Recent studies have highlighted the growing global burden of type 2 diabetes, with over 600 million people projected to have the disease by 2045. In particular, Egypt will face explosive growth in cases. While control of blood sugar levels is important for reducing complications, most patients do not achieve treatment goals. Intensifying treatment in a timely manner when blood sugar is poorly controlled can reduce cardiovascular risks. Inertia on the part of both physicians and healthcare systems often limits timely treatment changes needed to improve outcomes for patients with type 2 diabetes.
6. 6
Contents
Overview of diabetes burden and some basic data
Clinical efficacy and safety of sitagliptin therapy in a
broad range of patients with T2DM:
–In newly-diagnosed patients, as initial treatment in
combination with metformin
–In patients inadequately controlled on metformin alone
–In Patients with renal insufficiency
–In elderly patient
Safety of sitagliptin therapy
T2DM = type 2 diabetes mellitus.
7. 7
The Global Burden of Diabetes Is Projected to Grow
to More Than 600 Million People by 20451
Adapted with permission from the International Diabetes Foundation.1
1. International Diabetes Federation. IDF Diabetes Atlas. 8th ed. International Diabetes Federation; 2017.
Europe
2017: 58 million
2045: 67 million
Middle East and
North Africa
2017: 39 million
North America
and Caribbean
2017: 46 million
2045: 62 million
South and
Central America
2017: 26 million
2045: 42 million
Southeast Asia
2017: 82 million
2045: 151 million
Africa
2017: 16 million
2045: 41 million
Western Pacific
2017: 159 million
2045: 183 million
Estimated number of people aged 20–79 years with diabetes per region in 2017 and 2045
9. 9
Egypt will face explosive growth of diabetes
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
9,000
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b
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a
B
a
h
r
a
i
n
2003
2025
Due to a rapidly increasing & ageing population, Egypt will have
the largest number of people with diabetes in the region by
2025
Source:
Diabetes
Atlas,
2nd
edition,
IDF
11. 11
aHbA1c ≤6.5%.
HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.
Liebl A, et al. Diabetologia. 2002; 45: S23–S28.
• In the CODE study of a European cohort of over 7000 patients
with T2DM, ONLY 31% of patients had adequate glycaemic
control
Patients
with
adequate
glycaemic
control
(%)
Approximately 70% of patients with T2DM do not reach
HbA1c goals
12. 52.2
39.7
48.4
41.5 40.6
43.8 41.9
26.2
33.7
23.4
41.8
26 27.7
0
10
20
30
40
50
60
70
80
90
100
Country
HbA
1c
Attainment,
%
US (n=1,444)
AUS (n=146)
BEL (n=173)
FRA (n=144)
GER (n=256)
GRE (n=176)
NOR (n=142)
RUS (n=95)
SPA (n=182)
SWE (n=164)
SWI=205)
TUR (n=210)
UK (n=153)
EURIKA (Europe)2: May 2009–January 2010
HbA1c <6.5%
EURIKA=European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice; NHANES=National Health and Nutrition Examination Survey.
1. Ali MK et al. N Engl J Med. 2013;368:1613–1624. 2. Banegas JR et al. Eur Heart J. 2011;32:2143–2152.
NHANES (US)1: 2007–2010
HbA1c <7.0%
Majority of type 2 diabetes patients
are not at HbA1c goal
14. 14
Diabetes Kills
Overall, 75% of patients with
type 2 diabetes die from cardiovascular
disease1
1-Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences.
15. 15
Diabetes is a Serious Chronic Disease
1 Fong DS, et al. Diabetes Care. 2003; 26 [Suppl. 1]:S99–S102.
2 Molitch ME, et al. Diabetes Care. 2003; 26 [Suppl.1]:S94–S98.
3 Kannel WB, et al. Am Heart J. 1990; 120:672–676.
4 Gray RP & Yudkin JS. In Textbook of Diabetes. 1997.
5 Mayfield JA, et al. Diabetes Care. 2003;26 [Suppl. 1]:S78–S79.
Diabetic
retinopathy
Leading cause
of blindness in working-age adults1
Diabetic
nephropathy
Leading cause of
end-stage renal
disease2
Cardiovascular
disease
Stroke
2- to 4-fold increase
in cardiovascular
mortality and stroke3
Diabetic
neuropathy
Leading cause of non-
traumatic lower extremity
amputations5
8/10 diabetic patients
die from CV events4
16. Higher HbA1c Is Associated
With Increased Microvascular
Complications1
aMicrovascular outcomes included retinopathy, nephropathy, and neuropathy.
UKPDS = United Kingdom Prospective Diabetes Study.
1. Reproduced with permission from Stratton IM et al. BMJ. 2000;321:405–412.
Hazard
Ratio
Updated Mean HbA1c
1
10
15
0 5 6 7 8 9 10 11
UKPDS: Microvascular
End Pointsa
37% increase per 1% increase in
HbA1c P<0.0001
0.5
Hazard
Ratio
Updated Mean HbA1c
1
5
0 5 6 7 8 9 10 11
0.5
UKPDS: Fatal and
Nonfatal
Myocardial Infarction
14% increase per 1% increase in
HbA1c P<0.0001
Increasing Macrovascular
Risk with Increasing HbA1c
Has Been Observed1
UKPDS = United Kingdom Prospective Diabetes Study.
1. Reproduced with permission from Stratton IM et al. BMJ. 2000;321:405–412.
17.
18. Delay in Treatment Intensification Increases the
Risks of Cardiovascular Events in Patients with
T2DM
Adapted from Paul SK et al. Cardiovasc Diabetol. 2015 Aug 7;14:100.
