HYPOGLYCEMIC ORAL THERAPY

Dr.Mohamed FarghalyFRCGP(UK),MRCGP(I),DMSc(UK)

DIH(I) MBChB (EG)

Pathogenesis Concepts in Type 2 Diabetes Insulin resistance occurs early, before glucose intolerance

◦ Genetic cause?◦ Environmental: obesity, aging, lifestyle, etc.

Healthy cells compensate and remain euglycemic “Susceptible” cells (in predisposed individuals)

◦ -cell dysfunction results in imperfect compensation◦ Progress to prediabetes stage◦ Onset of acquired abnormalities leads to worse

hyperglycemia=glucotoxicity (a vicious cycle)

Major Metabolic Defects in Type 2 Diabetes

Decreased pancreatic insulin secretion

Peripheral insulin resistance in muscle and fat tissue

Increased hepatic glucose output

Deficient incretin hormonesresponse

Other pathological defect involved in the development of type 2 diabetes

Decreased incretin effects from GIT Dysregulated pancreatic α-cell activity Lipotoxicity Maldaptive kidney responses Central neurotransmitter dysfunction

Reprinted with permission from DeFronzo R et al. Diabetes. 2009;58:773-795. Copyright © 2009 American Diabetes Association. All rights reserved.

Ominous Octet

IncreasedHGPHyperglycemia

ETIOLOGY OF T2DM

DEFN75-3/99 Decreased GlucoseUptake

Impaired InsulinSecretion Increased Lipolysis

DecreasedIncretin Effect

Decreased InsulinSecretion

IncreasedHepatic Glucose

Production

Islet– cell

IncreasedGlucagonSecretion

Decreased Glucose Uptake

Increased Lipolysis

IncreasedGlucose

Reabsorption

HYPERGLYCEMIA

NeurotransmitterDysfunction

Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM

-glucosidase inhibitorsDelay intestinal carbohydrate absorption

ThiazolidinedionesDecrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver

SulfonylureasIncrease insulin secretion from pancreatic -cells

BiguanidesIncrease glucose uptakeand decreases hepatic glucose production

Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14.

GlinidesIncrease insulin secretion from pancreatic -cells

Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM

-glucosidase inhibitorsDelay intestinal carbohydrate absorption

ThiazolidinedionesDecrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver

SulfonylureasIncrease insulin secretion from pancreatic -cells

GLP-1 analoguesImprove pancreatic islet glucose sensing, slow gastric emptying, improve satiety

BiguanidesIncrease glucose uptakeand decreases hepatic glucose production

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14.

GlinidesIncrease insulin secretion from pancreatic -cells

DPP-4 inhibitorsProlong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake

Impact of Intensive Therapy for Diabetes:

Summary of Major Clinical Trials

Study Microvasc CVD Mortality

UKPDS DCCT / EDIC*

ACCORD ADVANCE

VADT

Long Term Follow-up

Initial Trial

* in T1DM

Kendall DM, Bergenstal RM. © International Diabetes Center 2009

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.

Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977.

Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545.

Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum:

Moritz T. N Engl J Med 2009;361:1024)

Breakdown of Treatments for Diabetes in the United States

58%

16%

14%12%

Percentage of adults with diagnosed diabetes receiv-ing treatment with insulin or oral medication, United

States, 2007-2009

Oral medication onlyNo medicationInsulin and oral medica-tionInsulin only

ANTI-HYPERGLYCEMIC THERAPY

Therapeutic options: Oral agents

- Metformin

- Sulfonylureas

- Thiazolidinediones

- DPP-4 inhibitors

- SGLT-2 inhibitors

- Meglitinides

- a-glucosidase inhibitors

Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015

Major Classes of Medications

1. Drugs that sensitize the body to insulin and/or control hepatic glucose production

2. Drugs that stimulate the pancreas to make more insulin

3. Drugs that slow the absorption of starches

ThiazolidinedionesBiguanides

SulfonylureasMeglitinides

Alpha-glucosidase inhibitors

Biguanides

Biguanides decrease hepatic glucose production and increase insulin-mediated peripheral glucose uptake.

