Transcript Slide 1

Background
 Definition of Diabetes Mellitus (DM)
DM is a metabolic disorder of multiple aetiology characterized by
chronic hyperglycaemia with disturbances of carbohydrate, fat, and
protein metabolism resulting from defects of insulin secretion, insulin
action, or a combination of both. (1)
 Types of Diabetes Mellitus
- Type 1 diabetes: due to a virtually complete lack of endogenous pancreatic
insulin production;
- Type 2 diabetes: the rising blood glucose results from a combination of genetic
predisposition, unhealthy diet, physical inactivity, and increasing weight
with a central distribution resulting in complex pathophysiological
processes;(2)
1)
2)
RA. International Textbook of Diabetes Mellitus. 3rd ed. Chichester, West Sussex, Hoboken, NJ: John Wiley; 2004.
Lars Rydén et al. EuropeanHeart Journal, 2007, page 4
Background
Prevalence
- Rises with age up to the seventh and eighth decades in both men and women
- This suggests that the lifetime risk of diabetes in European people is 30–
40%. (3)
3) The DECODE Study Group. Age- and sex-specific prevalences of diabetes and impaired glucose regulation in 13 European cohorts.
Diabetes Care 2003;26:61–69.
Backgroud
 Treatment
• Oral antidiabetic drugs: Sulfonylureas;
Biguanides;
Thiazolidinediones;
Alpha-glucosidase inhibitors.
 Insulin
6) Nathan DMet al. Management of hyperglycemia in type 2 diabetes, Diabetes Care 2006;29: 1963–72.
Background
 Complications
 Fewer than half of the adults with type 2 diabetes reach a hemoglobin A1c
(HbA1c) level of less than 7% despite several available therapies. (7)
 Ineffective implementation of existing pharmacotherapies is a significant
factor contributing to suboptimal care (8)
 However, efficacy of available therapies, even when used appropriately,
diminishes as the disease progresses because of a steady, decline in
pancreatic beta cell function and current therapies for type 2 diabetes are
often limited by adverse effects such as weight gain, edema, or
hypoglycemia (9)
7) Resnick HE Achievement of American Diabetes Association clinical
practice recommendations among US adults with diabetes,1999-2002: the National Health and Nutrition
Examination Survey. Diabetes Care. 2006;29(3):531- 537.
8) Nathan DM et al. N Engl J Med. 2007;356(5):437-440.
9) Turner JAMA. 1999; 281(21):2005-2012.
Background
•
Dipeptidyl peptidase-4 inhibitors (DPP-4)
• DPP4 inhibitors are new drugs that are being developed.
• Incretin therapy:
- Principal types of incretins: GLP1 and GIP.
- Based on the inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4) resulting
on the manteinance of the incretin GLP 1 for a longer time.
- Examples:
(10)
vildagliptin (Januvia), sitagliptin (Galvus), saxagliptin (Onglyza).
10) Barnett A et al. Int J Clin Pract, November 2006, 60, 11, 1454–1470
Research question and Aims
• Efficacy and safety of DDP-4 inhibitors in the treatment of type 2 diabetes
mellitus
•Aims:
•Primary
•Evaluate the efficacy of DPP4 inhibitors in the treatment of DM when
compared with standard oral antidiabetic drugs
•Evaluate the reduction of the HbA1c, glicemic fasting level
•Secundary
•Evaluate the safety profile and complication rates of DPP4 inhibitors in
the treatment of DM
Methods
 Sistematic review of randomized controlled trials.
 Data Sources and Searches:
 Databases: Pubmed, ISI Web of Knowledge and Scopus.
 Bibliographic research until30/11/2009
Methods
 Research query:
(("Diabetes Mellitus, Type 2"[Mesh] OR diabetes mellitus OR
"Diabetes Mellitus, Type 2/drug therapy"[Mesh] OR hyperglycemia)
AND
("dipeptidyl peptidase-4 inhibitor" OR "DPP-4 inhibitor“ OR
"sitagliptin "[Substance Name]) OR "3-hydroxyadamantylglycine4,5-methanoprolinenitrile "[Substance Name] OR linagliptin OR
Alogliptin OR "vildagliptin "[Substance Name])
Methods
 Study selection
 Two reviewers independently screened abstracts according to the
inclusion and exclusion criteria.
 Full-text articles were retrieved and reviewed if a decision on inclusion
could not be made solely based on the abstract.
 Any discrepancies were resolved by a third reviewer.