Retrospective cohort study (n = 105,477) from the United Kingdom Clinical
Practice Research Datalink
Compared to patients with HbA1c <7%, patients with HbA1c ≥7%,
with a ≥ 12 month delay in receiving treatment intensification had an
increased risk:
MI
67%
HR 1.67
(CI: 1.39,
2.01)*
51%
HR 1.51
(CI: 1.25,
1.83)*
HF
64%
HR 1.64
(CI: 1.40,
1.91)*
CVE
62%
HR 1.62
(CI: 1.46,
1.80)*
MI= myocardial infarction, HF=Heart Failure, CVE= composite MI, Stroke & HF
Retrospective cohort study (n = 105,477) from the United Kingdom Clinical Practice
Research Datalink
Not Proof of Cause and Effect Relationship
* P <0.01
STROKE
20. 20
Multiple Factors Contribute to Clinical Inertia1
Adapted with permission from Reach G et al.
1. Reach G et al. Diabetes Metab. 2017;43:501–511.
Factors
Poor communication between
physician and staff
No clinical guidelines No disease registry
No visit planning
No active outreach
to patients
No decision support
No team
approach to care
30%
50%
20%
Healthcare System-Related
Side effects from
medications
Inability to follow complex
treatment regimens
Lack of acknowledgment
of disease severity
Poor physician–patient
communication
Low health literacy
Reluctance to have
treatments intensified
Patient-Related
Time and resource
constraints
Uncertainty regarding the
reality of poor disease control
and the need to intervene
Concerns relating
to avoidance
of treatment side effects
Underestimation of patient’s
need for therapy
Failure to set and/or monitor
progress toward treatment goals
Physician-Related
Relative
Contributions
21. 21
HbA1c=haemoglobin A1c; OAD, oral antidiabetic drugs.
Jacob AN, et al. Diabetes Obes Metab. 2007; 9:386–393;
Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443;
Wright AD, et al. J Diabetes Complications. 2006; 20: 395–401.
Decreasing HbA1c is associated with increased risks
of hypoglycaemia and weight gain
Weight gain
and
hypoglycaemia
Body
weight
HbA1c
Plasma
glucose
33. The Incretin Effect in Healthy Subjects
C-Peptide
(nmol/L)
Time (min)
0.0
0.5
1.0
1.5
2.0
Incretin Effect
*
*
*
*
*
*
*
Oral Glucose
Intravenous (IV) Glucose
Plasma
Glucose
(mg/dL)
200
100
0
Time (min)
60 120 180
0
60 120 180
0
N = 6; Mean (SE); *P0.05
Data from Nauck MA, et al. J Clin Endocrinol Metab 1986;63:492-498.
34.
35. Insulin
(mU/L)
The Incretin Effect Is Reduced in
Type 2 Diabetes
Time (min)
Healthy Subjects
Insulin
(mU/L)
Time (min)
Type 2 Diabetes
N = 22; Mean (SE); *P0.05
Data from Nauck M, et al. Diabetologia 1986;29:46-52.
0
20
40
60
80
0 60 120 180
0
20
40
60
80
0 60 120 180
Intravenous (IV) Glucose
Oral Glucose
Incretin Effect
Incretin Effect
*
*
*
*
*
*
*
*
*
*
36. Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
Oral Glucose Tolerance Test
Glucose
(mg/dL)
50 g glucose
0
50
100
150
200
-30 0 30 60 90 120 150 180 210
Time (min)
Insulin
(pmol/L)
0
100
200
300
400
-30 0 30 60 90 120 150 180 210
Time (min)
Insulin Secretion Increases
Dramatically in Response to Oral
Glucose Ingestion
37. Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
OGTT and Matched IV Infusion
Glucose
(mg/dL)
0
50
100
150
200
-30 0 30 60 90 120 150 180 210
Time (min)
Insulin
(pmol/L)
0
100
200
300
400
-30 0 30 60 90 120 150 180 210
Time (min)
Proof of a Gastrointestinal ‘Incretin
Effect’: Different Responses to Oral vs.
IV Glucose
Oral IV
38. Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
OGTT and Matched IV Infusion
Glucose
(mg/dL)
0
50
100
150
200
-30 0 30 60 90 120 150 180 210
Time (min)
Insulin
(pmol/L)
0
100
200
300
400
-30 0 30 60 90 120 150 180 210
Time (min)
Proof of a Gastrointestinal ‘Incretin Effect’: Different
Responses to Oral vs. IV Glucose
Oral IV
39. In patients with Type 2 DM
In patients with Type 2 diabetes, incretin effect is
either greatly impaired or absent, and it is
assumed that this could contribute to the inability
of these patients to adjust their insulin secretion to
their needs
Diabetologia (2004) 47:357–366
41. The two main candidate molecules
that fulfill criteria for an incretin are
glucagon-like peptide-1 (GLP-1) and
Gastric inhibitory peptide (aka
glucose-dependent insulinotropic
peptide or GIP).
42. What are incretins?
Gastric Inhibitory Polypeptide
(GIP)
• Secreted by the K cells of the proximal gut. However,
type 2 diabetes patients are resistant to its action (high
blood level), making it a less attractive therapeutic target.
43. What are incretins?
Glucagon-like peptide-1 (GLP-1)
• a 30-amino acid peptide secreted in response to the oral
ingestion of nutrients by L cells, primarily in the ileum
and colon.
• There are GLP-1 receptors in islet cells and in the
central nervous system, among other places.
• GLP-1 is metabolized by the enzyme dipeptidyl
peptidase-IV (DPP-IV) .
44. The GLP-1 receptor is expressed on α and β cells of
the pancreas, as well as in peripheral tissues such as
the nervous system, heart, kidney, lung, and
gastrointestinal tract.
Whereas the GIP receptor is predominantly
expressed on islet β cells and to some extent in
adipose tissue and the central nervous system.
