Episode 52
Host Aaron Lohr talks about incretins and type 2 diabetes management with Zhenqi Liu, MD, the James M. Moss Professor of Diabetes at the University of Virginia School of Medicine. This episode is certified for up to 0.5 American Medical Association Physician’s Recognition Award (AMA PRA) Category 1 credits and American Board of Internal Medicine Maintenance of Certification (ABIM MOC) points. Access our complementary certification course.
This activity is supported by an educational grant from Lilly.
Thank you for having me here.
Twincretins are agents that are able to activate both the glucagon-like peptide 1, in short GLP-1, receptor and glucose-dependent insulinotropic polypeptide, in short the GIP receptor. To understand the importance of the twincretins, let us first review the physiology and pathophysiology behind the incretin hormones.
Both GLP-1 and GIP are incretin hormones secreted from the intestine upon nutrients intake. They are responsible for regulating post-meal insulin secretion, and this is what we call incretin effect. This effect helps to decrease post-meal glucose excursion. GLP-1 and GIP exert their effects by binding to their specific receptors, and those receptors belong to the G-protein coupled receptor family. In pancreatic islets, both GLP-1 receptor and GIP receptor are expressed in β cells, but only GIP receptor is the predominant receptor in α cells. In addition to regulating insulin secretion, GLP-1 and GIP affect the functions of many tissues and organs that express their respective receptors.
There are several major differences between GLP-1 and GIP actions. GLP-1 inhibits appetite and food intake, whereas GIP generally has no significant impact on food intake. GLP-1 suppresses postprandial glucagon secretion, while GIP enhances postprandial glucagon response. They both slow gastric emptying, but GLP-1 is much more potent than GIP. In adipose tissues, GIP but not GLP-1 facilitates fat deposition, so there’s a possibility that GIP might promote obesity. Additionally, GIP receptor is expressed in bone, including osteoclasts, osteoblasts, and osteocytes, and mediates meal-induced suppression of bone resorption.
In people with type 2 diabetes, the incretin effect is reduced or completely lost. However, there is a big difference between the two incretin hormones. Infusion studies have shown that GLP-1 is capable of stimulating insulin secretion in people with type 2 diabetes, but GIP is almost ineffective. It has been reported that hyperglycemia reduces GIP receptor expression and β-cell responses to GIP. On the other hand, better glycemic control with intensive insulin therapy can partially restore GIP’s insulinotropic effect possibly by restoring GIP receptor expression in the islets.
Because of the similarity and differences between GLP-1 and GIP in healthy humans and those with type 2 diabetes, it has long been speculated that people with type 2 diabetes might benefit from synergistic or additive actions between these two incretin hormones.
The fact that people with type 2 diabetes have a decreased or complete loss of the incretin effect but a robust insulin secretion response to GLP-1 infusion makes GLP-1 a clear therapeutic target for type 2 diabetes management. Two approaches have been successfully used to develop GLP-1–based therapeutic agents.
The first approach was to inhibit the activity of an enzyme called dipeptidyl-peptidase 4, in short DPP4. This enzyme breaks down GLP-1 and GIP in vivo and this is the reason why GLP-1 and GIP both have a very short half-life of a few minutes. Inhibition of this enzyme increases the endogenous GLP-1 concentrations by approximately 2–3-fold. We have nowadays 4 DPP4 inhibitors available in the U.S. markets. They are sitagliptin, saxagliptin, linagliptin, and alogliptin. Another DPP4 inhibitor called vildagliptin is available outside of the U.S. market. DPP4 inhibitors cause a moderate decrease in hemoglobin A1c by approximately 0.5 to 0.8 percent. These agents are weight-neutral. Therefore, they are a good choice in those patients who are not at high risk of or have established atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure and need additional help to control glycemia after Metformin and lifestyle modification.
The second approach was the development of GLP-1 analogs or GLP-1 receptor agonists. These agents are resistant to DPP4 degradation with much longer half-life than native GLP-1. We now have 6 injectable agents and one oral agent available for clinical use. The injectables include daily exenatide, weekly exenatide, weekly dulaglutide, daily liraglutide, daily lixisenatide, and weekly semaglutide. Semaglutide is also available in daily oral preparation. These agents have much stronger potency in decreasing glycemia than DPP4 inhibitors and can reduce hemoglobin A1c by up to 2 percent. Another major benefit is that use of these agents is associated with a variable degree of weight loss. They should be considered in those patients whose glycemic control is well above the glycemic target after Metformin and lifestyle modification, particularly if they are overweight. In those at high risk of or having established atherosclerotic cardiovascular disease or chronic kidney disease, agents with proven cardiovascular and renal benefits should be considered independently of baseline hemoglobin A1c, individualized hemoglobin A1c target, or Metformin use.
In addition to the islet β cells, many tissues express GLP-1 receptors, including the central nervous system, cardiovascular system, liver, adipose tissue, kidneys, and the gastrointestinal tract. As a result, there are many other actions of GLP-1 receptor agonist beyond glycemic control that can benefit patients with type 2 diabetes. The most important nonglycemic control actions include the cardiovascular protection, renal protection and weight loss. Thus far, three GLP-1 receptor agonists have been demonstrated to have cardiovascular and renal protective benefits. These are once-daily liraglutide, once-weekly dulaglutide, and once-weekly semaglutide. In terms of weight loss, two GLP-1 receptor agonists have received FDA-approved, specific indication for weight loss. They are liraglutide at 3 mg once daily and semaglutide at 2.4 mg once weekly. Additional, multiple studies have shown a promising effect of GLP-1 receptor agonist in reducing liver fat accumulation, so these agents are potentially very useful for the treatment of nonalcoholic fatty liver disease, which is frequently associated with type 2 diabetes.
GIP actually was discovered well before GLP-1, but the understanding of GIP’s physiology lags behind. GIP receptor and GLP-1 receptor share approximately 40 percent sequence homology, but they display extremely high selectivity for their respective ligands. As a result, previous efforts have been focused on developing respective ligands for either GLP-1 receptor or GIP receptor. As I just mentioned, GLP-1–based therapy has evolved rapidly to become major treatment options for people with type 2 diabetes. On the other hand, the development of GIP-based therapy has been limited due to the fact that the GIP-mediated insulin secretion is impaired in people with type 2 diabetes and the possible obesity-promoting action of GIP.
Early work using the loss-of-function approach suggested that GIP promotes obesity by increasing fat deposition. This has limited the interest in developing GIP receptor agonist and promoted the interest in developing its antagonist to treat type 2 diabetes. While the loss-of-function studies suggest that GIP drives weight gain, there’s no convincing evidence that GIP receptor agonism increases adiposity or body weight. Thus far, there is evidence supporting both cases, and this apparent paradox has not been reconciled. It has been speculated that GIP receptor antagonism may enhance GLP-1 receptor activity while chronic GIP agonism may downregulate and desensitize GIP receptor activity. Clearly more study is needed for a better understanding of the GIP paradox.
Given the difference in physiology and pathophysiology between GLP-1 and GIP, it has long been speculated that a combined activation of the GIP as well as the GLP-1 system could result in beneficial effects beyond those obtained by a simple addition of the two separate effects, either by concomitant or by sequential activation of the two hormone systems. Multiple pre-clinical studies have suggested the possibility of a synergistic effect between GLP-1 receptor agonist and GIP receptor agonist in terms of glycemic control and weight loss, and these results have served as both the basis and the motivation for the development of dual GLP-1 receptor and GIP receptor agonist to treat type 2 diabetes.
Another corroborative evidence is that bariatric surgery, which is the most effective treatment for type 2 diabetes and obesity, is associated with elevated plasma levels of GLP-1, GIP, and glucagon and also altered GIP pattern with an earlier rise. The structural homology among GLP-1, GIP, and glucagon allows for the development of intermixed, unimolecular peptides with activity at each of their respective receptors.