Methods
 Inclusion criteria
 Exclusion criteria
 Randomized controlled
clinical trials
 Studies comparing DPP4
inhibitor based therapy with
other hipoglycemic
treatment or placebo
 Minimum follow up of 12
weeks
 Articles with information
about HbA1c or fasting
glucose levels
11) Renee E. Amori et al. JAMA, July 11, 2007—Vol 298, No. 2
 Not written in portuguese or
english
 Study not performed in
humans
 Review articles
Methods
 Evaluation of article quality:
 Of the articles included, we assessed the quality acording to the criteria of
the Consort. Articles which did not respect 60 % of the 22 criteria stated
were eliminated.
 In this fase were included 5 articles, being excluded 7 because of denied
access.
Methods
Figure 2: Articleflow in the study
Methods
 Data were extracted according to the following 4 topics:
- Methods;
- Participants;
- Interventions;
- Outcomes and Results
These criteria were used according to the Cochrane Handbook for
Systematic Reviews of Interventions , 4.2.6
Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventios Version 5.0.2 [updated
September 2009]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.
Methods
 Data Synthesis and Analysis
 For data synthesis we used a table which summarised the information about
study duration, population size, drug used and dosage, HbA1c and FPG
baseline levels and their difference from baseline and the adverse effects,
represented by the hypoglycemic events.
 We also used, for Data analysis, the RevMan software to create forest plots to
assess the efficacy of the DPP-4 Inhibitors versus placebo. We created two
forest plots, one for each of the two primary outcomes, HbA1c and FPG
Results
 Data Extraction :
 The following articles are included in the systematic
review:
 1) R. Scott, M. Wu, M. Sanchez, P. Stein: Efficacy and tolerability of the
dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks
in patients with type 2 diabetes. Int J Clin Pract , 61: 171 – 180, 2006
 2) J. Rosenstock, M. Niggli and M. Maldonado-Lutomirsk: Long-term 2-
year safety and efficacy of vildagliptin compared with rosiglitazone in
drug-naïve patients with type 2 diabetes mellitus. Diabetes, Obesity and
Metabolism, 11: 571-578, 2009
Results
 3) Pablo Aschner, MD; Mark S. Kipnes, MD; Jared K. Lunceford, PHD; Matilde
Sanchez, PHD; Carolyn Michel, MS; Debora E. Williams-Herman, MD. Effect
of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin as Monotherapy on
Glycemic Control in Patients with Type 2 Diabetes. Diabetes Care, Volume 29,
number 12, 2006
 4) R. E. Pratley; S. Jauffret−Kamel; E. Galbreath; D. Holmes: Twelve−week
Monotherapy with the DPP−4 Inhibitor Vildagliptin Improves Glycemic
Control in Subjects with Type 2 Diabetes. Horm Metab Res, volume 38, pages
423 to 428, 2006
 5) S. Dejager; S. Razac; J. E Foley; A. Schweizer: Vildagliptin in Drug-naïve
Patients with Type 2 Diabetes: A 24-Week, Double-blind, Randomized,
Placebo-controlled, Multiple-dose Study. Horm Metab Res , volume 39, pages
218 – 223, 2007
Results
Reference
R. Scott et Al., 2006
J. Rosenstock et Al., 2009
Pablo Aschner, MD, et Al., 2006
Study Duration
12 weeks
104 weeks
24 weeks
Population
Sample
Treatment
Glyceamic control
Hypoglicaemic events and other adverse effects
743
Mean age 48 years
HbA1c baseline(%):
HbA1c: - 0.15 (sitagliptin
7,8 sitagliptin 50
5 mg) to -0.54 (sitagliptin
mg and 7,9 all
Placebo(n=125);
50 mg) vs. - 0.76
others; FPG
Sitagliptin:5mg (n=125);
(glipizide) vs. 0.23
baseline(mmol/l): 12,5mg(n=123);25mg(n=123);
3 in Placebo; 5, 5, 2 in Sitagliptin 12,5, 25 and 50 mg;
(placebo); FPG: - 0.04
9,4 (sitagliptin 12,5 50mg(n=124); Glipizide 5-20
21 in Glipizide
(sitagliptin 5 mg) to - 1.01
and 50 mg), 9,5
mg (n=123); All taken twice
(sitagliptin 50 mg) vs. - 1.
