oral anti-diabetic medications mario skugor, md face endocrine and metabolic institute cleveland...
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Oral Anti-diabetic Medications
Mario Skugor, MD FACEEndocrine and Metabolic InstituteCleveland Clinic
Insulin secretaguages
Insulin sensitizers
Incretin based therapies
Alpha-glucosidase inhibitors
CNS acting
Long acting
Sulphonylureas
Liver
Metformin
PPD-4 inhibitors
Acarbose Bromocriptine
Short acting
Meglitinides
Muscle and Fat
Thiazolidinediones
Miglitol
Other
Bile acid sequestrants
Orlistat
CLASSES OF ORAL ANTIDIABETIC MEDICATIONS
In development
Dual PPAR gamma agonists
SGLT-2 antagonists
Insulin secretaguages
Insulin sensitizers
Incretin based therapies
Alpha-glucosidase inhibitors
CNS acting
Long acting
Sulphonylureas
Liver
Metformin
PPD-4 inhibitors
Acarbose Bromocriptine
Short acting
Meglitinides
Muscle and Fat
Thiazolidinediones
Miglitol
Other
Bile acid sequestrants
Orlistat
CLASSES OF ORAL ANTIDIABETIC MEDICATIONS
In development
Dual PPAR gamma agonists
SGLT-2 antagonists
Canagliflozin just approved.
METFORMIN
French lilac – used in folk medicine for centuries.
Synthesized in 1920s
In 1950 Metformin was used to treat influenca and noted to lower blood glucose to physiologic levels.
METFORMIN
• In 1957 first clinical trial of diabetes treatment was published in France
• Approved in 1958 in UK, 1972 in Canada and in 1995 in US.
METFORMIN
• Suppression of hepatic gluconeogenesis through activation AMP-activated protein kinase (AMPK).
• Improves glucose uptake in muscle and fat.
• Causes weight loss in some individuals.
• Improves menstrual cycle and fertility in PCOS
• May improve NASH.
• May reduce risk of range of different carcinomas
METFORMIN
• Comes in 500, 850 and 1000 mg pills.
• Extended release pills are available (but more expensive)
• Usual dose is 1000 mg twice a day.
• Main side effects is abdominal cramping and diarrhea
• Metformin extended release is better tolerated by some patients
• Even mild renal failure (Cr>1.4 in males and >1.5 in females) is contraindication for use
Metformin – Bottom line
• Clearly the first line.
• Cheap
• Improves physiology
• Has other benefits.
• Unfortunately, significant proportion of patients has contraindications or cannot tolerate it.
SULPHONYLUREAS
• Marcel Janbon and co-workers discovered hypoglycemic effect of sulfonylurea in 1942.
• They were studying sulfonamide antibiotics and discovered that the compound sulfonylurea induced hypoglycemia in animals
Sulphonylureas
• First sulfonylurea for treatment of DM introduced in 1955.
– General structure:
Sulphonylurea
• First generation – Binds to the proteins in the blood.
–Tolbutamide
–Chlorpropamide
–Tolazamide
–Acetohexamide
–Carbutamide
Sulphonylurea
• Second generation – Not bound to serum proteins.
–Glipizide
–Glyburide (glibenclamide)
–Gliclazide
– Glibornuride
– Gliquidone
– Glisoxepide
– Glyclopyramide
Sulphonylurea
• Third generation
– Glimepiride
SUFONYLUREAS
Sulfonylurea
• Advantages
–Fast acting
–Once a day dosing
–Gliclazide may be particularly beneficial
• Disadvantages
–Risk of hypoglycemia
–Weight gain
–Possible problems with ischemic preconditioning
Glicilizide
• Inhibits platelet aggregation
• Associated with lower mortality from malignant neoplasms.
• Improves repair of DNA damage caused by oxidative stress in tissue cultures.
Sulfonylureas – Bottom line
• Fast acting
• Older ones are cheap
• Do not improve physiology
• Hypoglycemia is significant risk
• Require strict regime of diet
Meglitinides
• Nategelinde
• Repaglinide
• Act on same potassium channel as sulfonylurea but bind to different part of the molecule.
