GLP-1-RA and DPP-4 inhibitors in the management of type 2 diabetes.

Insulin secretion by pancreatic beta cells is primarily influenced by glucose levels in the portal vein. In addition, secretion is also modulated by the so-called incretins. After food intake, they lead to an increased release of insulin in a glucose-dependent manner.

This is particularly evident from the fact that orally administered glucose leads to two to three times greater stimulation of insulin secretion than parenterally administered glucose – despite the same increase in blood glucose levels. This phenomenon is called the incretin effect [1,2]. This effect is due to hormones that are secreted in the small intestine depending on food intake or carbohydrate content. These so-called incretin hormones include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The secretion of both hormones is stimulated very rapidly by food intake as soon as food passes from the stomach into the small intestine [1]. The incretin effect is intact in healthy individuals and deficient or absent in patients with impaired glucose tolerance, hyperglycemia, and type 2 diabetes [3].

Effect of incretins

The incretins GIP and GLP-1 are peptide hormones of 42 and 30/31 amino acids, respectively. They are released by endocrine epithelial cells in the small intestine called K (GIP) and L (GLP-1) cells [1]. Pancreatic beta cells express specific receptors for both incretins in high numbers. High plasma concentrations of incretin stimulate insulin secretion [1].

Both hormones enhance glucose-induced insulin secretion and have no hypoglycemic effect in the absence of a glucose stimulus. The glucose-dependent effect of GLP-1 can be uncoupled by sulfonylureas. Because of the resulting risk of hypoglycemia, sulfonylureas should not be combined with GLP-1 receptor agonists [1].

However, the two incretin hormones GIP and GLP-1 differ in important ways [1]: GIP promotes glucagon secretion from alpha cells, GLP-1 inhibits it. GLP-1 has an additional appetite suppressant effect, slowing gastric emptying, leading to less food intake, and ultimately weight loss.

While the effect of GIP is almost completely lost in type 2 diabetes mellitus disease, GLP-1 retains its stimulatory activity [1], which is why the therapeutic focus is on GLP-1 (Fig. 1).

Incretin mimetics: same pathway, different effects.

Incretin hormones are substrates of the enzyme dipeptidylpetidase-4 (DPP-4), which cleaves the incretins in plasma within a few minutes, thereby causing them to lose their insulinotropic property. Two strategies have been advanced to prolong the insulinotropic activity of incretins: DPP-4 inhibition and GLP-1 receptor agonists (GLP-1-RA) that are resistant to degradation by DPP-4. Whereas DPP-4 inhibitors maintain endogenous levels of incretin hormones essentially within the physiological range, GLP-1 RAs can lead to supraphysiological and sustained stimulation of GLP-1 receptors.

DPP-4 inhibitors have a moderate effect on glycemic control, are well tolerated, are weight neutral, and do not increase the risk of hypoglycemia. There are two groups of GLP-1-RAs: on the one hand, peptide derivatives of exendin-4, a glycoprotein from the Gila crustacean, and on the other hand, genetically engineered derivatives of human GLP-1. GLP-1-RAs have a more potent effect than many oral antidiabetic drugs, improve weight control, and do not cause hypoglycemia when used as monotherapy or in combination with metformin [5].

DPP-4 inhibitor

DPP-4 inhibitors are small-molecule, orally available compounds that specifically inhibit DPP-4 activity. As a result, they increase the incretins GLP-1 and GIP available after a meal by 2 to 3 times.

All available DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin) lower HbA1c to a similar extent (0.5-0.8%). DPP-4 inhibitors are weight neutral due to the small increase in GLP-1 activity [5].

GLP-1 receptor agonists

All GLP-1 RAs bind specifically to the GLP-1 receptor and stimulate insulin secretion in the beta cell in a glucose-dependent manner. However, the various substances to be administered subcutaneously differ in their pharmacokinetic properties, especially the half-life: short-acting representatives (exenatide, lixisenatide) have a half-life of about 2-4 hours, long-acting 13 hours (liraglutide) up to 7-14 days (dulaglutide, exenatide ER, semaglutide), which allows once-weekly dosing for the latter substances.

The pharmacodynamic effect also differs between short- and long-acting GLP-1-RAs: Short-acting GLP-1-RAs lower postprandial blood glucose by delaying gastric emptying and activating insulin secretion. Long-acting GLP-1 RAs lower fasting and postprandial blood glucose levels by activating insulin secretion and lowering glucagon secretion over a longer period of time. The effect on postprandial glycemia may be less prominent, possibly because the slowing effect on gastric emptying flattens somewhat over time (tachyphylaxis) [5].

In a meta-analysis across 17 randomized trials, GLP-1 RAs showed a 1-1.2% reduction in HbA1c compared with placebo, with semaglutide as the newest GLP-1 RA showing potentially even greater glycemic efficacy and weight loss compared with other GLP-1 RAs [5,20].

