Oral Antidiabetic Agents Flashcards
Typ I Diabetes (6-7 %)
- autoimmunological or idiopathic deletion of pancreatic b cells
(6-7%) -> absolute insulin deficiency - manifestation: childhood (age 4-5) and adolescence (age 12-14
- No plasma insulin
Typ 2 Diabetes (90 %)
- Insulin resistance
- manifestation: >40 years
- normal - high plasma insulin levels
Diabetes mellitus Typ 2 - key facts
- 347 million people worldwide have diabetes.
- In 2012, an estimated 1.5 million deaths were directly caused by diabetes.
- More than 80% of diabetes deaths occur in low- and middle-income countries.
- WHO projects that diabetes will be the 7th leading cause of death in 2030.
- Healthy diet, regular physical activity, maintaining a normal body weight and avoiding
tobacco use can prevent or delay the onset of type 2 diabetes.
Co-Morbidities of T2DM in Germany
every
* 12 min one stroke
* 19 min one myocardial infarction
* 19 min one amputation
* 60 min one new dialysis patient
* 90 min one new blind patient
Therapy of Typ-2-Diabetes
- Wahl Metformin
Monotherapie nach DDG/DGIM bei Metformin-Unverträglichkeit/-Kontraindikationen:
- DPP-4-Inhibitor
- Insulin (häufig Verzögerungsinsulin)
- SGLT-2-Inhibitor
- SUlfonylharnstoff/Glinid
- Glukosidasehemmer
- Pioglitazon
Dritte Stufe: Insulin allein oder Pharmaka-Zweifachkombination
Biguanides in therapy of T2DM
- no lipophilic side chain,
- no intramolecular hydrogen bridge
- central amino group is not protonated at physiological pH
-> lower intracellular concentrations
-> better tolerability
Bsp: Metformin (Glucophage), Phenformin, Buformin
Effects of Metformin
GLUCOSE METABOLISM
- lowered gluconeogenesis
- lowered glycogenolysis
- higher glucose uptake (muscle, erythrocytes)
- higher glycogen synthesis
LIPID METABOLISM
- lowered fatty acids oxidation
- lowered LDL and cholesterol in serum
- lowered turnover of fatty acids
- lowered VLDL synthesis
- higher VLDL elimination
OTHERS
- lowered PAI-1, higher fibrinolytic activity
- higher t-PA activity
- lowered AGE
- lowered body weight
Discussed mode of actions of Metformin
- decreased gluconeogenesis
- reduced intestinal glucose resorption
- increased release of GLP-1
- increased production of lactate in enterocyten
- inhibition of „glucagon signaling“
- Inhibition of glycolytic enzymes
- decreased transcription of mitochondrial complex I
- activation of „AMP activated protein kinase“
- Inhibition of mitochondrionspecific isoform glycerophosphate dehydrogenase D
Metformin: adverse effects
frequency 1/10: gastrointestinal impairmentssustained-release preparation, slow dose increase
frequency 1/10.000: lactacidosis (50% lethal)
* partially metabolized by CYP2C11 and CYP2D1
- careful attention of restrictions on use (renal failure , liver failure, alcohol consumption)
* mainly unchanged eliminated by tubular secretion, t1/2 3h.
- restrictions on use were ignored in 80 % of all registered Methformin induced lactacidosis
Metformin at renal failure
- Until now, Metformin was contraindicated when creatinine clearance was <45ml/min due to the risk to develop lactacidosis.
- Based on latest result, the EMA has recommended to use Metformin also in patients with moderate renal failure (state 3b).
- Recommended maximal daily doses: 2000 mg when GFR is 45-59 ml/min/1,73m2,
1000 mg when GFR is 30 - 44 ml/min/1,73m2.
