Effects of Saxagliptin on Endothelial Function
Condition: Diabetes Mellitus Type 2
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

Summary: 
      Diabetes mellitus is a metabolic disease with a growing prevalence worldwide. Currently
      available therapies for type 2 diabetes have various limitations and are associated with
      increased risk of hypoglycemia, weight gain, gastrointestinal side effects or edema and heart
      failure.

      A new and promising class of drugs are the gliptins. Several efficacy studies demonstrated a
      significant improvement of HbA1c with gliptins. In addition, gliptins improved fasting as
      well as prandial glucose levels and did not induce weight gain. Due to these positive
      metabolic effects in combination with a very small spectrum of side effects gliptins might
      very well be part of the standard therapy for type 2 diabetes in the future.

      Apart form surrogate parameters like reduction of fasting and postprandial blood glucose
      levels or improvement of HbA1c, the effect of gliptins on micro- and macrovascular function
      and cardiovascular outcome has not been the primary focus of current studies. Diabetes
      mellitus is strongly associated with microangiopathy and macroangiopathy and is a strong
      independent risk factor for cardiovascular disease and cardiovascular mortality. Endothelial
      dysfunction which plays a crucial role in the atherosclerotic process is commonly observed in
      patients with diabetes mellitus and already prediabetes and has - amongst other factors -
      been linked to fasting and postprandial hyperglycemia. Taken into account that gliptins
      reduce hyperglycemia and hyperglycemic peaks by preventing inactivation of GLP-1, which
      exerted beneficial effects on the endothelium in previous studies it is of major interest
      whether therapy with gliptins improves endothelial function.
    

Detailed description: 
      Diabetes mellitus is a metabolic disease with a growing prevalence worldwide, affecting 171
      million people in 2000 and an expected 366 million people in 2030 [1].. Currently available
      therapies for type 2 diabetes have various limitations and are associated with increased risk
      of hypoglycemia, weight gain, gastrointestinal side effects or edema and heart failure.

      A new and promising class of drugs are the gliptins. Gliptins act by inhibiting the enzyme
      dipeptidyl peptidase-4 (DPP-4), which is responsible for the rapid inactivation of
      glucagon-like peptide-1 (GLP-1) - an incretin hormone of the gut [2-4], thereby enhancing and
      prolonging the effects of GLP-1. GLP-1 - member of the incretin hormones - is released into
      the blood after meal ingestion and stimulates the insulin secretion in a glucose dependent
      manner. This accounts for the marked prandial insulin response, which prevents prandial
      hyperglycemia. Several efficacy studies demonstrated a significant improvement of HbA1c with
      gliptins. In addition, gliptins improved fasting as well as prandial glucose levels and did
      not induce weight gain. Due to these positive metabolic effects in combination with a very
      small spectrum of side effects gliptins might very well be part of the standard therapy for
      type 2 diabetes in the future.

      Apart form surrogate parameters like reduction of fasting and postprandial blood glucose
      levels or improvement of HbA1c, the effect of gliptins on micro- and macrovascular function
      and cardiovascular outcome has not been the primary focus of current studies. However,
      infusion of GLP-1, the incretin hormone affected by gliptins has been reported to ameliorate
      endothelial dysfunction in patients suffering from coronary artery disease [5] and it was
      recently shown that infusion of GLP-1 into healthy human subjects increases both normal and
      ACh-induced vasodilatation [6]. In studies on rats with diabetes, GLP-1 infusion nearly
      re-established their normal vascular tone [7] and there are further data from experimental
      animals that indicate a beneficial effect of GLP-1 on endothelial function [8].

      Diabetes mellitus is strongly associated with microangiopathy and macroangiopathy and is a
      strong independent risk factor for cardiovascular disease and cardiovascular mortality [9].
      Endothelial dysfunction which plays a crucial role in the atherosclerotic process is commonly
      observed in patients with diabetes mellitus and already prediabetes and has - amongst other
      factors - been linked to fasting and postprandial hyperglycemia. Taken into account that
      gliptins reduce hyperglycemia and hyperglycemic peaks by preventing inactivation of GLP-1,
      which exerted beneficial effects on the endothelium in previous studies it is of major
      interest whether therapy with gliptins improves endothelial function of the micro- and
      macrovasculature and thereby might prove to affect cardiovascular morbidity and mortality in
      diabetic patients in the long term. The retina offers the unique opportunity to directly
      visualize and investigate the microvasculature in vivo [10-14].

      References

        1. Wild S, Roglic G, Green A, Sicree R, King H: Global prevalence of diabetes: Estimates
           for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-1053.

        2. Deacon CF, Ahren B, Holst JJ: Inhibitors of dipeptidyl peptidase iv: A novel approach
           for the prevention and treatment of type 2 diabetes? Expert Opin Investig Drugs
           2004;13:1091-1102.

        3. Deacon CF: Therapeutic strategies based on glucagon-like peptide 1. Diabetes
           2004;53:2181-2189.

        4. Holst JJ, Deacon CF: Glucagon-like peptide-1 mediates the therapeutic actions of dpp-iv
           inhibitors. Diabetologia 2005;48:612-615.

        5. Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, Sjoholm A: Effects of
           glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable
           coronary artery disease. Am J Physiol Endocrinol Metab 2004;287:E1209-1215.

        6. Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ: Beneficial effects of
           glp-1 on endothelial function in humans: Dampening by glyburide but not by glimepiride.
           Am J Physiol Endocrinol Metab 2007;293:E1289-1295.

        7. Ozyazgan S, Kutluata N, Afsar S, Ozdas SB, Akkan AG: Effect of glucagon-like
           peptide-1(7-36) and exendin-4 on the vascular reactivity in
           streptozotocin/nicotinamide-induced diabetic rats. Pharmacology 2005;74:119-126.

        8. Yu M, Moreno C, Hoagland KM, Dahly A, Ditter K, Mistry M, Roman RJ: Antihypertensive
           effect of glucagon-like peptide 1 in dahl salt-sensitive rats. J Hypertens
           2003;21:1125-1135.

        9. Laakso M: Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes
           1999;48:937-942.

       10. Delles C, Michelson G, Harazny J, Oehmer S, Hilgers KF, Schmieder RE: Impaired
           endothelial function of the retinal vasculature in hypertensive patients. Stroke
           2004;35:1289-1293.

       11. Harazny JM, Ritt M, Baleanu D, Ott C, Heckmann J, Schlaich MP, Michelson G, Schmieder
           RE: Increased wall:Lumen ratio of retinal arterioles in male patients with a history of
           a cerebrovascular event. Hypertension 2007;50:623-629.

       12. Ritt M, Schmieder RE: Wall-to-lumen ratio of retinal arterioles as a tool to assess
           vascular changes. Hypertension 2009;54:384-387.

       13. Oehmer S, Harazny J, Delles C, Schwarz T, Handrock R, Michelson G, Schmieder RE:
           Valsartan and retinal endothelial function in elderly hypertensive patients. Blood Press
           2006;15:185-191.

       14. Ott C, Schlaich MP, Harazny J, Schmidt BM, Michelson G, Schmieder RE: Effects of
           angiotensin ii type 1-receptor blockade on retinal endothelial function. J Hypertens
           2008;26:516-522.
    

Intervention name(s): Saxagliptin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): orally 5 mg/d for 6 weeks; orally for 6 weeks
Other intervention name(s): Onglyza
Intervention MeSH terms: Saxagliptin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment