Abstract The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide–1 (GLP-1), which are secreted by cells of the gastrointestinal tract in response to meal ...ingestion, exercise important glucoregulatory effects, including the glucose-dependent potentiation of insulin secretion by pancreatic β-cells. Research on the defective incretin action in type 2 diabetes mellitus suggests that the observed loss of insulinotropic activity may be due primarily to a decreased responsiveness of β-cells to GIP. GLP-1 does retain efficacy, albeit not at physiologic levels. Accordingly, augmentation of GLP-1 is a logical therapeutic strategy to ameliorate this deficiency, although the short metabolic half-life of the native hormone renders direct infusion impractical. GLP-1 receptor agonists that resist degradation by the enzyme dipeptidyl peptidase–4 (DPP-4) and have protracted-action kinetics have been developed, and DPP-4 inhibitors that slow the enzymatic cleavage of native GLP-1 provide alternative approaches to enhancing incretin-mediated glucose control. However, GLP-1 receptor agonists and DPP-4 inhibitors are premised on highly divergent mechanisms of action. DPP-4 is ubiquitously expressed in many tissues and is involved in a wide range of physiologic processes in addition to its physiologic influence on incretin hormone biological activity. GLP-1 receptor agonists provide a pharmacologic level of GLP-1 receptor stimulation, whereas DPP-4 inhibitors appear to increase levels of circulating GLP-1 to within the physiologic range. This article examines the physiology of the incretin system, mechanistic differences between GLP-1 receptor agonists and DPP-4 inhibitors used as glucose-lowering agents in the treatment of type 2 diabetes, and the implications of these differences for treatment. The results of recent head-to-head trials are reviewed, comparing the effects of incretin-based therapies on a range of clinical parameters, including glycemia, β-cell function, weight, and cardiovascular function.
There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy ...comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to an increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative preceding the counterpoint narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative provided below, Dr. Nauck provides a defense of incretin-based therapies and that benefits clearly outweigh any concern of risk.
There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy ...comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to an increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative preceding the counterpoint narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative provided below, Dr. Nauck provides a defense of incretin-based therapies and that benefits clearly outweigh any concern of risk.
—William T. Cefalu, MD Editor in Chief, Diabetes Care
The importance of the kidney's role in glucose homeostasis has gained wider understanding in recent years. Consequently, the development of a new pharmacological class of anti-diabetes agents ...targeting the kidney has provided new treatment options for the management of type 2 diabetes mellitus (T2DM). Sodium glucose co-transporter type 2 (SGLT2) inhibitors, such as dapagliflozin, canagliflozin, and empagliflozin, decrease renal glucose reabsorption, which results in enhanced urinary glucose excretion and subsequent reductions in plasma glucose and glycosylated hemoglobin concentrations. Modest reductions in body weight and blood pressure have also been observed following treatment with SGLT2 inhibitors. SGLT2 inhibitors appear to be generally well tolerated, and have been used safely when given as monotherapy or in combination with other oral anti-diabetes agents and insulin. The risk of hypoglycemia is low with SGLT2 inhibitors. Typical adverse events appear to be related to the presence of glucose in the urine, namely genital mycotic infection and lower urinary tract infection, and are more often observed in women than in men. Data from long-term safety studies with SGLT2 inhibitors and from head-to-head SGLT2 inhibitor comparator studies are needed to fully determine their benefit-risk profile, and to identify any differences between individual agents. However, given current safety and efficacy data, SGLT2 inhibitors may present an attractive option for T2DM patients who are failing with metformin monotherapy, especially if weight is part of the underlying treatment consideration.
GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the ...original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.).
To summarize current knowledge about GLP-1 receptor agonist.
At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.
•The GLP-1 receptor agonists class comprises seven compounds/preparations with a similar mode of action.•GLP-1 receptor agonists differ with respect to pharmacokinetic properties, duration of action, and clinical effectiveness.•Plasma glucose is lowered by effects on insulin and glucagon secretion, and by decelerating gastric emptying.•GLP-1 receptor agonists lower body weight by their influence on the central nervous system.•GLP-1 R reduce cardiovascular events (myocardial infarction, stroke, and associated mortality).
