The efficacy and safety of Inhibitors of Dipeptidil Peptidase 4 (DDP-4) in

the treatment of Type 2 Diabetes Mellitus – a systematic review of

randomized controlled trials

Authors:Tiago Millner, Petra Santos, Sara Figueiroa Silva, André Pereira, Elizabete Branco, Sofia Sousa, Miriam Sousa, Natacha

Sousa,Vanessa Silva, João Andrade, Alice Pimentel, Filipa Sousa

BackgroundDefinition 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) RA. International Textbook of Diabetes Mellitus. 3rd ed. Chichester, West Sussex, Hoboken, NJ: John Wiley; 2004.2) 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.

BackgroundComplications

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 clinicalpractice recommendations among US adults with diabetes,1999-2002: the National Health and NutritionExamination 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: vildagliptin (Januvia), sitagliptin (Galvus), saxagliptin (Onglyza). (10)

10) Barnett A et al. Int J Clin Pract, November 2006, 60, 11, 1454–1470

• 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

Research question and Aims

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-

hydroxyadamantylglycine-4,5-methanoprolinenitrile "[Substance Name] OR linagliptin OR Alogliptin OR

"vildagliptin "[Substance Name])

Methods

Study selectionTwo 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

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

Exclusion criteria

Not written in portuguese or english

Study not performed in humans

Review articles

11) Renee E. Amori et al. JAMA, July 11, 2007—Vol 298, No. 2

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

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

Methods

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

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

ResultsReference Study Duration Population Sample Treatment Glyceamic control Hypoglicaemic events and other adverse effects

R. Scott et Al., 2006 12 weeks 743

Mean age 48 years HbA1c baseline(%): 7,8 sitagliptin 50

mg and 7,9 all others; FPG

baseline(mmol/l): 9,4 (sitagliptin 12,5

and 50 mg), 9,5 (sitagliptin 5 mg

and glipizide) and 9,6 (sitagliptin

25mg and placebo)

Placebo(n=125); Sitagliptin:5mg (n=125);

12,5mg(n=123);25mg(n=123); 50mg(n=124); Glipizide 5-20 mg (n=123); All taken twice

daily

HbA1c: - 0.15 (sitagliptin 5 mg) to -0.54 (sitagliptin

50 mg) vs. - 0.76 (glipizide) vs. 0.23

(placebo); FPG: - 0.04 (sitagliptin 5 mg) to - 1.01 (sitagliptin 50 mg) vs. - 1.

38 (glipizide) vs. 0.44 (placebo)

3 in Placebo; 5, 5, 2 in Sitagliptin 12,5, 25 and 50 mg; 21 in Glipizide

J. Rosenstock et Al., 2009 104 weeks 598

Mean age 49 years Baseline HbA1c(%): 8.58 (Vildagliptin 50

mg) and 8.63 (Roseglitazone 8

mg); Baseline FPG(mmol/l): 9.90 (Vildagliptin 50mg)

and 9.97 (Roseglitazone 8

mg)

Rosiglitazone 8 mg (n=396) vs. Vildagliptin 50 mg (n=202); daily dose

HbA1c: - 0.82 (vildagliptin) vs. -1.44 (rosiglitazone)

both with p< 0.001; FPG: higher reduction in

rosiglitazone, with mean difference of 1.50 mmol/l

4 Mild suspected drug-related hypoglycaemic events in 4 patients (1%) in the vildagliptin group

Pablo Aschner, MD, et Al., 2006 24 weeks 741

Mean age 47 years Baseline HbA1c(%): 8.01 (sitagliptin 100

mg) , 8.08 (sitagliptin 200 mg) and 8.03 (placebo);

Baseline FPG(mmol/l): 9.5

(sitagliptin 100 mg) , 9.7 (sitagliptin

200 mg) and 9.8 (placebo).

Sitagliptin 100 mg (n= 238) vs. Sitagliptin 200 mg (n= 250) vs. Placebo (n= 253)

daily dose

HbA1c: - 0.61 (sitagliptin 100 mg) and -0. 76

(sitagliptin 200 mg) vs. 0.18 (placebo), FPG: - 0.7 (sitagliptin 100 mg) and -

0.9 (sitagliptin 200 mg) vs. 0.3 (placebo).

3 in Sitagliptin 100 mg; 2 in Sitagliptin 200mg; 2 in Placebo

Results

Reference Study Duration Population Sample Treatment Glyceamic control Hypoglicaemic events and other adverse effects

R. E. Pratley et Al., 2006 12 weeks 98

Mean age 55 years Baseline HbA1c(%):

8 (vildagliptin 25 mg), 8.1 (placebo);

Baseline FPG (mmol/l): 9.4

(vildagliptin 25 mg), 10.1 (placebo).

vildagliptin 25 mg (n=70) vs. Placebo (n=28) daily dose

HbA1c: -0.6 (vildaglipti 25 mg) vs. 0 8placebo), FPG: -0.9 (vildagliptin 25 mg) vs. 0.2 (placebo)

S. Dejager et Al., 2007 24 weeks 632

Mean age 53 years Baseline HbA1c(%): 8.2 (vildagliptin 50

mg), 8.6 (vildagliptin 50 mg

twice daily), 8.4 (vildagliptin 100

mg) and 8.4 (placebo) Baseline FPG(mmol/l): 9.8

(vildagliptin 50 mg), 10.1 (vildagliptin 50 mg twice daily), 9.9

(vildagliptin 100 mg) and 9.9 (placebo).

vildagliptin 50 mg (n=163) vs. vildagliptin 50 mg twice daily (n= 152) vs. vildagliptin 100 mg (n= 157) vs. Placebo (n= 160)

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)

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.

DPP-4 (sitagliptin and vildagliptin) versus placebo:

incidence of adverse effects similar majority of adverse effects classified as mild and of moderate

severity.

Results

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.

good safety profile Lead to a smaller number of adverse effects than with other usual

hypogliceamic agents.

DPP 4 Inhibitors

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