Recently, chimeric peptides that combine elements of both GLP-1 and GIP and are capable of activating both receptors have been demonstrated to have remarkable glucose lowering efficacy and weight-loss effect in people with type 2 diabetes and obesity. There are multiple agents under development with a clear front runner called tirzepatide. Tirzepatide is a 39-amino acid synthetic peptide with agonist activity at both GIP and GLP-1 receptors. It includes a C20 fatty di-acid moiety. This allows a half-life extension to approximately five days. Thus far, five large, randomized phase-3 trials in the SURPASS program have been completed, evaluating the efficacy and safety of tirzepatide.
The first study is the SURPASS-1 study. It evaluated tirzepatide at three doses. That is 5 mg, 10 mg, 15 mg once weekly as monotherapy against placebo among people with type 2 diabetes inadequately controlled by diet and exercise alone and if they were naïve to injectable diabetes therapy. At 40 weeks, tirzepatide lowered hemoglobin A1c by up to 2 percent and dose dependently decreased body weight ranging from 7 to 9.5 kg. It was well tolerated, with a safety profile similar to that of GLP-1 receptor agonists, and there was no increased risk of hypoglycemia.
The SURPASS-2 study compared tirzepatide to injectable semaglutide in people with type 2 diabetes. It was an open-label, 40-week trial with patients being randomized to tirzepatide — again three doses: 5 mg, 10 mg, or 15 mg once weekly — or semaglutide 1 mg once weekly as a control. Tirzepatide was superior to semaglutide in decreasing hemoglobin A1c as well as reducing weight.
The SURPASS-3 study compared tirzeptide — 5 mg, 10 mg, or 15 mg once weekly — with once-daily injection of titrated insulin degludec in people with type 2 diabetes inadequately controlled by Metformin. Overall, tirzeptide was superior to titrated insulin degludec with greater reductions in hemoglobin A1c and body weight at week 52 and a lower risk of hypoglycemia.
The SURPASS-4 study compared tirzepatide at either 5 mg, 10 mg, or 15 mg once weekly with insulin glargine in type 2 diabetes with either established cardiovascular disease or increased cardiovascular risk. Compared with glargine, tirzepatide demonstrated greater hemoglobin A1c reduction with a lower incidence of hypoglycemia at week 52.
The SURPASS-5 study evaluated tirzepatide as an add-on to insulin glargine compared to placebo in patients with uncontrolled type 2 diabetes. Tirzepatide was more effective than placebo in improving glycemia at week 40.
Additionally, there are several ongoing phase-3 studies involving tirzepatide, including the SURPASS-CVOT in people with type 2 diabetes and confirmed cardiovascular disease and the SURMOUNT-1 study, which tests the ability of tirzepatide to produce weight loss in people with type 2 diabetes and obesity over 72 weeks. Both are estimated to complete in 2024. A meta-analysis, including seven randomized, controlled trials with a duration of at least 26 weeks, showed that tirzepatide did not increase the risk of major cardiovascular events in participants with type 2 diabetes.
This is an exciting area in diabetes research and management. Right now multiple co-agonists are under active development. GLP-1, GIP, and glucagon share complimentary activities and the tissue-specific distribution of their respective receptors, thus functions raise the possibility for synergistic interactions at the systemic level. As such, interests are very high in developing a variety of co-agonists. Because of the similar structures at the N-terminal region shared by these peptides, it is technically not difficult to synthesize sequence-intermixed peptide for this purpose.
In addition to unimolecular GIP receptor and GLP-1 receptor agonist, GLP-1 receptor and glucagon receptor dual agonist and GLP-1 receptor, GIP receptor, and glucagon receptor triagonist are all under active development.
One synthetic peptide triagonist called SAR441255 should be mentioned here. It is a unimolecular GLP-1 receptor, GIP receptor, and glucagon receptor triagonist. It has high and balanced activity at each receptor. Pre-clinical data have shown added benefit for triagonist that integrate glucagon receptor agonism over GLP-1 receptor and GIP receptor co-agonist. A recently published phase-1 study showed that in healthy humans, SAR441255 improved glycemic control during a mixed-meal tolerance test and was well tolerated. More studies are clearly needed and are ongoing.
Thank you for having me here. It has been fun!
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