Efficacy◦ Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)◦ Reduce A1C 1.0-2.0%

Other Effects◦ Diarrhea and abdominal discomfort◦ Lactic acidosis if improperly prescribed◦ Cause small decrease in LDL cholesterol level and triglycerides◦ No specific effect on blood pressure◦ No weight gain, with possible modest weight loss◦ Contraindicated in patients with impaired renal function (Serum Cr > 1.4 mg/dL

for women, or 1.5 mg/dL for men) Medications in this Class: metformin (Glucophage), metformin hydrochloride

extended release (Glucophage XR)

0

400

800

1200

1600

2000

0 4 8 12 16 20 24

Time (h)

Pla

sm

a C

on

c. (

mg

/mL

) 2 x 500 mg metformin

2 x 500 mg metformin XR

Sustained Metformin Release Metformin XR Tablet

Absorption

Slower and longer

Timmins P. Clin Pharmacokinet 2005; 44: 721-729

AUCs matched –identical drug exposurefor both dosage forms

Metformin XR – GI Tolerability

UK Location

Liverpool

Isle of Wight b

Clatterbridge

London

PatientNo

22

24

28

21

(46)(54)

(62)

(82)(11)

(90)

(30)

(7)

(10)

a Tolerant < 1.5g/day b 2 patients lost to follow-up c Tolerant with minor symptoms

1012a

15

23 3c

19

--

7

2-

2

TolerantNo (%)

IntolerantNo (%)

3 out of 4 patientstolerate Metformin XR

Feher. Br J Diabetes Vasc Dis 2007; 7: 225-8

Thiazolidinediones (TZDs)

Thiazolidinediones(TZDs): decrease insulin resistance by making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose production.

Efficacy◦ Decrease fasting plasma glucose ~35-40 mg/dl (1.9-2.2 mmol/L)◦ Reduce A1C ~0.5-1.0%◦ 6 weeks for maximum effect

Other Effects◦ Weight gain, edema ◦ Hypoglycemia (if taken with insulin or agents that stimulate insulin release)◦ Contraindicated in patients with abnormal liver function or CHF◦ Improves HDL cholesterol and plasma triglycerides; usually LDL neutral

Medications in this Class: pioglitazone (Actos), rosiglitazone (Avandia), [troglitazone (Rezulin) - taken off market due to liver toxicity]

Sulfonylureas Sulfonylureas increase endogenous insulin secretion Efficacy

◦ Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)◦ Reduce A1C by 1.0-2.0%

Other Effects◦ Hypoglycemia◦ Weight gain ◦ No specific effect on plasma lipids or blood pressure◦ Generally the least expensive class of medication

Medications in this Class:◦ First generation sulfonylureas: chlorpropamide (Diabinese), tolazamide,

acetohexamide (Dymelor), tolbutamide◦ Second generation sulfonylureas: glyburide (Micronase, Glynase and

Glucovance), glimepiride (Amaryl), glipizide (Glucotrol, Glucotrol XL)

Meglitinides

Meglitinides stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose.

Efficacy◦ Decreases peak postprandial glucose◦ Decreases plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)◦ Reduce A1C 1.0-2.0%

Other Effects◦ Hypoglycemia (although may be less than with sulfonylureas if patient has a

variable eating schedule)◦ Weight gain ◦ No significant effect on plasma lipid levels◦ Safe at higher levels of serum Cr than sulfonylureas

Medications in this Class: repaglinide (Prandin), nateglinide (Starlix)

Alpha-glucosidase Inhibitors

Alpha-glucosidase inhibitors block the enzymes that digest starches in the small intestine

Efficacy◦ Decrease peak postprandial glucose 40-50 mg/dl (2.2-2.8 mmol/L)◦ Decrease fasting plasma glucose 20-30 mg/dl (1.4-1.7 mmol/L)◦ Decrease A1C 0.5-1.0%

Other Effects◦ Flatulence or abdominal discomfort ◦ No specific effect on lipids or blood pressure◦ No weight gain◦ Contraindicated in patients with inflammatory bowel disease or

cirrhosis Medications in this Class: acarbose (Precose), miglitol

(Glyset)

Years

7

6

0

8

0 3 6 9 12 15

UKPDS Group. Lancet. 1998;352:854-865.

Median HbA1c

(%)

UKPDS: Effect of Glibenclamide and Metformin Therapy on HbA1c

IDF Treatment

Goal:<6.5%

Conventional Glibenclamide Metformin

9

7

6

ANTI-HYPERGLYCEMIC THERAPY

Therapeutic options: Oral agents

- Metformin

- Sulfonylureas

- Thiazolidinediones

- DPP-4 inhibitors

- SGLT-2 inhibitors

- Meglitinides

- a-glucosidase inhibitors

Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015

What is Incretin?