Metformin: results from the UKPDS trial
- Diabetes related end points:
sudden death, hyper-/hypoglycemia rekated death, myocardial infarction, heart or renal failure, stroke, amputation, retinopathia, getting blind, peripheral vessel disease , bleeding - Diabetes related mortality
death due to myocardial infarction, stroke, peripheral vessel disease , renal failure, hypo-, hyperglycemia, sudden cardiac death - Total mortality
Sulfonylurea derivatives (SUD): structures
BSP: Glibenclamid, Gliquidon, Glimepirid
increase of lipophilicity at R1 -> higher potency
R2: cycloalipathic residues -> higher potency
-> increase insulin release via binding at SUR1
Results from UKPDS trial
Important side effects
1. Hypoglycaemia:
Results from the UKPDS trial
2 episodes/y in response to conventional therapy
47 episodes/y after Insulin, 10-30 episodes/y after Glibenclamide
- Gain of body weight:
2.5 kg/Y in response to conventional therapy
6.5 kg/y after Insulin, 4.2 kg/y after Glibenclamide
Glucosidase inhibitors i
Bsp: Acarbose, Miglitol, Voglibose
Therapeutic doses of Miglitol and Acarbose:
* initially: 50 - 100 mg/d
* Dose increase up to 150 - 300 mg/d
* Drug intake: 3xd before meals
side effects:
artery
* flatulence, borborygmus(>10%)
* diarrhoea, abdominal pain (1-10%)
Glitazones: mode of action
-> Target genes of PPAR gamma
- Triglyceride hydrolysis: lipoprotein lipase
- Fatty acid uptake/esterification: CD36, fatty-acid transport protein 1, Fatty acid binding protein 4 (aP2), AcylCoA synthase
- Lipogenesis and triglyceride synthesis: Phosphoenolpyruvate carboxykinase, Glycerol kinase
- Lipolysis regulation: Perilipin
- Adipokines: Adiponectin, Resistin
Insulin signaling and glucose uptake: Cbl-associated protein, Insulin receptor substarte 2, Glucose transporter 4
Metabolic Effects of Glitazones
-> Thiazolidindione
MUSCULATURE
- higher glucose uptake
- higher glycolysis
- higher glycogenolysis
- higher glucose oxidations
ADIPOSE TISSUE
- higher glucose uptake
- higher uptake of fatty acids
- higher lipogenesis
- higher glucose oxidations
LIVER
- lower gluconeogenesis
- lower glucose uptake
- higher glucose uptake
- higher lipogenesis
- higher glycogen synthesis
Impact of FFA for insulin resistance
MUSCULATURE
- substrate competition
-> lower insulin mediated glucose uptake
-> lower glucose utilisation
PANCREAS
- lipotoxicity
-> decline of beta cell function
-> lower insulin secretion
-> hyperglycemia/dyslipidemia
-> T2DM
LIVER
- higher triglycerid synthesis
- higher glucose production
- lower insulin secretion
Cardiovascular effects of Glitazones
CONTRACTILITY
- lower Ca2+ influx
- HIGHER [Mg2+]intracellular
- higher vasodilatation
LDL CHOLESTEROL
- lower Small dense LDL
- lower LDL oxidation
COAGULATION
- lower PAI-1
ADHESION
- lower monocyte adhesion
- lower VCAM-1
- lower ICAM-1
- lower plasma E selection
SMC
- lower proliferation
- lower migration
- lower hypertrophy
Contraindication sand adverse effects of Pioglitazone
CONTRAINDICATIONS
* renal failure
* hepatic dysfunction
* NYHA I-IV
* Insulin therapy
* anaemia
* pregnancy
ADVERSE EFFECTS
* metabolic: higher body weight + Metformin (5.4%) + SUD (5.5%)
- GUT: flatulence
- oedema: 3.5-4 %
- CNS: cephalgia
- hepatic: higher GPT
Incretins
GLP-1 (glucagon-like peptide-1) and GIP (glucose dependent insulinotropic polypeptide) are GUT hormones, being responsible to induce higher insulin release after oral glucose administration compared to i.v. injection.
-> The incretin effect is reduced in T2DM
GLP-1 is metabolized by Dipeptidylpeptidase IV (DPP-IV)
Cleavage of dipeptide when proline or alanine residue at 2nd position of amino acid sequence
His1-Asp2-Glu3-Phe4-Glu5-Arg6-His7–Ala8–Glu9–Gly10–Thr11–Phe12 -
-> (GLP-1) His7–Ala8–Glu9–Gly10–Thr11–Phe12 -
-> Glu9–Gly10–Thr11–Phe12 -
Incretin analogues
-> Exenatide (Byetta)
- Half life 2.5 h
- hypoglycemia in combination with SUD
- antibodies (44 %, 6% with high titers, 3 % with reduced efficacy)
- 53 % homology
Liraglutide, a humanized GLP-1 analogue
high homology (97%) compared to human GLP-1 -> lower AB
-> no reduced efficacy due to liraglutide related AB
Among overweight or obese adults, orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate and liraglutide, compared with placebo, were each associated with achieving at least 5 % weight loss at 52 weeks. Phentermine-topiramate and liraglutide were associated with the highest odds of achieving at least 5 % weight loss.