Incretins : Potentiate glucose-dependent insulin
secretion (2)
Clinical Therapeutics/Volume 33, Number 5, 2011
46. GLP-1 Modulates Numerous Functions
in Humans
Stomach:
Helps regulate
gastric emptying
Promotes satiety and
reduces appetite
Liver:
Glucagon reduces
hepatic glucose output
Beta cells:
Enhances glucose-dependent
insulin secretion
Alpha cells:
Glucose-dependent
postprandial
glucagon secretion
GLP-1: Secreted upon
the ingestion of food
Data from Flint A, et al. J Clin Invest 1998;101:515-520. Data from Larsson H, et al. Acta Physiol Scand 1997;160:413-422.
Data from Nauck MA, et al. Diabetologia 1996;39:1546-1553. Data from Drucker DJ. Diabetes 1998;47:159-169.
47. Mechanisms of GLP-1 action:
Role of incretins in plasma glucose regulation
Meal-induced secretion of GLP-1
Increased satiety
Decreased appetite
↓ ß-cell stress
↑ ß-cell
response
ß-cells:
Stimulation of glucose
dependent insulin secretion
α-cells:
↓ postprandial
glucagon secretion
Liver:
↓ glucagon decreases
hepatic glucose production
Stomach:
slowing of gastric emptying
Modified from Flint A, et al. J Clin Invest. 1998;101:515-520.; Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.;
Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Drucker DJ. Diabetes. 1998;47:159-169.
48. Other effects of GLP-1 and GIP
Journal of Diabetes Investigation Volume 1 Issue 1/2 February/April 2010
49. Activation of the GLP-1 receptor alone
may account for up to 70% of insulin
secretion
The Major Effect
Clinical Therapeutics/Volume 33, Number 5, 2011
50. GLP-1 acts at many levels to promote insulin
secretion
• Potentiates glucose-dependent insulin secretion
• Enhances all steps of insulin biosynthesis
• Up-regulates insulin gene expression
• Up-regulates expression of genes essential for β-cell
function
• Promotes β-cell neogenesis and progenitor cell
differentiation*
• Inhibits apoptosis*
Clinical Therapeutics/Volume 33, Number 5, 2011
Adapted from Holst JJ. Diabetes Metab Res Rev. 2002;18:430-441.
*Observed in animal models
51. Actions of GLP-1
Important, as glucose levels approach the normal
range, the GLP-1 effects on insulin stimulation and
glucagon inhibition declined (glucose dependence
- reduction of hypoglycemia. - therapeutic
advantage)
53. Incretins : Potentiate glucose-dependent insulin
secretion (1)
GIP and GLP-1 exert their effects by binding to their specific
receptors.
Receptor binding activates and increases the level of
intracellular cAMP in pancreatic β cells, thereby stimulating
insulin secretion glucose-dependently.
1-Clinical Therapeutics/Volume 33, Number 5, 2011
2-Journal of Diabetes Investigation Volume 1 Issue 1/2 February/April 2010
56. Actions of GLP-1
The Problem
Unfortunately, GLP-1 is rapidly broken down by the DPP-IV
enzyme (very short half-life in plasma - requires continuous
IV infusion).
57. 57
The solution
Two options:
Incretin mimetics are glucagon-like peptide-1 (GLP-1)
agonists.
Dipeptidyl peptidase-IV (DPP-IV) antagonists inhibit the
breakdown of GLP-1.
62. DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus
Adapted from Unger RH. Metabolism. 1974; 23: 581–593. Ahrén B. Curr Enzyme Inhib. 2005; 1: 65–73.
Insulin
Glucagon
Improved
glycemic control
Incretin
activity
prolonged
Improved islet
function
DPP-4 inhibitor
Insulin
Glucagon
Hyperglycemia
Incretin
response
diminished
Further impaired
islet function
T2DM
Blocking DPP-4 Can Improve Incretin Activity and
Correct the Insulin:Glucagon Ratio in T2DM
63. 63
Dipeptidyl Peptidase-IV Antagonists
The concept is to allow the endogenous GLP-1 to remain in
circulation for a longer period.
DPP-IV inhibitors are oral, rather than injectable.
Weight neutral.
associated with a low incidence of hypoglycemia or
gastrointestinal side effects. Diabetes Care. 2004;27:2874-2880.
Preliminary long-term studies suggest a durable effect on
glycemia and improvement in some parameters of beta-cell
function. (www.glucagon.com).
64. 64
64
Mechanisms of Action of Major Oral Monotherapies Do Not Target 3
Core Defects in Type 2 Diabetes
Oral Monotherapies
SUs Meglitinides TZDs Metformin
α-Glucosidase
Inhibitors
DPP-4
Inhibitors
Improves insulin
secretion
Improves insulin
resistance
Lowers hepatic
glucose production
SUs=sulfonylureas; TZD=thiazolidinediones; DPP-4=dipeptidyl peptidase 4.
Inzucchi SE. JAMA 2002;287:360–372; Gallwitz B. Minerva Endocrinol. 2006;31:133–147.
Key
Defects
65. 65
Sitagliptin and Metformin Target Multiple Metabolic
Defects of Type 2 Diabetes
1. Vardarli I et al. Diabetes. 2014;63:663–674. 2. Aschner P et al. Diabetes Care. 2006;29:2632–2637. 3. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33. 4. Abbasi F et al. Diabetes
Care. 1998;21:1301–1305. 5. Zhou G et al. J Clin Invest. 2001;108:1167–1174. 6. Solis-Herrera et al. Diabetes Care. 2013;36:2756–2762.