(sitagliptin 5 mg
daily
38 (glipizide) vs. 0.44
and glipizide) and
(placebo)
9,6 (sitagliptin
25mg and placebo)
598
Mean age 49 years
Baseline HbA1c(%):
8.58 (Vildagliptin 50
HbA1c: - 0.82 (vildagliptin)
mg) and 8.63
vs. -1.44 (rosiglitazone)
(Roseglitazone 8 Rosiglitazone 8 mg (n=396)
both with p< 0.001; FPG: 4 Mild suspected drug-related hypoglycaemic events
mg); Baseline
vs. Vildagliptin 50 mg
higher reduction in
in 4 patients (1%) in the vildagliptin group
FPG(mmol/l): 9.90
(n=202); daily dose
rosiglitazone, with mean
(Vildagliptin 50mg)
difference of 1.50 mmol/l
and 9.97
(Roseglitazone 8
mg)
741
Mean age 47 years
Baseline HbA1c(%):
8.01 (sitagliptin 100
HbA1c: - 0.61 (sitagliptin
mg) , 8.08
100 mg) and -0. 76
(sitagliptin 200 mg) Sitagliptin 100 mg (n= 238)
(sitagliptin 200 mg) vs.
and 8.03 (placebo); vs. Sitagliptin 200 mg (n=
3 in Sitagliptin 100 mg; 2 in Sitagliptin 200mg; 2 in
0.18 (placebo), FPG: - 0.7
Baseline
250) vs. Placebo (n= 253)
Placebo
(sitagliptin 100 mg) and FPG(mmol/l): 9.5
daily dose
0.9 (sitagliptin 200 mg) vs.
(sitagliptin 100 mg)
0.3 (placebo).
, 9.7 (sitagliptin 200
mg) and 9.8
(placebo).
Results
Reference
R. E. Pratley et Al., 2006
S. Dejager et Al., 2007
Study Duration
12 weeks
24 weeks
Population
Sample
Treatment
Glyceamic control
98
Mean age 55 years
Baseline HbA1c(%):
8 (vildagliptin 25
mg), 8.1 (placebo); vildagliptin 25 mg (n=70) vs.
Baseline FPG
Placebo (n=28) daily dose
(mmol/l): 9.4
(vildagliptin 25 mg),
10.1 (placebo).
HbA1c: -0.6 (vildaglipti 25
mg) vs. 0 8placebo), FPG: 0.9 (vildagliptin 25 mg) vs.
0.2 (placebo)
632
Mean age 53 years
Baseline HbA1c(%):
8.2 (vildagliptin 50
mg), 8.6
(vildagliptin 50 mg
twice daily), 8.4
vildagliptin 50 mg (n=163) vs.
(vildagliptin 100
vildagliptin 50 mg twice daily
mg) and 8.4
(n= 152) vs. vildagliptin 100
(placebo) Baseline
mg (n= 157) vs. Placebo (n=
FPG(mmol/l): 9.8
160)
(vildagliptin 50 mg),
10.1 (vildagliptin 50
mg twice daily), 9.9
(vildagliptin 100
mg) and 9.9
(placebo).
HbA1c: -0.8 (vildagliptin
50 mg and 50 mg twice
daily), -0.9 (vildagliptin
100 mg) vs. -0.3 (placebo);
FPG: -1 (vildagliptin 50
mg) , -0.8 (vildagliptin 50
mg twice daily and 100 mg
daily) vs. -0.1 (placebo)
Hypoglicaemic events and other adverse effects
minimal hypoglicemia
Results
Figure 5: Comparison of DPP-4
versus placebo concerning HbA1c
difference from baseline in all drug
dosages
Results
Comparison of DPP-4 versus placebo
concerning FPG difference from
baseline in all drug dosages
Results
Comparison of DPP-4 versus placebo concerning HbA1c difference from
baseline in the most efficient drug dosages of each study
Results
Comparison of DPP-4 versus placebo concerning FPG difference from
baseline in the biggest drug dosages of each study
Results
Sitagliptin versus glipizide:
 incidence of drug-related clinical adverse experiences modestly higher in the
glipizide group
 This difference was result of increased incidence of hypoglycaemia adverse
experiences in the glipizide group
Vildagliptin versus rosiglitazone:
 overall occurrence of adverse effects similar
 The majority of events were mild to moderate in severity.
 Suspected study drug related adverse effects higher proportion in the
rosiglitazone
 A notable observation was the lower incidence of peripheral oedema in the
vildagliptin treatment group compared with the rosiglitazone treatment group.
Results
DPP-4 (sitagliptin and vildagliptin) versus placebo:
 incidence of adverse effects similar
 majority of adverse effects classified as mild and of moderate severity.
Discussion
 Efficacy of the DPP 4 inhibitors greater than of placebo in all studies
DPP 4 vs. Other hipoglicemic agents (glipizide and rosiglitazone):
 greater reduction of HbA1c and FPG with usual hypoglicemic agents
 DPP 4 inbitors present better safety profile.
DPP 4 Inhibitors
 good safety profile
 Lead to a smaller number of adverse effects than with other usual
hypogliceamic agents.
Limitations
 The limitations of this systematic review are:
 Small number of included studies;
 Studies present different drug dosages which difficult agreggation of data;
 Heterogeneity of the data, which does not allow us to perform a
metanalysis .
THE END