The incretin effect describes the phenomenon whereby oral glucose elicits higher insulin secretory responses than does intravenous glucose, despite inducing similar levels of glycaemia, in healthy ...individuals. This effect, which is uniformly defective in patients with type 2 diabetes, is mediated by the gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The importance of the incretin effect for the maintenance of glucose homoeostasis is clearly established, and incretin-based therapies are among the most promising new therapies for type 2 diabetes. However, despite the effectiveness of these therapies in many patients, the idea that they restore the incretin effect is a common misconception. In type 2 diabetes, the endocrine pancreas remains responsive to GLP-1 but is no longer responsive to GIP, which is the most likely reason for a reduced or absent incretin effect. Incretin-based drugs, including GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, stimulate GLP-1 receptors and thus augment insulin secretion in response to both oral and intravenous glucose stimulation, thereby abolishing any potential difference in the responses to these stimuli. These drugs therefore do not restore the defective incretin effect in patients. By contrast, some bariatric surgical procedures enhance GLP-1 responses and also restore the incretin effect in obese individuals with type 2 diabetes. Thus, not all biological actions elicited by the stimulation of GLP-1 receptors lead to quantitative changes to the incretin effect.
Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose‐dependent insulinotropic polypeptide) und GLP‐1 ...(glucagon‐like peptide‐1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP‐1, L cells) gut. Together, they are responsible for the incretin effect: a two‐ to three‐fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present. This is the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP‐1 in mediating the incretin effect even in healthy subjects. However, the insulinotropic and glucagonostatic effects of GLP‐1 are preserved in subjects with type 2 diabetes to the degree that pharmacological stimulation of GLP‐1 receptors significantly reduces plasma glucose and improves glycaemic control. Thus, it has become a parent compound of incretin‐based glucose‐lowering medications (GLP‐1 receptor agonists and inhibitors of dipeptidyl peptidase‐4 or DPP‐4). GLP‐1, in addition, has multiple effects on various organ systems. Most relevant are a reduction in appetite and food intake, leading to weight loss in the long term. Since GLP‐1 secretion from the gut seems to be impaired in obese subjects, this may even indicate a role in the pathophysiology of obesity. Along these lines, an increased secretion of GLP‐1 induced by delivering nutrients to lower parts of the small intestines (rich in L cells) may be one factor (among others like peptide YY) explaining weight loss and improvements in glycaemic control after bariatric surgery (e.g., Roux‐en‐Y gastric bypass). GIP and GLP‐1, originally characterized as incretin hormones, have additional effects in adipose cells, bone, and the cardiovascular system. Especially, the latter have received attention based on recent findings that GLP‐1 receptor agonists such as liraglutide reduce cardiovascular events and prolong life in high‐risk patients with type 2 diabetes. Thus, incretin hormones have an important role physiologically, namely they are involved in the pathophysiology of obesity and type 2 diabetes, and they have therapeutic potential that can be traced to well‐characterized physiological effects.
Patients with type 2 diabetes and high cardiovascular risk were assigned to receive either the glucagon-like peptide 1 analogue liraglutide or placebo. The rate of first occurrence of cardiovascular ...death, nonfatal MI, or nonfatal stroke was lower with liraglutide.
Type 2 diabetes is a complex metabolic disorder that is characterized by hyperglycemia and associated with a high risk of cardiovascular, microvascular, and other complications.
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Although glycemic control is associated with reductions in the risk of microvascular complications, the macrovascular benefits of glycemic control are less certain. Furthermore, concern has been raised about the cardiovascular safety of antihyperglycemic therapies.
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Consequently, regulatory authorities have mandated cardiovascular safety assessments of new diabetes treatments.
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Liraglutide, an analogue of human glucagon-like peptide 1 (GLP-1),
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has been approved for the treatment of type 2 diabetes. Its efficacy in lowering glucose levels has been . . .
Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. ...Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A
1c (HbA
1c) (1–2%), associated with weight loss (2–5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA
1c by 0·5–1·0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand β-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.
Abstract
Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes in the USA, Europe, and the UAE. Tirzepatide is an acylated peptide engineered to ...activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1–5) have shown that tirzepatide at 5–15 mg per week reduces both HbA
1c
(1.24 to 2.58%) and body weight (5.4–11.7 kg) by amounts unprecedented for a single agent. A sizable proportion of patients (23.0 to 62.4%) reached an HbA
1c
of < 5.7% (which is the upper limit of the normal range indicating normoglycaemia), and 20.7 to 68.4% lost more than 10% of their baseline body weight. Tirzepatide was significantly more effective in reducing HbA
1c
and body weight than the selective GLP-1 RA semaglutide (1.0 mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2 year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio > 1.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were < 1.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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