Beta-Cell
Dysfunction
Hepatic Glucose
Overproduction (HGO)
Insulin Resistance
Sitagliptin improves
markers of beta-cell
function and increases
insulin synthesis and
release1,2
Sitagliptin reduces
HGO through
suppression of
glucagon from alpha
cells6
Metformin decreases
HGO by targeting the
liver to decrease
gluconeogenesis and
glycogenolysis3
Metformin has insulin-
sensitizing properties3–5
(Liver > Muscle)
Sitagliptin increases
intact GLP-1 levels1
Metformin increases
total GLP-1 levels1
66. 66
Complementary Effects of Sitagliptin and Metformin on
Active GLP-1, Glucagon, and Endogenous Glucose
Production in Patients With T2DM1
aResponses to a 6-hour meal tolerance test.
bP<0.01 vs placebo and metformin at baseline; P<0.001 vs placebo and metformin postMTT.
cP<0.01 vs placebo and metformin (0-120 min).
dP<0.01 vs placebo.
GLP-1 = glucagon-like peptide 1; T2DM = type 2 diabetes mellitus; MTT = meal tolerance test; SITA = sitagliptin; MET = metformin; PBO = placebo.
1. Adapted with permission from Solis-Herrera C et al. Diabetes Care. 2013;36:2756–2762.
Active GLP-1a
0 60 120 180 240 300 360
Bioactive
GLP-1
(pmol/L)
Time (min)
SITA+METb
SITAb
MET
PBO
Plasma
Glucagon
(pg/mL)
360
300
240
180
120
60
0
120
40
60
100
80
Time (min)
SITA+METc
SITAc
MET
PBO
Glucagona
Time (min)
Endogenous Glucose Productiona
2.5
2.0
360
300
240
180
120
60
0
0.5
1.0
1.5
0
EGP
(mg/kg·min)
SITA+METd
SITAd
METd
PBO
80
20
40
60
0
67. Initial Fixed-Dose Combination Therapy With Sita/Met vs
Metformin Monotherapy: Change from Baseline in HbA1c
by Baseline HbA1c at Week 18
FAS=full analysis set; FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
HbA
1c
LS
Mean
Change
from
Baseline,
%
Baseline HbA1c,% <8 ≥8 and <9 ≥9 and <10 ≥10 and <11 ≥11
FAS (Week 18)
P=0.009
P<0.001
P<0.001
Mean HbA1c,% 7.6 8.4 9.5 9.4 10.4 12.2
n=
–1.1
–1.6
–2.0
–2.9
–2.7
–2.1
–1.7
–1.1
–0.8
–4.0
–3.5
–3.0
–2.5
–2.0
–1.5
–1.0
–0.5
0
Sitagliptin/metformin FDC
Metformin
99 95 99 111
87 101 124 109 150 148
P=0.158
P=0.111
–3.6
68. 69
Significantly Greater Proportion of Patients at HbA1c Goal
of <7% at Week 18 With Sitagliptin/Metformin FDC vs
Metformin Monotherapy1
aExcludes data obtained after initiation of additional antihyperglycemic agents.
bid = twice a day; FAS = full analysis set; FDC = fixed-dose combination.
1. Reasner C et al. Diabetes Obes Metab. 2011;13:644–652.
FAS Populationa
Patients at goal:
49%
Mean baseline HbA1c = 9.9% Mean baseline HbA1c = 9.8%
Patients at goal:
34%
Sitagliptin/metformin FDC 50/1000 mg bid
(n=559)
Metformin 1000 mg bid
(n=564)
P<0.001
69. 70
Clinical Efficacy and Safety of Sitagliptin Therapy
in Patients Inadequately Controlled on Metformin
Alone: Sitagliptin vs SU
70. 71
Retrospective cohort study of patients with T1DM or T2DM (N=1,013; 79% with T2DM) attending a specialty
diabetes clinic (August 2005–July 2006); severe hypoglycemic events were reported by 76 (7.5%) patients
Self-reported Severe Hypoglycemia Was Associated With an Increased
5-Year Mortality Rate Compared With Mild or No Hypoglycemia1
aOR for 5-year mortality adjusted for age, sex, diabetes type and duration, HbA1c, CCI, and hypoglycemia history.
T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; CCI = Charlson comorbidity index; CI = confidence interval; OR = odds ratio.
1. McCoy RG et al. Diabetes Care. 2012;35:1897–1901.
Type 1 diabetes
0 1 2
Diabetes duration
OR (95% CI)a
Age
Male sex
Mild hypoglycemia
Severe hypoglycemia
HbA1c
CCI
3
0.836 (0.410, 1.706)
1.006 (0.985, 1.027)
1.047 (1.027, 1.066)
1.716 (1.135, 2.596)
1.564 (0.986, 2.481)
3.381 (1.547, 7.388)
1.127 (0.965, 1.316)
1.437 (1.323, 1.561)
8
4 7
P Value
0.623
0.595
<0.001
0.011
0.468
0.005
0.131
<0.001
71. 72
Moderate-to-Severe Hypoglycemia Increased the Likelihood
of Discontinuation of Antihyperglycemic Treatment1
CI = confidence interval; OR = odds ratio.
aAnalysis adjusted for age, gender, region, insurance, antihyperglycemic class, and comorbidities.
bDefined as any inpatient or outpatient visit associated with an ICD-9 code for hypoglycemia.
cDefined as a gap of ≥30 days without any antidiabetic medication supply.
1. Bron M et al. Postgrad Med. 2012;124:124–132.
Retrospective analysis of the Ingenix IMPACT database of ≈45 managed care health plans with
>30 million enrollees between January 1999 and September 2008
Effecta of ≥1 Hypoglycemic Eventb on Risk of Discontinuationc
OR (95% CI)
Discontinuation
within 6 months
Discontinuation
over next 6 months
1.26 (1.22, 1.31)
1.14 (1.09, 1.19)
P Value
<0.0001
<0.0001
1 2
0
72. 73
The Severity of Hypoglycemia Can Impact Health Care
Resource Utilization in Patients With T2DM1
0
2
4
6
8
10
12
HCP visits ED visits Hospitalizations
Mean
Number
of
Visits
Per
Patient
Over
the
Past
6
Months
No hypoglycemia (n=1,729)
Nonsevere hypoglycemia (n=1,729)
Severe hypoglycemia (n=172)
A Cross-sectional Data Analysis From the 2013 US National Health and Wellness Survey
Highlighting Annual, Self-Administered, Internet-Based Survey of US Adults Treated for T2DM
T2DM = type 2 diabetes mellitus; US = United States; HCP = health care provider; ED = emergency department.