• Short acting – taken 0-30 min before meal.
• Risk of hypoglycemia is small
Meglitinides – Bottom line
• Useful in small number of patients for relatively short period of time.
• Allow for some flexibility in timing of the meals.
TZD-s – actually Pioglitazone
• The proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α agonist in the muscle, adipose tissue, and the liver.
• Pioglitazone reduces insulin resistance in the liver and peripheral tissues.
• Pioglitazone decreases the level of triglycerides and increases HDL without changing LDL and total cholesterol.
• Pioglitazone - 15 - 30 - 45 mg pills
• Peripheral edema is main side effect.
• More hospitalizations for CHF in studies with all TZD-s
• Effect is maintained when combined with metformin and incretin based therapies.
Pioglitazone
Thiazolidinediones and bladder cancer.
Colmers IN, et al. CMAJ 2012I:10.1503
TZD-s and fracture risk
Toulis KA, et al. CMAJ, 2009, 180 (8) 841-842
TZD-s and fractures
TZD-s are associated with fractures in females over 50 years of age.In men risk is increased if TZD-s are used with loop diuretic
Bilik D, et al. JCEM. 2010 (10) 1210.
Bottom line on Pioglitazone
• Benefits are still higher than risks.
• There is some evidence that lower dose is not associated with risk of bladder cancer.
• However – at this time Metformin and PPD-4 inhibitors are clearly ahead of Pioglitazone as choices for treatment.
Incretins
• Gut-derived hormones, secreted in response to nutrient ingestion, that potentiate insulin secretion from islet cells in a glucose-dependent fashion, and lower glucagon secretion from islet cells
• Two predominant incretins:
– Glucagon-like peptide–1 (GLP-1)
– Glucose-dependent insulinotropic peptide (GIP) (also known as gastric inhibitory peptide)
• Incretin effect is impaired in type 2 diabetes
– Known as GLP-1 deficiency
Incretin system and DPP-4 physiologic action
Native GLP-1 is rapidly degraded by DPP-IV
Human ileum, GLP-1 producingL-cells
Capillaries,DPP-IV (Di-Peptidyl Peptidase-IV)
Adapted from: Hansen et al. Endocrinology 1999;140:5356–5363.
Double immunohistochemical staining for DPP-IV (red) and GLP-1 (green) in the human ileum
Slide Source:Lipids Online Slide Librarywww.lipidsonline.org
Glucagon-Like Peptide–1Glucagon-Like Peptide–1 Normalizes Normalizes Postprandial Hyperglycemia in Patients Postprandial Hyperglycemia in Patients with Type 2 Diabeteswith Type 2 Diabetes
Nauck MA et al. Acta Diabetol. 1998;35:117-129.
Time (h)
Pla
sma g
luco
se (
mg/d
l)
0
300
100
50
150
200
250
2 3 4 1 0 –1
Infusion
GLP-1 [7-36 amide] 1.2 pmol/kg/min
Placebo
Liquid meal
0
300
100
50
150
200
250
2 3 4 1 0 –1
Infusion
GLP-1 [7-36 amide] 1.2 pmol/kg/min
Placebo
Liquid meal
Pla
sma g
luco
se (
mg/d
l)
Healthy subjects T2DM patients
Time (h)
Slide Source:Lipids Online Slide Librarywww.lipidsonline.org
Continuous Continuous Glucagon-Like Peptide–1Glucagon-Like Peptide–1 Infusion Reduces Appetite over 6 WeeksInfusion Reduces Appetite over 6 Weeks
All data for patients treated with glucagon-like peptide–1 (n = 10).No changes in these parameters were observed in the saline group.
0
100
200
300
400
500
Mean (SE) AUC for Visual
Analogue Score (mm) vs Time (h)
Time (wk)
610
Zander M et al. Lancet. 2002;359:824–830.
