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At least 3 other reasons why you should use GLP1-RAs early in diabetes management

13th July 2019, Dr Chee L Khoo

New anti-diabetic agents are coming thick and fast. It is easy to get confused as to which agent to use. For injectables, there are currently at least a dozen different insulin preparations and 5 GLP1 -Receptor Analogues (GLP1-RAs) available in Australia. Some are on the Pharmaceutical Benefits Scheme (PBS), some not. It is easy to put them all in the too hard basket. To some of you, they are all injectables and they belong to the specialist endocrinologist domains. Nothing can be further from the truth for the GLP1-RAs. This hesitation to use GLP1-RAs because they are injectables may be compromising your patients’ clinical outcomes.

GLP-1RAs are a relatively new class of injectables that are effective at reducing HbA1c, have a low risk of hypoglycaemia especially when given as monotherapy without sulphonylureas (SU) or insulin. They have the potential for weight loss which is most helpful as many patients with T2DM are either overweight or obese. In addition, GLP-1RAs may help to overcome some of the common barriers to self-injection by offering a lower injection burden (i.e. weekly vs. daily injections) and devices with a ‘hidden’ pre-attached needle (e.g. dulaglutide). There are no dose adjustments needed by patient or physician which remove that complexity in management. Many patients know about the risk of hypoglycaemia with insulin and we can reassure patients that this class of injectables have very low risk of that.

In addition to the low incidence of hypoglycaemia, weight loss potential and the simplicity of its regimen, there are 3 other major reasons why you should strongly consider GLP1-RAs very early in your diabetes treatment algorithm:

1. GLP1-RA corrects a core defect in T2DM

The ominous octet refers to the eight underlying pathophysiological defects in T2DM (1):

  1. Decrease insulin secretion (beta cell failure)
  2. Increased glucagon secretion (alpha cell overstimulation)
  3. Increased hepatic glucose production
  4. Decreased glucose uptake
  5. Increased lipolysis
  6. Increased glucose reabsorption
  7. Neurotransmitter dysfunction
  8. Decreased incretin effect (GLP1 deficiency)

 

GLP1-RAs attempts to restore the last of that list of pathophysiological defects. GLP-1RAs work by stimulating insulin secretion and inhibiting glucagon secretion in a glucose-dependent manner which explains their associated low risk of hypoglycaemia. Importantly, GLP-1RAs are able to improve b-cell sensitivity to glucose and have the ability to improve the glycaemic profile indirectly by delaying gastric emptying, inhibiting hepatic glucose production and suppressing appetite, thereby promoting weight loss.

DPP4 inhibitors also tries to correct the decreased incretin effect in T2DM but often, in the later stage of T2DM, there are no more GLP1 for the DPP4 inhibitors to work on

2. Cardiovascular benefits of GLP1-RAs

Liraglutide and semaglutide (not available in Australia yet) have demonstrated a reduction in the risk of major adverse cardiovascular events  (MACE)  [2,3],  The once-weekly injectable glucagon-like peptide-1 (GLP-1) agonist dulaglutide for the treatment of type 2 diabetes significantly reduce the risk of MACE in the REWIND cardiovascular (CV) outcomes trial, primarily by reducing the risk of stroke (4). It is important to note that while GLP-1RAs have demonstrated CV safety, not all result in an  actual reduction in CV  adverse events. Exenatide QW (Bydureon®) and lixisenatide (Lyxumia®) both reported to be non-inferior to placebo for MACE.

It is uncertain whether the differences between the different GLP1-RAs are real or whether they relate to the different populations being studied in the different trials.