1. Pawaskar M et al. J Diabetes Complications. 2018;32:451–457.
5.99
6.92
8.06
0.29 0.31 0.64
0.15 0.15 0.41
73. 74
Addition of Sitagliptin or Glimepiride in Patients
Inadequately Controlled on Metformin: Study Design1
Week 30
Continue stable dose of metformin
Single-blind
Placebo Run-in
Double-blind
Treatment Period
Week –2 Day 1
Patients age ≥18 years with T2DM
on stable dose of metformin
(≥1500 mg/day) for ≥12 weeks
and HbA1c 6.5%– 9.0% Glimepiride
(started at 1 mg qd and up-titrated until week 18 as
needed up to maximum dose of 6 mg qd)
qd = once daily; R = randomization; T2DM = type 2 diabetes mellitus.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13:160–168.
Sitagliptin 100 mg qd
Week –4
Screening
Period
R
74. 75
Per-Protocol Population
Change from baseline at 30 weeks (for both groups): –0.5%
Sitagliptin Was Noninferior to Glimepiride in Reducing
HbA1c at Week 301
Adapted with permission from Arechavaleta R et al.1
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13:160–168.
Week
Change
in
HbA
1c
From
Baseline,
%
6.0
6.2
6.4
6.6
6.8
7.0
7.2
7.4
7.6
7.8
8.0
0 6 12 18 24 30
(95% CI)
0.07% (–0.03, 0.16)
Sitagliptin 100 mg + metformin (n=443)
Glimepiridea + metformin (n=436)
Achieved primary
hypothesis of
noninferiority to
sulfonylurea
Primary End Point:
Change in HbA1c from
baseline at week 30
75. 76
All patients inadequately controlled on metformin monotherapy (≥1500 mg/day)
(APaT Population)
Sitagliptin Was Associated With a Lower Incidence of
Hypoglycemia and Reduced Body Weight vs Glimepiride1
APaT = all patients as treated; CI = confidence interval; LS = least-squares.
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13:160–168. 2. Data on file, MSD.
Hypoglycemia Over 30 Weeks Body Weight Change at Week 30
Patients
With
≥1
Hypoglycemic
Episode,
%
LS
Mean
(95%
CI)
Change
in
Body
Weight
From
Baseline,
kg
(95% CI)
–15.0% (–19.3, –10.9) (P<0.001)
Sitagliptin 100 mg + metformin Glimepiridea + metformin
= –2.0 kg
(P<0.001)
–0.8
1.2
–1.5
–1.0
–0.5
0.0
0.5
1.0
1.5
2.0
n=461
n=465
7
22
0
5
10
15
20
25
n=516 n=518
77. J. Mu, et al.10-LB, 2007 ADA Meeting, Chicago, Il.
0.0
0.1
0.2
0.3
0.4
0.5
*
*
a
cell
/
total
islet
area
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
*
*
Diabetic control
Non-diabetic control
Sitagliptin
Glipizide
* p<0.001 vs. diabetic control
b
cell
/
total
islet
area
Sitagliptin Causes ↑ β-Cell Mass and ↓ α-Cell Mass in Mice
HFD/STZ mice treated with sitagliptin or glipizide for 10 weeks
• Pancreatic sections were stained with anti-insulin (green) or anti-glucagon (red) antibodies
78. Chronic Sitagliptin Treatment in Diabetic HFD/STZ
ICR Mice Normalizes Islet Morphology
-2 0 2 4 6 8 10
0
100
200
300
400
500
Diabetic control
Sitagliptin 0.3%
*
*
Glipizide 0.02%
*
*
*
*
*
*
*
*
*
*
*
* * *
Non-diabetic control
Weeks of treatment
Glucose
(mg/dL)
Pancreatic sections stained with anti-insulin antibody (green) or anti-glucagon antibody (red)
Ambient Glucose
• A model of insulin resistance
due to high fat diet and reduced
insulin secretion
• Compounds admixed in diet
for 10 weeks
79. The objectives of the study were to assess:
• The differences in time to initiation of insulin use.
• The proportion of the population initiating insulin among patients
taking the combination of JANUVIA and metformin, and patients
taking the combination of a sulfonylurea and metformin.
“Assessing time to insulin use among type 2 diabetes patients treated with
Sitagliptin or sulfonylurea plus metformin dual therapy”
Real-world research study provides insight about different oral treatment
regimens and their possible effect on initiation of insulin under real-world
conditions.
initially including 7,728 patients with type 2 diabetes who used
JANUVIA (n=3,864) or a sulfonylurea (n=3,864) as dual therapy with
metformin for (for Six Years) in 2006 to 2013
80. Results…
This Analysis indicated that at year six, patients in the JANUVIA group were 24 percent less
likely to initiate insulin during the period of observation compared to patients taking a sulfonylurea
(p=0.0011).
Inzucchi et al published online: 22 JUN 2015Diabetes, Obesity and Metabolism 2015
24%
Conclusions: In this real-world matched cohort study, patients
with T2DM treated with sitagliptin had a significantly lower risk of
insulin initiation compared with patients treated with sulphonylurea,
both as add-on to metformin.
82. 83
Renal Insufficiency Is a Recognized Comorbidity Among Patients
With T2DM1
aBased on eGFR, which was calculated using the CKD-EPI equation.
bAge adjusted to 2012 NHIS diabetes population.
cProportion of patients did not meet CKD criteria based on eGFR or albuminuria.
T2DM = type 2 diabetes mellitus; NHANES = National Health and Nutrition Examination Survey; eGFR = estimated glomerular filtration rate; CKD = chronic kidney disease; CKD-EPI = Chronic
Kidney Disease Epidemiology Collaboration.
1. Bailey RA et al. BMC Research Notes. 2014;7:415.
Based on US NHANES Database 1999–2012 Data (N=2,915), Patients with Mild
Renal Impairmenta Comprise an Estimated 40% of Patients With T2DMb
Proportion of T2DM Population
<15
15–29
30–44
45–59
60–89
≥90
eGFR, mL/min/1.73 m2
c
c
39.7%
38.3%
12.9%
5.8%
2.8%
0.4%
83. 84
Longer Duration of T2DM Is Associated With a Lower eGFR1
Figure adapted from Cea Soriano L et al.
T2DM = type 2 diabetes mellitus; eGFR = estimated glomerular filtration rate.
1. Cea Soriano L et al. Cardiovasc Diabetol. 2015;14:38.
Association Between a Longer Duration of T2DM and Lower eGFR
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<1 1–4 5–9 10–14 ≥15
≥60 45–59 30–44 15–29
Percent
of
Patients,
%
Duration of Diabetes, y
eGFR:
(n=2848) (n=23,201) (n=17,123) (n=8503) (n=6271)
74.7%
19.6%
4.8%
0.9%
73.9%
19.6%
5.7%
0.9%
68.7%
22.1%
7.4%
1.7%
63.3%
24.6%
9.7%
2.2%
57.4%
26.0%
12.5%
4.1%
Retrospective cohort study of 57,946 adult patients with diagnosed T2DM registered in
the UK-based Health Improvement Network primary care database
84. 85
DPP-4 inhibitors: No restricted use in patients with renal impairment, but
may require dose adjustment1,2
Insulin: May require dose adjustment, as impaired renal function is
associated with a prolonged half-life of insulin1,2
Metformin: Restricted use in patients with moderate to severe renal
impairment and may vary by country1,3,4
SGLT2 inhibitors: Restricted use in patients with severe renal impairment,
and efficacy is limited in patients with moderate renal impairment5
SUs: No dosage adjustment necessary for second-generation SUs. Patients
with impaired renal function may be at increased risk of hypoglycemia.2,5
TZDs: No restricted use in patients with renal impairment, but fluid retention
may be a concern1,2
A Refer to respective DPP-4 Prescribing Information for details regarding use in patients with renal impairment, including appropriate dosages. DPP-4 = dipeptidyl peptidase-4; SGLT2 = sodium glucose cotransporter 2; SU =
sulfonylurea; TZD = thiazolidinedione. 1. Inzucchi SE et al. Diabetes Care. 2012;35:1364–1379. 2. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl2):S1–S179. 3. Food and Drug Administration Drug Safety
Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM494140.pdf. Accessed
December 4, 2016. 4. European Medicines Agency: Use of metformin to treat diabetes now expanded to patients with moderately reduced kidney function.
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Metformin_31/WC500214235.pdf. Accessed December 4, 2016. 5. InzucchiSE et al. Diabetes Care.2015;38:140–149.
Guidelines Recommend Individualization of Antihyperglycemic Therapy
Based on Renal Function:-
85. 86
Dose Adjustment of Sitagliptin in Patients With Renal Impairment1–3
GFR = glomerular filtration rate; ESRD = end-stage renal disease.
1. JANUVIATM (sitagliptin) [Summary of product characteristics]. Merck. 2018. 2. Bergman AJ et al. Diabetes Care. 2007;30:1862–1864. 3. Evans M et al. Diabetes Ther. 2015;6:1–5.
Dose adjustment of sitagliptin for patients with moderate to severe renal impairment or ESRD is
recommended to achieve plasma concentrations comparable to those in patients with normal renal function,
and not based on a risk of adverse effects or renal toxicity2,3
Normal renal function or
mild or moderate renal
impairment
(GFR ≥45 mL/min)
Sitagliptin 100 mg
Moderate renal
impairment
(GFR ≥30 to <45
mL/min)
Sitagliptin 50 mg
Severe renal
impairment
or ESRD, including
those requiring
hemodialysis or
peritoneal dialysis
(GFR <30 mL/min)
Sitagliptin 25 mg
86. 87
Sitagliptin Efficacy Is Similar Regardless of
Renal Function (1-Year Data)
aNo renal function impairment inconsistent with the use of metformin.
bGFR <50 mL/min.
ESRD = end-stage renal disease; SU = sulfonylurea; LS = least squares; GFR = glomerular filtration rate.
1. Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205. 2. Arjona Ferreira JC et al. Diabetes Care. 2013;36:1067–1073. 3. Arjona Ferreira JC et al. Am J Kidney Dis. 2013;61:579–587.
HbA1c Reductions In 3 Active-Controlled Clinical Trials
ESRD on Dialysis
Moderate-to-Severe Renal
Impairmentb
Normal Renal Function to
Mild Renal Impairmenta
–1.5
–1.3
–1.1
–0.9
–0.7
–0.5
–0.3
–0.1
0.1
Sitagliptin 25 mg
once daily3
–1.5
–1.3
–1.1
–0.9
–0.7
–0.5
–0.3
–0.1
0.1
Sitagliptin 50 mg or
25 mg once daily2
–1.5
–1.3
–1.1
–0.9
–0.7
–0.5
–0.3
–0.1
0.1
Sitagliptin 100 mg
once daily1
LS
Mean
Change
in
HbA
1c
From
Baseline,
%
LS
Mean
Change
in
HbA
1c
From
Baseline,
%
LS
Mean
Change
in
HbA
1c
From
Baseline,
%
52 weeks 54 weeks 54 weeks
SU (glipizide) HbA1c reduction: –0.7% SU (glipizide) HbA1c reduction: –0.6% SU (glipizide) HbA1c reduction: –0.9%
Mean Baseline HbA1c: 7.5% Mean Baseline HbA1c: 7.8% Mean Baseline HbA1c: 7.9%
–0.7 –0.7
–0.8
87. 88
Scott RS and col. Safety and Efficacy of Sitagliptin [SITA] Compared with Dapagliflozin [DAPA} in Subjects with T2D, Mild Renal Impairment and Inadequate Glycemic Control on
Metformin [MET] With or Without a Sulfonylurea. Poster presented at: ADA 2018; June 22–26, 2018; Orlando, Florida. 1142-P
Change from Baseline in A1C through Week 24
CompoSIT R Study:
Study Objective was:
To compare the efficacy and safety of the DPP-4 inhibitor
Sitagliptin with the SGLT-2 inhibitor Dapagliflozin in patients
with type 2 diabetes and mild renal impairment ,Mean eGFR:
78 mL/min/1.73m².
