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Diabetes Management DPP-4 Inhibitors
change from baseline to end-point was -0.7 and -1.1% in patients sminotransferase [ALT] >3 x upper limit of normal [ULN]) was observed
receiving 50 and 100mg, respectively, suggesting a dose–response with vildagliptin relative to comparators, although this did not translate
effect.
87
Improvements were also seen in fasting and post-prandial into an increased risk for hepatic adverse events.
97
Nonetheless,
glucose levels. Gastrointestinal adverse events were significantly less assessment of hepatic function is recommended prior to initiation of
frequent among patients who received vildagliptin 50mg daily in therapy and monitoring should continue while on treatment, consistent
combination with metformin than in those receiving metformin and with the product label. Use of vildagliptin is not recommended in
placebo,
87
again suggesting that the addition of a DPP-4 inhibitor may patients with moderate to severe renal impairment, including patients
improve the tolerability of metformin. on hemodialysis, due to lack of clinical experience.
Vildagliptin was non-inferior to pioglitazone as add-on therapy to stable- Vildagliptin 50mg once or twice daily was not associated with an
dose metformin over 24 weeks, with comparable HbA
1c
reductions increased risk of pancreatitis-related adverse experiences relative to
maintained in both groups during a 28-week extension period.
89,90
comparators.
98
Another analysis showed no increased risk of infections
Hypoglycemia occurred rarely in both groups; however, pioglitazone and infestations with vildagliptin.
99
caused significant weight gain from a baseline of 2.4kg compared with
vildagliptin. Vildagliptin demonstrated comparable glycemic efficacy to The cardiovascular safety of vildagliptin was assessed in a meta-analysis
glimepiride when added to ongoing metformin and displayed favorable of 20 phase III double-blind clinical trials including 6,978 patients treated
tolerability with reduced bodyweight relative to glimepiride and a 10-fold with vildalgiptin compared with 4,773 patients in placebo or active-
lower incidence of hypoglycemia at 52 weeks.
91
Vildagliptin (50 or 100mg controlled treatment groups. Vildagliptin was not associated with an
daily) was also well tolerated and improved glycemic control compared increased risk for adjudicated cardiovascular and cerebrovascular
with placebo in patients failing monotherapy with a sulfonylurea
92
or events: odds ratio 0.89 (95% CI 0.75–1.05) and 1.05 (95% CI 0.97–1.15) for
thiazolidinedione
93
in studies of 24 weeks duration. vildagliptin 50mg once daily and 50mg twice daily, respectively.
100
Add-on Therapy to Insulin Comparison of Agents
Vildagliptin was studied in 296 patients with type 2 diabetes Although several studies are under way, at present little evidence
inadequately controlled on insulin monotherapy.
94
The mean diabetes exists from direct head-to-head studies to distinguish among the
duration on entry was 14.7 years, duration of insulin use six years, and DPP-4 inhibitors or compare these agents with GLP-1 analogs with
mean insulin dose 82 units per day, indicating advanced disease. The respect to efficacy or safety. One study compared the effectiveness of
adjusted mean change in HbA
1c
from a baseline average of 8.4% to 24 vildagliptin (50mg twice daily) and sitagliptin (100mg once daily) in just
weeks was -0.5 and -0.2% in patients receiving vildagliptin and placebo, 63 patients using metformin and/or other hypoglycemic agents and/or
respectively. Although somewhat modest, the between-treatment insulin over six months.
101
Baseline HbA
1c
was 8.0% for sitagliptin and
difference was significant. Hypoglycemic events were less common and 7.9% for vildagliptin with reduction to 7.4 and 7.0%, respectively
less severe among patients receiving vildagliptin compared with (p=0.28). Patients treated with vildagliptin presented with a higher
placebo, which is in contrast to the previously mentioned study of post-prandial glucose; however, no differences were observed on
sitagliptin added on to insulin, likely because this study design allowed comparison of the two drugs.
adjustments of insulin dose.
Conclusions
Initial Combination Therapy The development of novel incretin-based therapies has expanded our
The efficacy and safety of initial combination therapy with vildagliptin/ armamentarium of agents for the management of type 2 diabetes.
metformin (Eucreas) was studied in treatment-naïve patients with type DPP-4 inhibitors possess a mechanism of action complementary to
2 diabetes.
95
Patients were randomized equally to receive vildagliptin currently existing therapies and have demonstrated efficacy across a
plus high-dose metformin combination therapy (50mg + 1,000mg broad range of treatment contexts. They effectively lower HbA
1c
when
twice daily), vildagliptin plus low-dose metformin (50mg + 500mg twice used as monotherapy or in combination with other antihyperglycemic
daily), vildagliptin monotherapy (50mg twice daily), or high-dose medications. Even in patients already on insulin, with more advanced
metformin monotherapy (1,000mg twice daily). Mean change in HbA
1c
disease, and the presence of significant beta-cell failure, DPP-4 inhibitors
from baseline was greater with combination therapy than with either continue to lower glucose, likely due in part to beneficial effects on the
agent as monotherapy. Rates of hypoglycemia were low with all pancreatic alpha cell and suppression of glucagon production.
treatment strategies. However, vildagliptin plus low-dose metformin
combination therapy resulted in better gastrointestinal tolerability Although head-to-head studies comparing existing DPP-4 inhibitors
than metformin monotherapy. First-line treatment with combination are lacking, they do not appear to differ significantly with respect to
vildagliptin and pioglitazone also provided better glycemic control glycemic efficacy. Compound-related differences may ultimately
than either component monotherapy and was well tolerated with low differentiate between agents in this class.
risk of hypoglycemia.
96
Established benefits of DPP-4 inhibitors include their neutral effect on
Safety weight profile and a glucose-dependent mechanism of action, which
In a large pooled safety analysis, a slightly higher risk of mild minimizes the risk of hypoglycemia. DPP-4 inhibitors are also convenient
liver enzyme elevation (aspartate aminotransferase [AST]/alanine to take due to their oral route of administration independent of meal
68 US ENDOCRINOLOGY
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