• Incretins are gut hormones that enhance glucose stimulated insulin secretion

• Incretin effect designates amplification of insulin secretion following oral glucose load

NATURAL INCRETINS

Two types:

1. Glucose dependent insulinotropic polypeptide (GIP)

2. Glucagon like peptides (GLPs) -GLP-1

These two hormones are rapidly degraded by an enzyme DPP-4

Pancreas

Stomach

Heart

Brain

Liver

Adapted from Baggio & Drucker. Gastroenterol 2007;132;2131–57

Intestine

Cardioprotection

Cardiac function

Satiety

Gastricemptying

Glucose production

Glucose-dependentinsulin secretion

Insulin synthesis

Glucose-dependent glucagon secretion

β

GLP-1: an incretin hormone with multiple direct effects on human physiology

β

β

α

α

GLP-1

L-cells secrete GLP-1 degraded by DPP-4

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Release ofactive incretinsGLP-1 and GIP

Blood glucose in fasting and

postprandial states

Ingestion of food

Glucagon(GLP-1)

Hepatic glucose

production

GI tract

DPP-4 enzym

e

InactiveGLP-1

X

Insulin(GLP-1and

GIP)

Glucose-dependen

t

Glucose depende

nt

Pancreas

InactiveGIP

Beta cells

Alpha cells

Glucose uptake by peripheral

tissue

Exenatide

Gliptin

INCRETIN SYSTEM

THE PROBLEM

Because of very short half life (1-2 min) therapeutic efficacy is

challenged

This led to idea of producing drugs that act as analogue or receptor agonist but longer half life

Another idea was to develops drugs that inhibit DPP-4 enzyme responsible for breakdown of GLP-1 or GIP

Thus one group of drugs is called incretin mimetics and the other group is known as incretin enhancers

DIPEPTIDYL PEPTIDASE - 4 INHIBITORS

Drugs belonging to this class:

Sitagliptin (FDA approved 2006) Vildagliptin (EU approved 2008) Saxagliptin (FDA approved 2009) Linagliptin (FDA approved 2011)

DPP-4 InhibitorsSulfonylureas/Meglitinides

Treatment of Type 2 Diabetes: A Sound

Approach Based Upon Its Pathophysiology

MetforminTZDs

TZDs

TZDs

TZDsMetformin

GLP-1 analogues

Islet b-cell

ImpairedInsulin Secretion

IncreasedLipolysis

Decreased GlucoseUptake

IncreasedHGP

DPP-4=dipeptidyl peptidase-4.

FastingPlasma Glucose

Pathophysiology of Type 2 Diabetes

10 mmol/L

Islet b-cell

Impaired Insulin Secretion

Insulin Resistance

Increased HGP

5 mmol/L

SGLT1

(180 L/day) (900 mg/L)=162 g/day

10%

Glucose

No Glucose

S1

S3

Renal Handling of Glucose

SGLT2

90%

Rationale for SGLT2 Inhibitors

Inhibit glucose reabsorption in the renal proximal tubule

Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity

This therapy is simple and nonspecific Even patients with refractory type 2 diabetes are likely

to respond

FastingPlasma Glucose

Pathophysiology of Type 2 Diabetes

10 mmol/L

Islet b-cell

Impaired Insulin Secretion

Insulin Resistance

Increased HGP

Glucosuria

FastingPlasma Glucose

Pathophysiology of Type 2 Diabetes

10 mmol/L

Islet b-cell

Impaired Insulin Secretion

Insulin Resistance

Increased HGP

5 mmol/L

Glucosuria

Unanswered Questions About

SGLT2 Inhibition

DurabilityThe efficacy of SGLT2 inhibition may wane once blood glucose falls into the normal range

Safety and tolerability

The long-term safety of this class remains to be proven

Risk of nocturia and genitourinary infections may limit use in some patients

Renal impairment

SGLT2 inhibition may not be effective in patients with renal impairment

SGLT2 Inhibition: Meeting Unmet Needs in Diabetes Care

WeightManagement

Type 2Diabetes

Multiple Defects in Type 2 Diabetes

Adverse Effectsof Therapy

Hyperglycemia

CVD Risk(Lipid andHypertensionControl)

Improvements inGlucose and WeightSupport OtherCVD Interventions

ComplementsAction of OtherAntidiabeticAgents

PromotesWeight Loss

Corrects a NovelPathophysiologicDefect

No Hypoglycemia

ImprovesGlycemicControl

1. Should be based upon known pathogenic abnormalities, and NOT simply on the reduction in HbA1c

2. Will require multiple drugs in combination to correct multiple pathophysiologic defects

3. Must be started early in the natural history of T2DM, if progressive -cell dysfunction is to be prevented

Treatment of Type 2 Diabetes

IDF Treatment Algorithm

Metformin Dose Response

Overall Conclusions

Understanding of the pathophysiology of type 2 diabetes is an evolving process

As new concepts emerge, there is potential for new treatment modalities

Optimal management of type 2 diabetes requires a multifaceted approach that targets multiple defects in glucose homeostasis

Establishing a goal for HbA1c and strategies to help accomplish that goal, including weight loss and exercise along with consistent use of medication

Strategies to increase adherence include creating a medication schedule, addressing the costs of medications, and reporting adverse events in a timely manner

The need for regular glucose testing and routine blood tests for HbA1c

What to Discuss With Your Patients

Thank You

52