Sitagliptin treatment was associated with Greater reduction from baseline
in A1C compared to Dapagliflozin
2018 UPDATES
88. 89
CompoSIT R:-
Percentage of Patients at Goal of A1C <7% at Week 24
8
Scott RS and col. Safety and Efficacy of Sitagliptin [SITA] Compared with Dapagliflozin [DAPA} in Subjects with T2D, Mild Renal Impairment and Inadequate Glycemic Control on
Metformin [MET] With or Without a Sulfonylurea. Poster presented at: ADA 2018; June 22–26, 2018; Orlando, Florida. 1142-P
Conclusion:- In patients with type 2 diabetes and mild renal impairment with inadequate glycemic control on
metformin alone or in combination with a sulfonylurea agent:
• Treatment with sitagliptin for 24 weeks resulted in greater improvements in A1C relative to
treatment with dapagliflozin
• Treatment with sitagliptin and treatment with dapagliflozin for 24 weeks were generally well
tolerated
92. 93
Hypoglycemia is a special concern ;-
Older adults are at higher risk of hypoglycemia for many reasons, including
insulin deficiency necessitating insulin therapy
progressive renal insufficiency.
higher rates of unidentified cognitive deficits, causing difficulty in complex self-
care activities (e.g., glucose monitoring, adjusting ).
These cognitive deficits have been associated with increased risk of
hypoglycemia, and, conversely, severe hypoglycemia has been linked to
increased risk of dementia.
American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets. Diabetes Care 2016;
94. 95
Objective: To assess the efficacy and safety of sitagliptin monotherapy over 24 weeks in elderly
patients (≥65 years of age) with type 2 diabetes who had inadequate glycemic control
Adapted with permission from Barzilai N et al.1
aSitagliptin was downtitrated to 50 mg (1 tablet instead of 2) in patients with CrCl <50 mL/min; patients with CrCl <30 mL/min were discontinued.
OHA = oral antihyperglycemic agent; qd = once daily; R = randomization; T2DM = type 2 diabetes mellitus.
1. Barzilai N et al. Curr Med Res Opin. 2011;27:1049–1058.
Sitagliptin in Elderly Patients With T2DM:
Study Design1
Primary efficacy end point: change from baseline in HbA1c at 24 weeks
Selected secondary end point: change in 4-point fingerstick glucose average at day 3 and day 7
Screening
Double-Blind Period
2-Week Single-Blind
Period
Week 0 Week 24
6–8 Weeks
Eligible if
HbA1c 7%–10%
Diet/Exercise and Washout Run-In
Period
Patients
≥65 years on
OHA or not on
OHA for
T2DM
R
Sitagliptin 100 mg qda (n=102)
Placebo (n=104)
95. 96
Significant Reduction in HbA1c From Baseline at 24 Weeks
With Sitagliptin in Elderly Patients With T2DM1
Adapted with permission from Barzilai N et al.1
LS = least-squares; SE = standard error.
1. Barzilai N et al. Curr Med Res Opin. 2011;27:1049–1058
–0.6
–0.4
–0.2
0.0
0.2
0.4
HbA
1c
LS
Mean
(±
SE)
Change
From
Baseline,
%
0 6 12 18 24
Placebo (n=91)
Mean baseline HbA1c=7.7%
Sitagliptin (n=101)
Mean baseline HbA1c=7.8%
Week
LS mean difference
–0.7%; P<0.001
Full Analysis Set
–0.5%
(95% CI: –0.7, –0.2)
0.2%
(95% CI: 0.0, 0.5)
Primary End Point:
Change from baseline
in HbA1c at week 24
98. Study design and participants
Data for this analysis were taken from patients using premixed insulin in
either of two 24-week, randomized, double-blind clinical trials. In both trials,
patients with inadequate glycaemic control (HbA1c ≥7.5% and ≤11%) on
long-acting, intermediate-acting or premixed insulin, with or without
metformin, were randomized 1:1 to the addition of once-daily sitagliptin 100
mg or matching placebo. One trial was multinational and one was carried
in China.
99. Background:
Despite the availability of many innovative oral antidiabetic drugs
(OADs), such as dipeptidyl peptidase 4 inhibitors (DPP4-i) and
its first-in-class sitagliptin (SITA), which entered the Italian
market in the last 10 years,
their usage is consistently lower than traditional drugs such as
sulfonylureas (SUs).
Lorenzoni et al, ClinicoEconomics and Outcomes Research 2017:9 699–710
100. Drug Cost: SITA is higher in cost than SUs
Total Cost: SITA saved around 20% of TOTAL cost
Lorenzoni et al, ClinicoEconomics and Outcomes Research 2017:9 699–710
102. Key published studies demonstrating the
safety and tolerability of DPP-4 inhibitors.
Deacon CF (2019) Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes. Front. Endocrinol.