Time (wk)
*Prospective food intake
*Hunger
*Satiety
*Fullness
*p<.05
Slide Source:Lipids Online Slide Librarywww.lipidsonline.org
Glycemic Control with GLP-1 Receptor Glycemic Control with GLP-1 Receptor Agonists in Head-to-Head Clinical TrialsAgonists in Head-to-Head Clinical Trials
*Significant difference vs comparator GLP-1 *Significant difference vs comparator GLP-1 receptor agonistreceptor agonist
1Buse JB et al. Lancet. 2009;374:39-47 | 2Drucker DJ et al. Lancet. 2008;372:1240-1250 | 3Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310 | 4Buse JB et al. Presented at 47th EASD Annual Meeting, Lisbon, Portugal, 14 September 2011.
Trial:Size (N):
Study length (weeks):
LEAD-61
46426
DURATION-12
30330
DURATION-53
25424
DURATION-64
91226
-0.8
-1.5
-0.9
-1.3-1.1
-1.9
-1.6-1.5
-2.0
-1.5
-1.0
-0.5
0.0A1
C Ch
ange
(%)
**
**
**
EXN BID
LIRA
EXN QW
Slide Source:Lipids Online Slide Librarywww.lipidsonline.org
Comparison of Incretin ModulatorsComparison of Incretin Modulators
GLP-1 Analogues DPP-4 Inhibitors
Administration route Injection Oral
GLP-1 Sustained Meal-related
Effect on A1C
Effects on body weight
Side effectsNausea,
Rare: pancreatitis
(Well tolerated) Nasopharyngitis, skin rashes, Stevens-Johnson syndrome
-cell function
GLP-1=glucagon-like peptide–1; DDP-4=dipeptidyl peptidase–4
DPP – 4 inhibitors
• Sitagliptin
• Saxagliptin
• Linagliptoin
• Alogliptin
• Vildagliptin – marketed in EU
• More in development
–Gemigliptin
DPP4 inhibitors
• All taken once a day
–Sitaglipitin 100 mg daily
–50 mg if Cr 1.7-3.0 for men and 1.5-2.5 for women
–25 mg in ESRD
–Saxagliptin 5 mg per day
–2.5 mg in renal impairment
–2.5 if taken with cytochrome P450 inhibitors (ketoconazole)
–Linagliptin 5 mg daily
Sitagliptin - example
DPP-4 inhibitors
• Side effects are minimal
• Acute pancreatitis is seen
–Linagliptin 15.2/10.000 patients
–Placebo 3.7/10,000 patients
–Saxaglipin – No data but some postmarketing cases are reported
–Sitagliptin – There is 88 cases in 2.5 years in postmarketing reporting.
DDP-4 inhibitors – Bottom Line
• Very well tolerated
• Improve physiology
• Expensive
• So far, no serious adverse effects with long term use.
• No increased risk of pancreatic caner.
Alpha-Glucosidase inhibitors
• Acarbose - 25, 50 or 100 mg tablets
• Miglitol - 25, 50 and 100 mg tablets
–They block intestinal enzyme breaking sugars to monosaccharides.
–This slows down and blocks some of carbohydrate absorption.
–Postprandial peak is diminshed and Hba1c improves.
Alpha-Glucosidase inhibitors
Alpha-glucosidase inhibitors
• Taken with each meal.
• Side effects are flatulence and diarrhea
• This can be diminished with low carb, high fiber diet and slow titration of the dose form 25 mg to 100 mg per day.
• Very low risk of hypoglycemia
Alpha-glucosidase inhibitors – Bottom line
• Very useful if tolerated
• Relatively cheap.
Bromocriptine
• Bromocriptine mesylate given within 2 hours of waking up in the morning improves glycemic control by unknown mechanism.
• It is given in escalating dose starting with 0.8 mg and increasing by 0.8 mg every week to maximal tolerated dose.
• Therapeutic dose is between 1.6 to 4.8 mg per day.
• Very low risk of hypoglycemia.
• About 25% of patients experience some nausea.
