FDA has completed a review of 88 cases of acute pancreatitis in
patients using sitagliptin or sitagliptin/metformin. The cases were
reported to FDA’s Adverse Event Reporting System (AERS) between
October 2006 and February 2009.
 Hospitalization: 66% of the patients, 4 to the intensive care unit. Two
cases of hemorrhagic or necrotizing pancreatitis.
 21% of pancreatitis cases occurred within 30 days of starting sitagliptin,
sitagliptin/metformin.
 The most common adverse events were abdominal pain, nausea and
vomiting.
FDA , U.S. Food and Drug Adminstration

62. Summary about DPP 4i
 Smart way of insulin secretion with minimal risk of
hypoglycemia
 No need of preventive intake for hypoglycemia, so as to
prevent from weight gain.
 Inducing satiety and reduced intake
 Delay gastric emptying, minimizing hungry sensation
 Acceptable side effect profile
 No human evidence of cancer risk now
 Preliminary data of CV and renal benefits available