Liraglutide, a humanized GLP-1 analogue
high homology (97%) compared to human GLP-1 -> lower AB
-> no reduced efficacy due to liraglutide related AB
Cardiovascular effects of GLP-1
HEART
- lower inflammation
- higher glucose uptake
- lower ischemic injury
- higher LV function
- higher heart rate
VASCULATURE
- lower inflammation
- higher endothelial function
- higher vasodilation
- higher plaque stability
- higher blood flow
- lower smooth muscle proliferation
- lower platelet aggregation
New developments of GLP-1 analogues
EXENATIDE
- homology: 53 %
- T1/2: 2.5 h
LIXISENATID
- homology: 53 %
- T1/2: 3 h
- withdrawal
LIRAGLUTID
- homology: 97 %
- T1/2: 24 h
DULAGLUTID
- homology: recombinant GLP-1 fusionprotein
- T1/2: 4.7 d
ALBIGLUTID
- homology: DPP-IV resistant GLP-1 dimer fused to human albumin
- T1/2: 5 d
- withdrawal
DPP-IV inhibitors
COMPETITIVE
Sitagliptine (Januvia®)
Vildagliptine (Galvus®, withdrawn 2014)
Linagliptine (Trajenta®, not available)
NON COMPETITIVE
Saxagliptine (Onglyza®)
Adverse effects (pf Sitagliptine)
- cold,diarrhoea,pharyngitis,headache,arthralgia
- insomecasesaftermarketrelease:anaphylaxis,angioedemaandskinirritation. * Lessselectivity?
– Beside GLP-1 and GIP other substrates (e.g. PACAP, trypsinogen, procolipase, somatoliberin, GLP-2, NPY) also contain a proline residue at the correct position enabling these peptides for DPP-4 degradation. The consequences of a reduced metabolism of these peptides is not known.
– DPP-4 inhibitors also block DPP-8 and DPP-9. The clinical relevance of blocking DPP-8/-9 is not known.
– DPP-4 is also involved in regulation of other biological functions (e.g. immune reactions, cell adhesion). Considering the presence of DPP-4 in various cell types and also in blood cells, GLP-1 independent effects are assumed to be of clinical relevance.
Sodium-glucose-co-transporter (SGLT)
When SGLT1 is blocked, more glucose remains in the lumen of the intestine being eliminated. Plasma glucose is indeed reduced, but higher GUT levels induced GUT related adverse effects (diarrhea).
When SGLT 2 is blocked, more glucose will be renally eliminated. This indeed decreases blood glucose but also induce caloric loss and reduction of blood pressure (by osmotic diuresis). Both effects are beneficial.
In Germany, Canagliflozin is withdrawn (2014).
Blocking the renal glucose reabsorption by SGLT-2 inhibitors
- but SGLT 2 is mainly (90%) responsible for renal glucose reabsorption
- However, using SGLT-2 knock out mice, glucose reabsorption was 40 %, thus indicating that the impact of SGLT-1 for glucose reabsorption is more than 10%. These results suggest that the contribution of SGLT1 to renal glucose reabsorption is greater under lower glycemic conditions than under hyperglycemic conditions.
- These results suggest that SGLT2-selective inhibitors pose a lower risk of hypoglycemia than SGLT1/2 inhibitors.
FDA strengthens kidney warnings for diabetes medicine canagliflozin (Invoking, Invokamet) and dapagliflozin
The U.S. Food and Drug Administration (FDA) has strengthened the existing warning about the risk of acute kidney injury for the type 2 diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Based on recent reports, we have revised the warnings in the drug labels to include information about acute kidney injury and added recommendations to minimize this risk.
From March 2013, when canagliflozin was approved, to October 2015, FDA received reports of 101 confirmable cases* of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use (see Data Summary). This number includes only reports submitted to FDA, so there are likely additional cases about which we are unaware. In approximately half of the cases, the events of acute kidney injury occurred within 1 month of starting the drug, and most patients improved after stopping it. Some cases occurred in patients who were younger than 65 years. Some patients were dehydrated, had low blood pressure, or were taking other medicines that can affect the kidneys.
We urge health care professionals and patients to report side effects involving canagliflozin, dapagliflozin, or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.
eGFR during therapy with Empagliflozin
- SGLT-2 inhibition reduces hyperfiltration via TGF
Risk of diabetic Ketoacedosis after Initiation of an SGLT2 inhibitor
Case reports have suggested that SGLT2 inhibitors may be associated with an increased risk of diabetic ketoacidosis, which led to a warning from the FDA in May 2015. The objective of our study was to assess the risk of diabetic ketoacidosis after the initiation of an SGLT2 inhibitor.
In conclusion, shortly after initiation, SGLT2 inhibitors were associated with approximately twice the risk of diabetic ketoacidosis as were DPP4 inhibitors, although cases of diabetic ketoacidosis leading to hospitalization were infrequent. The increased risk of diabetic ketoacidosis with SGLT2 inhibitors is among the factors to be considered at the time of prescribing and throughout therapy if patients present with symptoms suggestive of diabetic ketoacidosis.
Leber: higher Ketogenesis
Niere: higher Glucosuria
