cleveland clinic skugor oral antidiabetic medications

8/10/2019 Cleveland Clinic Skugor Oral Antidiabetic Medications

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Oral Anti-diabetic Medications

Mario Skugor, MD FACE

Endocrine and Metabolic Institute

Cleveland Clinic


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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


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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


Orlistat

CLASSES OF ORAL ANTIDIABETIC MEDICATIONS

In development

Dual PPAR gamma agonists

SGLT-2 antagonists

Canagliflozin just approved.


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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.


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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


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METFORMIN

Comes in 500, 850 and 1000 mg pills.

Extended release pills are available (but moreexpensive)

Usual dose is 1000 mg twice a day.

Main side effects is abdominal cramping and diarrhea

Metformin extended release is better tolerated bysome patients

Even mild renal failure (Cr>1.4 in males and >1.5 infemales) is contraindication for use


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MetforminBottom line

Clearly the first line.

Cheap

Improves physiology

Has other benefits.

Unfortunately, significant proportion of patients hascontraindications or cannot tolerate it.


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SULPHONYLUREAS

Marcel Janbon and co-workers discovered

hypoglycemic effect of sulfonylurea in 1942.

They were studying sulfonamide antibiotics and

discovered that the compound sulfonylureainduced hypoglycemia in animals


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Sulphonylureas

First sulfonylurea for treatment of DM introduced in 1955.

General structure:


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Sulphonylurea

First generationBinds to the proteins in the blood.

Tolbutamide

ChlorpropamideTolazamide

Acetohexamide

Carbutamide


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Sulphonylurea

Third generation

Glimepiride


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SUFONYLUREAS


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Sulfonylurea

Advantages

Fast acting

Once a day dosing

Gliclazide may be particularly beneficial Disadvantages

Risk of hypoglycemia

Weight gain

Possible problems with ischemic preconditioning


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Glicilizide

Inhibits platelet aggregation

Associated with lower mortality from malignantneoplasms.

Improves repair of DNA damage caused by oxidativestress in tissue cultures.


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SulfonylureasBottom line

Fast acting

Older ones are cheap

Do not improve physiology

Hypoglycemia is significant risk

Require strict regime of diet


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Meglitinides

Nategelinde

Repaglinide

Act on same potassium channel as sulfonylurea butbind to different part of the molecule.

Short actingtaken 0-30 min before meal.

Risk of hypoglycemia is small


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MeglitinidesBottom line

Useful in small number of patients for relatively shortperiod of time.

Allow for some flexibility in timing of the meals.


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TZD-sactually Pioglitazone

The proliferator-activated receptor gamma (PPAR-)and to a lesser extent PPAR- agonist in the muscle,

adipose tissue, and the liver.

Pioglitazone reduces insulin resistance in the liver andperipheral tissues.

Pioglitazone decreases the level of triglycerides andincreases HDL without changing LDL and total

cholesterol.


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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


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Thiazolidinediones and bladder cancer.

Colmers IN, et al. CMAJ 2012I:10.1503


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TZD-s and fracture risk

Toulis KA, et al. CMAJ, 2009, 180 (8) 841-842


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TZD-s and fractures

TZD-s are associated with fractures in females over 50years of age.

In men risk is increased if TZD-s are used with loop

diuretic

Bilik D, et al. JCEM. 2010 (10) 1210.


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Bottom line on Pioglitazone

Benefits are still higher than risks.

There is some evidence that lower dose is notassociated with risk of bladder cancer.

Howeverat this time Metformin and PPD-4 inhibitorsare clearly ahead of Pioglitazone as choices for

treatment.


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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 peptide1 (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


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Incretin system and DPP-4 physiologic action


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Native GLP-1 is rapidly degraded by DPP-IV

Human ileum,

GLP-1 producing

L-cells

Capillaries,

DPP-IV (Di-Peptidyl

Peptidase-IV)

Adapted from: Hansen et al. Endocrinology 1999;140:53565363.

Double immunohistochemical staining for DPP-IV (red)

and GLP-1 (green) in the human ileum


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Slide Source:

Lipids Online Slide Librarywww.lipidsonline.org

Glucagon-Like Peptide1NormalizesPostprandial Hyperglycemia in Patientswith Type 2 Diabetes

Nauck MA et al.Acta Diabetol.1998;35:117-129.

