The document discusses DPP-4 inhibitors, including sitagliptin and vildagliptin, for the treatment of type 2 diabetes. It summarizes that DPP-4 inhibitors work by inhibiting the DPP-4 enzyme, increasing active incretin levels like GLP-1 and GIP, and improving glucose control. Studies showed that both sitagliptin and vildagliptin improved glycemic measures like HbA1c and fasting glucose when used as monotherapy or add-on therapy to other diabetes medications like metformin. The document concludes that DPP-4 inhibitors are a promising new treatment option for type 2 diabetes.
An Update On Dpp 4 Inhibitors In The Management Of Type 2 Diabetes
1. An update on DPP-4 inhibitors in the
management of Type 2 diabetes:
potential roles in monotherapy and
combination therapy
Harvey L. Katzeff
Merck Research Laboratories
Rahway, New Jersey, USA
3. Inhibition of DPP-4 increases active incretin
levels, enhancing downstream incretin actions
Active GIP • Increased insulin secretion
Active GLP-1 • Decreased glucagon release
DPP-4 Χ DPP-4 inhibitor
Inactive GIP Glucose control improved
Inactive GLP-1
GIP=glucose-dependent insulinotropic peptide
4. Sitagliptin and vildagliptin overview
F
F
NH2 O
N N
N
F N
CF3
• DPP-4 inhibitors for the treatment of patients with Type 2
diabetes: sitagliptin has recently been FDA approved, and
vildagliptin is currently under FDA review
• Provide potent and highly selective inhibition of the
DPP-4 enzyme
• No CYP or drug-drug interaction
• 30%–85% excretion via the urine
21. Sitagliptin added to metformin improved
24-hour glucose profile in Type 2 diabetes
Placebo + metformin (n=13)
Sitagliptin 50 mg BID + metformin (n=15)
Breakfast Lunch Dinner
240 Dose 1 Dose 2
7:30 18:30 Difference in 24-hour weighted
220 LS mean glucose: -32.8 mg/dl
(-1.82 mmol/l), P<0.001
Glucose (mg/dl)
200
180
160
140
120
100
8:00 13:00 19:00 0:00 7:30
Day 1 Day 2
Time
Stein. ADA. 2006. Late-breaking clinical presentation; adapted from Brazg et al. ADA. 2005.
Abstract 11-OR
22. Sitagliptin added to ongoing metformin
or pioglitazone: change in body weight over time
0.0
2.0
LS mean change from baseline
-0.2 1.5
body weight (kg)
1.0
-0.4
0.5
-0.6
0.0
-0.8
Placebo + metformin (n=169) -0.5 Placebo + pioglitazone (n=174)
Sitagliptin 100 mg QD + metformin Sitagliptin 100 mg QD + pioglitazone
(n=399) (n=163)
-1.0 -1.0
0 12 24 0 6 12 18 24
Time (weeks) Time (weeks)
Karasik et al. ADA. 2006. Abstract 501-P; Rosenstock et al. ADA. 2006. Abstract 556-P
23. HbA1c during insulin add-on:
core and extension study
9.0 Pbo + insulin Vildagliptin 50 mg + insulin
Vildagliptin 50 mg BID + insulin
8.5
∆ HbA1c -0.4 ± 0.1, P=0.001
Mean HbA1c (%)
8.0
7.5
7.0
-8 0 12 24 52
Fonseca et al. ADA. 2006. Poster 467-P
Time (weeks)
Fonseca et al. EASD. 2006. PS 62. 0802
24. Sitagliptin once daily showed similar glycaemic
efficacy to glipizide when added
to metformin (52 weeks)
8.4 Glipizide (n=411)
8.2 Sitagliptin 100 mg QD
(n=382)
8.0
Mean change in HbA1c
7.8 Mean change from baseline (for both groups)*: 0.67%
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
0 12 24 38 52
Time (weeks)
*Per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysis
Stein. ADA. 2006. Late-breaking clinical presentation
25. Sitagliptin once daily showed better safety
and tolerability profile compared
with glipizide (52 weeks)
Change in Body Weight 50
Hypoglycaemia
94
Δ between groups = -2.5 kg (P<0.001)
40
92
32%
Body weight (kg)
Incidence (%)
30 P<0.001
90
20
88
10
4.9%
86 0
0 12 24 38 52
Time (weeks) Week 52
Glipizide (n=411) Glipizide (n=584)
Sitagliptin 100 mg QD (n=382) Sitagliptin 100 mg (n=588)
Stein. ADA. 2006. Late-breaking clinical presentation
26. Initial combination of vildagliptin
and pioglitazone (24 weeks)
Mean HbA1c reduction from baseline=8.7%
0.0
Change from baseline in HbA1c (%)
-0.5
-1.0
-1.1
-1.5 -1.4
-2.0 -1.9
*
Vildagliptin 100 mg daily (n=150)
-2.5 Pioglitazone 30 mg daily (n=157)
Vildagliptin 100 mg daily + pioglitazone
Intention-to-treat population 30 mg daily (n=146)
*P=0.001 vs pioglitazone 30 mg; low-dose combination arm is not included
Nathwani. ADA. 2006. Late-breaking clinical presentation
27. Metabolic effects of DPP-4 inhibitors
• Small decrease in VLDL with corresponding
increase in HDL
– No change in LDL
• Small decrements in blood pressure
• Small decrease in high-sensitivity C-reactive protein
• Animal models may reveal improvement in β-cell
mass
– Studies in humans have not yet been performed
to validate these findings
28. Safety and tolerability overview
of DPP-4 inhibitors
• Well tolerated in phase 1-3 trials; in completed and ongoing studies,
>4000 patients on sitagliptin (to doses of 200 mg QD in phase 3
studies)
• Pre-specified pooled phase 3 analysis, including monotherapy and
combination studies: over 1500 patients on sitagliptin and over 750
patients on placebo
– Summary measures of adverse experiences (AEs) were similar to
placebo
• Including overall clinical AEs, serious AEs, discontinuations due
to AEs, drug-related AEs, laboratory AE summary measures
– Small differences in incidence of specific AEs
• Between-group difference (sitagliptin 100 mg and placebo
group) in incidence >1% for only 1 specific AE (nasopharyngitis
1.2% difference)
29. Summary
• DPP-4 inhibitors administered for the treatment of Type 2 diabetes
– Significant reductions in HbA1c across a range of starting
HbA1c levels in monotherapy and combination use
– Sustained HbA1c reduction to 1 year
– Improvements in multiple measures of β-cell function
• Compared with a sulfonylurea or TZD, DPP-4 inhibitors provide
– Similar efficacy
– Superior improvements in β-cell function, less hypoglycaemia, and
weight loss (vs weight gain)
• DPP-4 inhibitors are well tolerated with summary measures of AEs similar
to placebo