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The Incretin System and Type 2 Diabetes
effect may reflect the fact that metformin increases GLP-1 secretion involved in immunoregulation in addition to its role in the incretin
and sitagliptin prolongs its half-life.
19
Measures of beta-cell function system. The possibility of immunological effects has been suggested
such as HOMA-B (12% improvement, 95% confidence interval [CI] as increased rates of infections (nasopharyngitis and urinary tract
9.45–14.60) and pro-insulin/insulin ratio (-0.06, 95% CI -0.08 to -0.04) infections) have been observed in some trials.
32
In addition, post-
were also significantly improved with sitagliptin versus placebo, marketing reports of serious allergic and hypersensitivity reactions in
although HOMA-B was not significantly improved versus active patients treated with sitagliptin, such as anaphylaxis, angioedema,
comparators (5.64%, 95% CI 0.38–10.90).
49
and exfoliative skin conditions, have been reported.
44
Overall,
however, the DPP-4 inhibitors appear to be very well tolerated in the
Saxagliptin majority of patients.
Saxagliptin has been studied as a monotherapy in treatment-naïve
patients or as an add-on therapy to metformin or an SU.
50–52
The lower Conclusions
recommended dosage of saxagliptin (2.5mg/day) should be used in Incretin-based antidiabetes therapies offer patients the potential to
individuals with moderate or severe renal disease.
53
In treatment-naïve target key pathogenic mechanisms in type 2 diabetes in addition
patients, 24 weeks of saxagliptin monotherapy (10mg dose) resulted in to lowering blood glucose. Across trials, GLP-1 receptor agonists
an HbA
1c
reduction from baseline (mean 7.9%) of -0.54 versus +0.19% for induced mean HbA
1c
reductions of approximately 0.8–1.5%. For DPP-4
placebo (p<0.0001).
50
Adjusted mean fasting plasma glucose was inhibitors HbA
1c
reductions were around 0.7–1.0%. The GLP-1 receptor
significantly reduced from baseline at -17mg/dl with saxagliptin versus agonists also bring additional benefits, such as weight loss and blood
+6mg/dl for placebo (p<0.0001).
50
No cases of confirmed hypoglycemia pressure reduction. These treatments are simple for patients to self-
were reported.
50
In patients failing with metformin monotherapy, administer and titrate and, for liraglutide, dosing is not dependent on
saxagliptin (10mg/day) plus metformin demonstrated statistically food intake. The risks of serious adverse side effects, such as
significant adjusted mean decreases from baseline to week 24 versus (particularly severe) hypoglycemia, are low; this, together with weight
placebo in HbA
1c
(-0.58 versus +0.13%; p<0.0001) and fasting plasma benefits and less/no necessity for daily blood glucose monitoring, is
glucose (-20.50 versus +1.24mg/dl; p<0.0001).
52
Approximately 5% of likely to facilitate improved patient adherence.
patients reported hypoglycemic episodes in each treatment arm.
52
Weight reductions were 0.53kg for saxagliptin plus metformin and 0.92kg From a physician’s perspective, therapies that target the incretin
for placebo plus metformin.
52
A third study examined the efficacy of system may be a useful treatment option for patients with type 2
adding saxagliptin to suboptimal doses of glyburide (7.5mg/day) versus diabetes, due to their clinical efficacy, good tolerability, and low risk
uptitration of glyburide (to a maximum of 15mg/day).
51
Saxagliptin 5mg of hypoglycemia and their potential to improve beta-cell function.
reduced HbA
1c
by 0.64 versus +0.08% for uptitrated glyburide (p<0.0001) Incretin-based therapies offer a promising novel treatment modality
and fasting plasma glucose by -10 versus +1mg/dl for uptitrated for individuals with diabetes, with added benefits and the potential
glyburide.
51
Reported hypoglycemic events were comparable for for beta-cell protection; the latter now requires study in long-term
saxagliptin (14.6%) and uptitrated glyburide (10.1%).
51
clinical trials. n
Comparison of the Two Drug Classes
Anthony H Barnett, MD, is a Professor of Medicine,
Like GLP-1 receptor agonists, DPP-4 inhibitors are associated with a low
Consultant Physician, and Clinical Director of Diabetes and
risk of hypoglycemia. Few hypoglycemic events have been reported in Endocrinology at the University of Birmingham and Heart
clinical trials, although as with GLP-1 receptor agonists higher rates
of England NHS Foundation Trust, which has one the
largest diabetes and weight management units in the UK.
have been reported in combination therapy with SUs. In contrast to
His research interests include the genetics of diabetes, the
GLP-1 receptor agonists, DPP-4 inhibitors are weight-neutral. Adverse causes of complications of diabetes, the development of
gastrointestinal events are less likely with DPP-4 inhibitors than with
new therapies to treat diabetes and its long-term vascular
complications, and health-service-related research
GLP-1 receptor agonists. These differences between the two drug
(including ‘difficult-to-reach’ groups). In addition to publishing over 500 original papers,
classes may reflect the level of GLP-1 receptor stimulation. While the Professor Barnett has written many books, review articles, and editorials on diabetes and
DPP-4 inhibitors can restore endogenous GLP-1 concentrations in
has contributed chapters to major textbooks on the subject. He also regularly acts as
adviser to the National Institute for Health and Clinical Excellence (NICE), the European
individuals with type 2 diabetes, they do not raise GLP-1 to the
Medicines Agency (EMEA), and the National Prescribing Centre on diabetes-related
pharmacological levels achieved by the GLP-1 receptor agonists.
13,20
therapies. For two years, he held the position of Medical Research Council Senior Fellow
in Diabetes at King’s College Hospital, London. He gained his MD from King’s College,
University of London, and subsequently trained at a number of hospitals and universities.
In addition to differences in GLP-1 activity, there is a potential concern
with the specificity of action of DPP-4 inhibitors because DPP-4 is
1. Centers for Disease Control and Prevention, National diabetes 3. Nauck M, Stöckmann F, Ebert R, et al, Reduced incretin 5. Nauck MA, Kleine N, Orskov C, et al., Normalization of
fact sheet: general information and national estimates on diabetes in effect in type 2 (non-insulin-dependent) diabetes, fasting hyperglycaemia by exogenous glucagon-like peptide
the United States, 2007, Atlanta, GA, US Department of Health Diabetologia, 1986;29:46–52. 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic
and Human Services, Centers for Disease Control and 4. Nauck MA, Heimesaat MM, Orskov C, et al., Preserved patients, Diabetologia, 1993;36:741–4.
Prevention, 2008. incretin activity of glucagon-like peptide 1 [7-36 amide] but 6. Aaboe K, Krarup T, Madsbad S, et al., GLP-1: physiological
2. International Diabetes Federation. The Diabetes Atlas, third not of synthetic human gastric inhibitory polypeptide in effects and potential therapeutic applications, Diabetes Obes
edition, IDF, 2008. Available at: www.eatlas.idf.org/ (accessed patients with type-2 diabetes mellitus, J Clin Invest, 1993;91: Metab, 2008;10:994–1003.
November 30, 2009). 301–7. 7. Flint A, Raben A, Astrup A, et al., Glucagon-like peptide 1
US ENDOCRINOLOGY 61
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