Time (h)

Plasmaglucose(mg/dl)

0

300

100

50

150

200

250

2 3 4101

Infusion

GLP-1 [7-36 amide]1.2 pmol/kg/min

Placebo

Liquid meal

0

300

100

50

150

200

250

2 3 4101

Infusion

GLP-1 [7-36 amide]1.2 pmol/kg/min

Placebo

Liquid meal

Plasmaglucose(mg/dl)

Healthy subjects T2DM patients

Time (h)


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Slide Source:


Continuous Glucagon-Like Peptide1Infusion Reduces Appetite over 6 Weeks

All data for patients treated with glucagon-like peptide1 (n = 10).

No changes in these parameters were observed in the saline group.

0

100

200

300

400

500

Mean (SE)AUC forVisual

AnalogueScore (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


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Slide Source:


Glycemic Control with GLP-1 ReceptorAgonists in Head-to-Head Clinical Trials

*Significant difference

vs comparator GLP-1

receptor 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 at47th 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

0.0

A1CChange

(%)

*

*

*

EXN BID

LIRA

EXN QW


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Slide Source:


Comparison 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 peptide1; DDP-4=dipeptidyl peptidase4


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DPP4 inhibitors

Sitagliptin

Saxagliptin

Linagliptoin

Alogliptin

Vildagliptinmarketed in EU

More in developmentGemigliptin


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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 ESRDSaxagliptin 5 mg per day

2.5 mg in renal impairment

2.5 if taken with cytochrome P450 inhibitors

(ketoconazole)Linagliptin 5 mg daily


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Sitagliptin - example


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DPP-4 inhibitors

Side effects are minimal

Acute pancreatitis is seen

Linagliptin 15.2/10.000 patients

Placebo 3.7/10,000 patients

SaxaglipinNo data but some postmarketing casesare reported

SitagliptinThere is 88 cases in 2.5 years inpostmarketing reporting.


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DDP-4 inhibitorsBottom Line

Very well tolerated

Improve physiology

Expensive

So far, no serious adverse effects with long term use.

No increased risk of pancreatic caner.


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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 Hba1cimproves.


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Alpha-Glucosidase inhibitors


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Alpha-glucosidase inhibitorsBottom line

Very useful if tolerated

Relatively cheap.


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Bromocriptine

Bromocriptine mesylate given within 2 hours of wakingup in the morning improves glycemic control by

unknown mechanism.

It is given in escalating dose starting with 0.8 mg andincreasing 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.


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Bromocriptine


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Bromocriptine


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BromocriptineBottom 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).


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Colesevelam

Cholestyramine

Colestid

Mechanism is unknown

In db/db mice these drugs increase metabolicutilization of glucose in peripheral tissues which

corelates with decrease in muscle long chainacylcarnitine content

Meissner M, et al. PLOS 2011 (6)11 e24564.


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Coleselavam


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Cholestyramine


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Colesevalam


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Colesevalam


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Orlistat


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Effect on weight


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Effects on Hba1c


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Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

Targeting the Kidney


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Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.

Renal Glucose Transport


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Rationale for SGLT2 Inhibitors

SGLT2 is a low-affinity, high capacity glucose transporter

located in the proximal tubule and is responsible for 90% ofglucose reabsorption

Mutation in SGLT2 transporter linked to hereditary renal

glycosuria, a relatively benign condition in humans

Selective SGLT2 inhibitors have a novel & unique mechanism ofaction 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.

C lifl i


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Canagliflozin

*P.001 vs. placebo calculated using LS meansRosenstock J, et al. Abstract 77-OR. ADA 2010.

Metformin + Canagliflozin Dose-Ranging Study

Mean BaselineA1C (%)

7.71 8.01 7.81 7.57 7.70 7.71 7.62

*

*

*

**

*

Changes from Baseline in Body Weight


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Changes from Baseline in Body Weight

in Phase 3 Dapagliflozin StudiesPlacebo 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.


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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.


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Treatment and colorectal cancer risk

metformin

sulphonylurea

metformin + sulpha

insulin


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Treatment and pancreatic cancer risk

metformin

sulphonylurea

metformin + sulpha

insulin


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ADOPT d RECORD T i l


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ADOPT and RECORD Trials


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METFORMIN


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METFORMIN

METFORMIN


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METFORMIN


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A ll l h l h ?


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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 insulintreatment- HR 3.56 (1.1-11.9)


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A ll l h l th ?


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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.

A ll l h l th ?


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P ibl h i


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Possible mechanism

New Classes Presently in Development


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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

cleveland clinic skugor oral antidiabetic medications

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