In general, long-acting GLP-1 RAs are more potent than short-acting ones in lowering blood glucose. This is exemplified by exenatide, whose HbA1c reduction is greater with the once-weekly formulation (exenatide ER [extended release]) than with the short-acting, twice-daily form. In comparative studies under long-acting, once-weekly GLP-1 RA, semaglutide lowered blood glucose and weight more than exenatide ER (SUSTAIN-3) or dulaglutide (SUSTAIN 7) [5]. The recently approved oral daily form of semaglutide has also been shown to significantly reduce HbA1c (to -1.5%) and weight (to -4.1 kg) [6].

GLP-1-RAs are also available as combination preparations with insulin (liraglutide/degludec and lixisenatide/glargine100), with the potential to simplify therapy and minimize the potential adverse effects of insulin (hypoglycemia; weight gain) (Table 1).

Cardiovascular effects of GLP-1-RA.

Cardiovascular safety has been evaluated in 7 GLP-1 RA studies involving more than 60 000 patients with different patient populations and endpoints. The ELIXA trial (lixisenatide 10-20 µg/d s.c.) had enrolled patients with recent acute coronary syndrome. The study showed no increase in the primary endpoint 4-point MACE (major adverse cardiovascular events in terms of cardiovascular death, nonfatal myocardial infarction, nonfatal cerebral stroke, unstable angina), demonstrating the cardiovascular safety of lixisenatide [5,7]. The LEADER trial (liraglutide 1.8 mg/d s.c. vs. placebo) demonstrated not only the cardiovascular safety of liraglutide but also statistical superiority over placebo in the reduction of 3-point MACE (major adverse events related to cardiovascular death, nonfatal myocardial infarction, nonfatal cerebrovascular accident) mainly due to the significant reduction in cardiovascular deaths. In addition, all-cause mortality decreased significantly under liraglutide [5,8]. In interpreting the studies, it is important to note that patients in the treatment and placebo groups were also treated with other antidiabetic agents, such as metformin and insulin, and that equivalent glycemic control was achieved in both groups in the study design and conduct. Thus, the positive cardiovascular outcomes with liraglutide treatment are not a consequence of better glycemic control, but an independent additional effect.

The findings from the LEADER trial, the first cardiovascular outcome trial with a GLP-1 RA, and the EMPA-REG-OUTCOME trial, the first cardiovascular outcome trial with an SGLT2 inhibitor, launched a new era in the treatment of type 2 diabetes: antidiabetic agents with additional cardiovascular risk reduction.

Subsequently, other large clinical trials were published showing cardiovascular risk reduction with modern GLP-1 analogues:

In the SUSTAIN-6 trial (semaglutide 1×/week 0.5 or 1 mg s.c.), the rate of 3-point MACE decreased mainly because of significant reduction in cerebral strokes, but the rate of cardiovascular death or all-cause mortality did not decrease [5,9]. In the PIONEER-6 trial of oral semaglutide 14 mg/day in high-risk cardiovascular patients, the primary end point 3-point MACE was not statistically significantly lower than in the placebo group; however, cardiovascular death and all-cause mortality were reduced [4,10]. As a pivotal study for the oral form, this study had a shorter duration (16 months) than the other studies (2-5.4 years) [5,7–12]. Dulaglutide 1×/week 1.5 mg s.c. also significantly reduced the rate of 3-point MACE in the REWIND trial [5,11].

The EXCSEL (Exenatide ER 1×/week 2 mg s.c.) trial included patients with or without prior cardiovascular disease. The study demonstrated noninferiority to placebo and thus cardiovascular safety, but superiority was not evident [5,10].

A possible explanation for the differences in cardiovascular benefit within the GLP-1 RA class of compounds is thought to lie in their structure: exendin-4-based GLP-1 RAs (exenatide, lixisenatide) have a less pronounced cardioprotective effect than GLP-1 RAs of human origin [13].

Thus, in addition to the blood glucose-lowering effect, GLP-1-RAs have an overall cardioprotective effect according to a systematic review with meta-analysis. In addition, they reduce the risk for heart failure and for deterioration of kidney function [13]. These properties make this class of compounds an important therapy for reducing morbidity and mortality in patients with type 2 diabetes [13]. In this systematic review with meta-analysis of 7 randomized controlled trials (n=56,004) of currently available GLP-1 RAs, GLP-1 RAs in patients with type 2 diabetes were shown to reduce the rate of 3-point MACE by 12 percent (hazard ratio [HR]: 0.88; confidence interval [KI]: 0.82-0.94) and reduce their individual components (cardiovascular death: HR 0.88 [KI 0,81–0,96]; cerebral stroke: HR 0.84 [KI 0,76–0,93]; Myocardial infarction: HR 0.91 [KI 0,84–1,00]). They also indirectly reduce the risk of heart failure-related hospitalizations via reduction of myocardial infarction as a precursor to heart failure (HR 0.91; CI 0.83-0.99). An increase in the risk of severe hypo-glycemia, pancreatic complications, or thyroid tumors was not observed [13].

