hypoglycemic oral therapy dr.mohamed farghaly frcgp(uk),mrcgp(i),dmsc(uk) dih(i) mbchb (eg)
TRANSCRIPT
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HYPOGLYCEMIC ORAL THERAPY
Dr.Mohamed FarghalyFRCGP(UK),MRCGP(I),DMSc(UK)
DIH(I) MBChB (EG)
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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)
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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)
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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
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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
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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]
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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)
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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)
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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)
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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
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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
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What is Incretin?
• Incretins are gut hormones that enhance glucose stimulated insulin secretion
• Incretin effect designates amplification of insulin secretion following oral glucose load
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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
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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
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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
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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
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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)
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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.
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FastingPlasma Glucose
Pathophysiology of Type 2 Diabetes
10 mmol/L
Islet b-cell
Impaired Insulin Secretion
Insulin Resistance
Increased HGP
5 mmol/L
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SGLT1
(180 L/day) (900 mg/L)=162 g/day
10%
Glucose
No Glucose
S1
S3
Renal Handling of Glucose
SGLT2
90%
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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
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FastingPlasma Glucose
Pathophysiology of Type 2 Diabetes
10 mmol/L
Islet b-cell
Impaired Insulin Secretion
Insulin Resistance
Increased HGP
Glucosuria
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FastingPlasma Glucose
Pathophysiology of Type 2 Diabetes
10 mmol/L
Islet b-cell
Impaired Insulin Secretion
Insulin Resistance
Increased HGP
5 mmol/L
Glucosuria
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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
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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
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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
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IDF Treatment Algorithm
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Metformin Dose Response
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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
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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
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Thank You
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