3. Pleiotropic effects of GLP1-RA

In T2DM, there is progressive loss of β-cells by apoptosis. Well, at least in animal models, GLP1 appears to reduce beta cell apoptosis and may even stimulate β-cells proliferation under certain metabolic circumstances (5-7). GLP-1 has been reported to alleviate glucotoxicity, lipotoxicity, excess nitric oxide (NO), Ca2+ depletion, oxidative stress, and cytokine-induced ER stress in b-cells. Treatment with GLP-1 analogues in a high fructose fed rat model resulted in apparent inhibition of β-cells autophagy and increase in β-cells mass and function (95). Unfortunately, the results in human cells are inconsistent depending on different physiological states (8-10).

However, in the DURATION 1 trial, patients randomised to Exenatide QW 2mg (i.e. Bydureon®) not only had significant and sustained improvements in several cardiovascular risk factors, including body weight, diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol but also had sustained glycaemic improvements from baseline even after 7 years (11). 53% of patients who completed 7 years of treatment did not require additional glucose lowering therapies. This suggest to me that Bydureon® is keeping the β-cells from dying and delaying or stopping the progression of diabetes.

GLP-1RAs are effective at improving glycaemic control and, by virtue of their mechanism of action, have a low risk of hypoglycaemia combined with the potential for weight loss. Considering that many  patients with T2DM are obese, these agents represent important options among the current therapeutic arsenal.  Further, there are suggestions that some of these agents may slow down the progression of diabetes.

Treatment selection should take into consideration efficacy, adverse event profile, hypoglycaemia risk, weight control, presence of comorbidities and CV/CKD risk, as well as cost to patient.

Recommended reading: GLP-1 Receptor Agonists for Type 2 Diabetes and Their Role in Primary Care: An Australian Perspective.

References:

  1. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–95.
  2. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.
  3. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.
  4. Gerstein H, Colhoun H, Dagenais Gilles, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised controlled trial. Lancet June 09, 2019, Vol 394 (10193), 121-130.
  5. Wang Q, Li L, Xu E, Wong V, Rhodes C, Brubaker P. Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells. Diabetologia (2004) 47:478–87. doi: 10.1007/s00125-004-1327-5
  6. Miao XY, Gu ZY, Liu P, Hu Y, Li L, Gong YP, et al. The human glucagonlike peptide-1 analogue liraglutide regulates pancreatic beta-cell proliferation and apoptosis via an AMPK/mTOR/P70S6K signaling pathway. Peptides (2013) 39:71–9. doi: 10.1016/j.peptides.2012.10.006
  7. Buteau J, Foisy S, Rhodes CJ, Carpenter L, Biden TJ, Prentki M. Protein Kinase Cz activation mediates glucagon-like peptide-1–induced pancreatic b-cell proliferation. Diabetes (2001) 50:2237–43. doi: 10.2337/diabetes.50.10.2237
  8. Dai C, Hang Y, Shostak A, Poffenberger G, Hart N, Prasad N, et al. Age-dependent human b cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. J Clin Investig. (2017) 127:3835–44. doi: 10.1172/JCI91761
  9. Ellenbroek JH, Töns HA, Westerouen van Meeteren MJ, de Graaf N, Hanegraaf MA, Rabelink TJ, et al. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice. Diabetologia (2013) 56:1980–6. doi: 10.1007/s00125-013-2957-2
  10. Gedulin BR,Nikoulina SE, Smith PA, Gedulin G,Nielsen LL, Baron AD, et al. Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight. Endocrinology (2005) 146:2069–76. doi: 10.1210/en.2004-1349
  11. Philis-Tsimikas, C.H.Wysham, E. Hardy, et al. Efficacy and tolerability of exenatide once weekly over 7 years in patients with type 2 diabetes: An open-label Extension of the DURATION-1 Study. Journal of Diabetes and Its Complications. https://doi.org/10.1016/j.jdiacomp.2018.11.012
  12. Roy Rasalam, John Barlow, Mark Kennedy, Pat Phillips, Alan Wright. GLP-1 Receptor Agonists for Type 2 Diabetes and Their Role in Primary Care: An Australian Perspective. Diabetes Ther (2019) 10:1205–1217 https://doi.org/10.1007/s13300-019-0642-2

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