In contrast, SGLT2 inhibitors are also cardioprotective antidiabetic agents. In a meta-analysis of cardiovascular outcomes of SGLT2 inhibitors, the relative risk reduction of MACE was 11 percent with an NNT (Number Needed to Treat) of 97 over 3.3 years [15] (GLP-1-RA 12% and NNT=75 over 3.2 years) [13]. Cardiovascular benefit occurs earlier with SGLT2 inhibitors and with greater weight on heart failure than with GLP-1 RAs, suggesting that the 2 classes reduce cardiovascular risk by different mechanisms, with GLP-1 RAs potentially having an antiatherothrombotic effect. A combination of SGLT-2 inhibitors and GLP1-RA makes pathophysiological sense and initial studies suggest that they act synergistically [13,15]. This combination is also recommended by the latest international and national guidelines; however, in Switzerland it is currently not automatically covered by health insurance.

Cardiovascular safety has been demonstrated for DPP-4 inhibitors in 5 trials involving nearly 50,000 patients; however, no additional cardiovascular benefit has been shown. However, the SAVOR-TIMI-53 study indicated an increased incidence of heart failure with saxagliptin [5,16,17].

Tolerance of incretin mimetics

DPP-4 inhibitors are well tolerated and have no effect on weight. They do not increase the risk of hypoglycemia unless combined with sulfonylureas. The most common side effects reported in the trials were nonspecific symptoms such as headache and nasopharyngitis, which were equally common with placebo [5].

Adverse effects of GLP-1 RA are mainly gastrointestinal in nature, especially nausea followed by vomiting and diarrhea, and occurred in 10 to 50 percent of patients in the studies. These complaints weaken with increasing duration and dose titration. The risk of hypoglycemia is small unless GLP-1-RA is co-administered with hypoglycemia-inducing drugs such as basal insulins or sulfonylureas.

Since their introduction, there have been ongoing concerns about adverse effects on the pancreas. However, no evidence for pancreatic toxicity of DPP-4 inhibitors or GLP-1-RA was shown, neither for an increased risk of pancreatitis nor for pancreatic cancer [5].

Incretin mimetics and renal insufficiency.

Renal insufficiency is a common microvascular complication of type 2 diabetes. Some DPP-4 inhibitors are renally excreted and require dose adjustment in patients with moderate to severe renal impairment. This is true for alogliptin, sitagliptin, saxagliptin, and vildagliptin. An exception is linagliptin, which is excreted hepatically. Among GLP-1 RAs, exenatide and lixisenatide are renally excreted and are not recommended in patients with a glomerular filtration rate (GFR) <30 ml/min [5]. In contrast, liraglutide, dulaglutide, and semaglutide are not renally excreted; liraglutide may be given even in severe renal insufficiency (eGFR ≥15 ml/min), and dulaglutide and semaglutide are not subject to any limit. GLP-1-RA or DPP-4 inhibitors are thus the preferred agents, apart from insulin, when eGFR <45 ml/min/1.73 ^m2 [18].

SGED recommendations

In 2020, the Swiss Society of Endocrinology and Diabetology updated its recommendations for the treatment of patients with type 2 diabetes. Treatment is not only based on the HbA1c value, but also on comorbidities. Therefore, in addition to clarifying three clinical situations (insulin deficiency, renal function, heart failure), the early combination of metformin with antidiabetic agents with proven cardiovascular benefit, namely GLP-1-RA or SGLT2 inhibitors, is important for the choice of therapy tailored to the patient and to avoid cardiorenal complications (Fig.3). In patients with low to moderate cardiovascular risk, DPP-4 inhibitors or a basic insulin can be used. However, since moderate risk, for type 2 diabetes, means patients <50 years with diabetes duration <10 years without risk factors, it may be assumed that most patients have a much higher risk.

The recommendation of early combination of GLP-1 RA or SGLT2 inhibitor with metformin has been included in the guidelines of several other professional societies, including the ADA (American Diabetes Association) and EASD (European Association for the Study of Diabetes) and the ESC (European Society of Cardiology) as well. Thanks to the benefits of these antidiabetic agents, the ESC has gone further and recommended the use of GLP-1 RA or SGLT2 inhibitors in some circumstances as first-line therapy [21,22].

Conclusion

Type 2 diabetes is a progressive disease. Until a few years ago, treatment and prevention of long-term complications was limited to glycemic control. With the introduction of modern antidiabetic agents, including GLP-1 receptor agonists, it has become possible to achieve cardioprotection in addition to glycemic control.

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