Bromocriptine
Bromocriptine
Bromocriptine – Bottom line
• Useful if tolerated.
• Still expensive
• Many patients are discuoraged by need to use 2-6 pills at once (In US only 0.8 mg pill is available).
Bile acid sequestrants
• Colesevelam
• Cholestyramine
• Colestid
–Mechanism is unknown
– In db/db mice these drugs increase metabolic utilization of glucose in peripheral tissues which corelates with decrease in muscle long chain acylcarnitine content
Meissner M, et al. PLOS 2011 (6)11 e24564.
Coleselavam
Cholestyramine
Colesevalam
Colesevalam
Orlistat
Effect on weight
Effects on Hba1c
Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.
Targeting the Kidney
Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.
Renal Glucose Transport
Rationale for SGLT2 Inhibitors
• SGLT2 is a low-affinity, high capacity glucose transporter located in the proximal tubule and is responsible for 90% of glucose reabsorption
• Mutation in SGLT2 transporter linked to hereditary renal glycosuria, a relatively benign condition in humans
• Selective SGLT2 inhibitors have a novel & unique mechanism of action reducing blood glucose levels by increasing renal excretion of glucose
• Decreased glycemia will decrease glucose toxicity leading to further improvements in glucose control
• Selective SGLT2 inhibition, would also cause urine loss of the calories from glucose, potentially leading to weight loss
Brooks AM, Thacker SM. Ann Pharmacother. 2009;42(7):1286-1293.
Canagliflozin
*P˂.001 vs. placebo calculated using LS meansRosenstock J, et al. Abstract 77-OR. ADA 2010.
Metformin + Canagliflozin Dose-Ranging Study
Mean Baseline A1C (%)
7.71 8.01 7.81 7.57 7.70 7.71 7.62
*
*
*
**
*
Changes from Baseline in Body Weight in Phase 3 Dapagliflozin Studies
Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg
Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.
Canagliflozin Trials
• Symptomatic genital infections in 3-8% canagliflozin arms– 2% placebo
– 2% SITA
• Urinary tract infections in 3-9% canagliflozin arms– 6% placebo
– 2% SITA
• Hypoglycemia in 0-6% canagliflozin arms– 2% placebo
– 5% SITA
Rosenstock J, et al. Abstract 77-OR. ADA 2010.
Treatment and cancer risk
metformin
sulphonylurea
metformin + sulpha
insulin
No treatment
Treatment and colorectal cancer risk
metformin
sulphonylurea
metformin + sulpha
insulin
Treatment and pancreatic cancer risk
metformin
sulphonylurea
metformin + sulpha
insulin
ADOPT and RECORD Trials
ADOPT and RECORD Trials
METFORMIN
METFORMIN
Are all sulphonylureas the same?
Retrospective cohort study
Glibenclamide treated N-378
Gliclizide treated N-190
5 year follow up
Cancer mortality higher for glibenclamide after adjustments for age and sex, BMI, metformin and insulin treatment- HR 3.56 (1.1-11.9)
Are all sulphonylureas the same?
Matched case-control study
195 diabetic patients with incident malignancy
195 matched diabetic patients with no malignancy
Matched for sex, age, BMI, duration of diabetes, Hba1c, smoking and alcohol abuse
Exposure to antidiabetic drugs over last 10 years was analyzed.
Are all sulphonylureas the same?
Possible mechanism
New Classes Presently in Development
• Long-acting GLP-1 receptor agonists
• Ranolazine
• 11 Hydroxysteroid Dehydrogenase (HSD)- 1 inhibitors
• Fructose 1,6-bisphosphatase inhibitors
• Glucokinase activators
• G protein-coupled Receptor (GPR)- 40 & -119 agonists
• Protein Tyrosine Phosphatase (PTB)- 1b inhibitors
• Camitine- Palmitoyltransferase (CPT)- 1 inhibitors
• Acetyl COA Carboxylase (ACC)- 1 & -2 inhibitors
• Glucagon receptor antagonists
• Salicylate derivatives