10:80. doi: 10.3389/fendo.2019.00080
103. CVD outcomes of post-marketing prospective trials in patients with
type 2 diabetes comparing cardiovascular safety with placebo
Bailey CJ, Marx N. Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials. Diabetes Obes Metab. 2019;21:3–14.
104. Methods:
All patients with T2D in Sweden who initiated second-line treatment with metformin +
Sulphonylurea or metformin + DPP-4i during 2006–2013 (n = 40,736 and 12,024, respectively)
were identified in this nationwide study.
The Swedish Prescribed Drug Register and the Cause of Death and National Patient Registers
were used, and Cox survival models adjusted for age, sex, fragility, prior CVD, and CVD-
preventing drugs were applied to estimate risks of events. Propensity score adjustments and
matching methods were used to test the results. http://dx.doi.org/10.1016/j.diabres.2016.04.055
0168-8227/ 2016 The Authors. Published by Elsevier Ireland Ltd.
105. Methods:
Using the population-based National Health Insurance Research
Database ofTaiwan, we conducted an 11-year retrospective cohort
study. A total of 3120 patients undergoing insulin therapy for type 2
diabetes mellitus (T2DM) during 2000–2010 were enrolled.
The overall incidence rates for all-cause mortality of 1560 DPP-4
inhibitor users and 1560 matched DPP-4 inhibitor nonusers were
compared.
106. 107
Sitagliptin Pooled Safety Analysis1
In this pooled analysis of >14,000 patients from 25 randomized controlled studies of up
to 2 years in duration, sitagliptin has been shown to have a favorable risk-to-benefit
profile.
Preclinical and clinical trial dataa do not indicate an increased risk of pancreatitis in
patients with type 2 diabetes treated with sitagliptin.
The incidence of drug-related AEs was higher in the non-exposed group, primarily
because of the increased incidence of hypoglycemia.
Patients in the sitagliptin and non-exposed groups had
SIMILAR RATES OF
– Cardiac disorders (including MACE)
– Bone fractures
– Infections
– Angioedema and angioedema-related events
– Malignancies
107
AE=adverse experience; MACE=major adverse cardiovascular event.
1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7.
113. 114
Learning Objectives
the progressive nature of diabetes
ADA diagnostic criteria for diabetes
incretin physiology in healthy individuals and in patients with type 2
diabetes
mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-
1 receptor agonists
incretin therapies can be used in the treatment of type 2 diabetes
114. 115
Criteria for the Diagnosis of Diabetes
1. A1c ≥ 6.5%. This test should be performed in a laboratory using a method that is NGSP certified and
standardized to the DCCT assay.*
OR
2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.*
OR
3. 2-h plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. This test should be performed as
described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous
glucose dissolved in water.*
OR
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥
200 mg/dl (11.1 mmol/l).
* In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing
American Diabetes Association. Diabetes Care 2010;33(suppl 1):S62-S69.
115. 116
Postprandial Glucose Contribution to A1C
%
Contribution
A1C Range (%)
0
20
40
60
80
100
FPG (Fasting Plasma Glucose)
PPG (Postprandial Plasma Glucose)
>10.2
70%
30%
9.3-10.2
60%
40%
8.5-9.2
55%
45%
7.3-8.4
50%
50%
<7.3
30%
70%
Data from Monnier L, et al. Diabetes Care 2003; 26:881-885.
116. 117
IFG=impaired fasting glucose; IGT=impaired glucose tolerance; NGT=normal glucose tolerance.
Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000.
Prediabetes
(IFG / IGT)
NGT Diabetes
Insulin resistance
Islet cell function
Diabetes onset
Transition from prediabetes to diabetes occurs when islet cell function
deteriorated
Age,life style, environmental factors
117. 118
Complications are usually started before diagnosis
-10 -5 0 5 10 15 20 25 30
Relative
Insulin
Resistance
Years
350
300
250
200
150
100
50
Insulin
Level
Insulin Resistance
Decreasing b-cell Function
250
200
150
100
50
0
Fasting
Glucose
Post-prandial
Glucose
Glucose
(mg/dl)
DIAGNOSIS
Clinical
Features
Macrovascular changes
Microvascular changes
Compensated
b-cell Function
Adapted from Type 2 Diabetes BASICS: International Diabetes Center; 2000.
119. 120
UKPDS : Acheiving early glycaemic control may generate a
good legacy effect
HbA1c=haemoglobin A1c.
Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed
12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853.
Median
HbA1c
(%)
0
6
7
8
9
UKPDS 1998
Conventional
Intensive
Holman et al 2008
Legacy effect
1997
Difference in HbA1c was lost after first
year but patients in the initial intensive arm
still had lower incidence of any complication:
• 24% reduction in microvascular
complications
• 15% reduction in MI
• 13% reduction in all-cause mortality
2007
Patients initially received intensive therapy had a lower incidence of any complication
120. 121
Legacy effect: early glycaemic control is key to
long-term reduction in complications
Bad legacy effect
Achieving glycaemic control late in the disease, after a prolonged period of poor control, does not improve long-term
risk of macrovascular complications2
Long-standing, preceding hyperglycaemia accounted for
the high rate of complications at baseline in VADT3
UKPDS=UK Prospective Diabetes Study; VADT=Veterans Affairs Diabetes Trial.
1Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589.
2Duckworth W, et al. N Engl J Med. 2009; 360: 129–139;
3Del Prato S. Diabetologia. 2009; 52: 1219–1226.
Good legacy effect
Early, strict glycaemic control brings benefits,
reducing the long-term risk of microvascular and macrovascular complications (UKPDS1)
124. 125
Side effects include:-
-nasopharyngitis
-urinary tract infection
-headache
-G.I.T.disturbances.
-actions on cell adhesions,cell movement,cytokines,
-immunomodulation raised some concern about long term
safety.
-Some cases of pancreatitis were recorded.
- pancreatic masses ??? 125