Pharmacodynamics (effect)
In the human body, neuroendocrine L-cells in the intestine and A-cells in the pancreas produce proglucagon GLP- 1. This enzyme is degraded by dipeptidyl peptidase- 4 (DPP- 4).
GLP- 1 together with the "gastric inhibitory polypeptide" (GIP) belongs to the incretins (Herold 2020).
The action of the enzyme GLP- 1 consists in:
- glucose-dependent stimulation of the secretion of insulin
- Delay of gastric emptying
- Inhibition of the release of glucagon (inhibits appetite and leads to weight loss).
(Herold 2020)
The chemical analogues GLP- 1- RA bind with high affinity to GLP- 1- receptors. However, unlike GLP- 1, they are not inactivated by DPP- 4. This causes an:
- Inhibition of the secretion of glucagon
- Increase in the secretion of insulin
- Delay of gastric emptying
- Decrease in appetite
- Weight loss (Herold 2020)
- Preferential lowering of postprandial BG (Kasper 2015).
Additional effect of liraglutide:
- Reduction in cardiovascular mortality.
- nephroprotection (Herold 2020)
- Reduction in all-cause mortality (Bahrmann 2018).
Additional effect of dulaglutide:
- Reduction of cardiovascular events by 12% compared to placebo according to the REWIND- study (Sonnet 2020).
Indications
-
Type 2 DM with
- metabolic syndrome
- manifest cardiovascular disease
- cardiovascular risk factors
- renal concomitant diseases (Diederich 2020) in combination with metformin and / or sulfonylureas (SH) and / or insulin, but these drugs alone are not sufficient to lower blood glucose appropriately (Herold 2020).
Since 2018, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have recommended the preferential use of GLP- 1- RA or SGLT- 2- inhibitors alongside treatment with metformin, sulfonylureas, insulin (Diederich 2020).
- before starting any insulin therapy in type 2 DM - especially with an increased body mass index - treatment with GLP1- RA should be considered (Bundesärztekammer 2021).
Dosage and method of administration
It is taken in relation to meals and as a combination therapy with e.g. metformin and / or sulfonylureas (SH) and / or insulin. In patients receiving insulin secretagogues, a reduction of insulin secretagogues may be required due to the risk of hypoglycemia during treatment with GLP1- RA (Kasper 2015).
Dosage recommendation:
- Byetta ®: approx. 30 min before main meals initially 2 x 5 µg / d s.c.
After approx. 4 weeks, a dose increase to 2 x 10 µg / d s.c. is possible.
- Victoza ®: initially 1 x / d 0, 6 µg / d s.c., subsequent increase up to 1,2 µg / d s.c., maximum dose 1, 8 µg / d s.c.
- Bydureon ®: 1 x weekly 2 mg s.c.
- Trulicity ®: 1 x weekly 0.75 - 1.5 mg s.c.
(Herold 2020)
The 1 x weekly administration of ultralong-acting GLP1- RA such as dulaglutide is not inferior to daily administration of liraglutide according to studies (Dungan 2014).
Adverse effects
- Hyperlipasemia (common)
- Nausea (common)
- Vomiting (up to 10% [Ritzmann 2008])
- Diarrhea (usually reversible)
- Pancreatitis (very rare; in some cases clinical treatment was required, deaths have not been described so far [Ritzmann 2008])
[Herold 2020)
-
Hypoglycemia: There is no risk of hypoglycemia with GLP- 1- RA, only in combination with other antidiabetic drugs (Herold 2020)
- under the combination with metformin in up to 39 % (also corresponds to the number of patients treated with placebo)
- under combination with sulfonylureas, the risk of hypoglycemia increased many times over, therefore an early dose reduction of the sulfonylureas should be considered here
- Formation of antibodies against GLP1- RA:
The formation of AK was found in almost 50% of cases. The clinical significance is still unclear. In patients with markedly high AK titers, a reduced effect with regard to exenatide has been reported (Ritzmann 2008).
Contraindication
- terminal renal failure with a creatinine clearance < 30 ml / min (Herold 2020)
- Not recommended in higher-grade renal insufficiency with a GFR < 50 ml / min (Bahrmann 2018).
- Z. n. pancreatitis
(Herold 2020)
Interactions
As GLP1- RA delay gastric emptying, absorption of other drugs may be delayed or reduced (Kasper 2015) such as with:
- Antibiotics
- Contraceptives
- Drugs with a narrow therapeutic range such as oral anticoagulants.
(Ritzmann 2008)
Preparations
- Short-acting GLP1- RA:
- Long-acting GLP1- RA:
- Ultra-long-acting GLP1- RA:
- exenatide LAR (Bydureon ®)
- Dulaglutide (Trulicity ®)