Download System Requirement

HYPOGLYCEMIC ORAL THERAPY
Dr.Mohamed Farghaly
FRCGP(UK),MRCGP(I),DMSc(UK)
DIH(I) MBChB (EG)



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)
Decreased
pancreatic
insulin
secretion
Peripheral
insulin
resistance
in muscle
and fat
tissue
Deficient
incretin
hormones
response
Increased
hepatic
glucose
output
 Decreased incretin effects from GIT
 Dysregulated pancreatic α-cell activity
 Lipotoxicity
 Maldaptive kidney responses
 Central neurotransmitter dysfunction
Decreased Insulin
Secretion
Decreased
Incretin Effect
Increased
Lipolysis
Islet– cell
ETIOLOGY OF T2DM
Impaired Insulin
Secretion
Increased Lipolysis
Hyperglycemia
Increased
HGP
Decreased Glucose
Uptake
DEFN75-3/99
HYPERGLYCEMIA
Increased
Glucagon
Secretion
Increased
Hepatic Glucose
Production
Increased
Glucose
Reabsorption
Decreased Glucose
Uptake
Neurotransmitter
Dysfunction
Reprinted with permission from DeFronzo R et al. Diabetes. 2009;58:773-795.
Copyright © 2009 American Diabetes Association. All rights reserved.
Sulfonylureas
Increase insulin secretion
from pancreatic -cells
Glinides
Increase insulin secretion
from pancreatic -cells
Thiazolidinediones
Decrease lipolysis in
adipose tissue, increase
glucose uptake in skeletal
muscle and decrease
glucose production in liver
-glucosidase inhibitors
Delay intestinal carbohydrate
absorption
Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–
226.Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14.
GLP-1 analogues
Improve pancreatic islet glucose sensing,
slow gastric emptying, improve satiety
Sulfonylureas
Increase insulin secretion
from pancreatic -cells
Glinides
Increase insulin secretion
from pancreatic -cells
DPP-4 inhibitors
Prolong GLP-1 action leading to improved
pancreatic islet glucose sensing, increase
glucose uptake
Thiazolidinediones
Decrease lipolysis in
adipose tissue, increase
glucose uptake in skeletal
muscle and decrease
glucose production in liver
-glucosidase inhibitors
Delay intestinal carbohydrate
absorption
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.
Study
Microvasc
UKPDS
 



DCCT /
EDIC*
 


 
ACCORD



ADVANCE
CVD
Mortality





VADT

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:

Initial Trial
Long Term Follow-up
* in T1DM
Percentage of adults with diagnosed diabetes receiving
treatment with insulin or oral medication, United
States, 2007-2009
12%
Oral medication only
14%
No medication
16%
58%
Insulin and oral
medication
Insulin only
ANTI-HYPERGLYCEMIC THERAPY
Therapeutic options: Oral agents
- Metformin
- Sulfonylureas
- Thiazolidinediones
- DPP-4 inhibitors
- SGLT-2 inhibitors
- Meglitinides
- -glucosidase inhibitors
Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
1. Drugs that sensitize
the body to insulin
and/or control hepatic
glucose production
Thiazolidinediones
Biguanides
2. Drugs that stimulate
the pancreas to make
more insulin
Sulfonylureas
Meglitinides
3. Drugs that slow the
absorption of starches
Alpha-glucosidase
inhibitors




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)
Plasma Conc. (mg/mL)
2 x 500 mg metformin
2000
2 x 500 mg metformin XR
1600
1200
800
400
0
0
4
Absorption
Slower and longer
8
12
16
20
24
Time (h)
AUCs matched –identical drug exposure
for both dosage forms
Timmins P. Clin Pharmacokinet 2005; 44: 721-729
3 out of 4 patients
tolerate Metformin XR
a
UK
Location
Patient
No
Tolerant
No (%)
Liverpool
22
10 (46)
12a (54)
-
Isle of Wight b
24
15 (62)
7 (30)
Clatterbridge
28
23 (82)
3c (11)
2 (7)
-
London
21
19 (90)
2 (10)
Intolerant
No (%)
Tolerant < 1.5g/day b 2 patients lost to follow-up c Tolerant with minor symptoms
Feher. Br J Diabetes Vasc Dis 2007; 7: 225-8




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 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 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 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)
Conventional
Glibenclamide
Metformin
9
8
Median
HbA1c
(%)
77
IDF
Treatment
Goal:
<6.5%
6
0
0
3
6
9
Years
UKPDS Group. Lancet. 1998;352:854-865.
12
15
ANTI-HYPERGLYCEMIC THERAPY
Therapeutic options: Oral agents
- Metformin
- Sulfonylureas
- Thiazolidinediones
- DPP-4 inhibitors
- SGLT-2 inhibitors
- Meglitinides
- -glucosidase inhibitors
Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
•
•
Incretins are gut hormones that
enhance glucose stimulated insulin
secretion
Incretin effect designates amplification
of insulin secretion following oral
glucose load
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
α
β
Pancreas
Brain
Satiety
Intestine
β
Glucose-dependent
insulin secretion
β
Insulin synthesis
α
Glucose-dependent
glucagon secretion
GLP-1
Stomach
Gastric
emptying
Heart
Cardioprotection
Liver
Glucose
production
Cardiac function
L-cells secrete GLP-1
 degraded by DPP-4
Adapted from Baggio & Drucker. Gastroenterol 2007;132;2131–57
Ingestion
Pancreas
of food
Release of
Beta cells
active incretins
GI tract
Alpha cells
GLP-1 and GIP
Exenatide
Gliptin
X
Inactive
GLP-1
DPP-4
enzym
e
Inactive
GIP
Glucose
depende
nt
 Insulin
(GLP-1and
GIP)
Glucosedependen
 Glucagon
t
(GLP-1)
 Glucose
uptake by
peripheral
tissue
 Blood glucose in
fasting and
postprandial states
 Hepatic
glucose
production
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic
polypeptide.
 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
Drugs belonging to this class:
 Sitagliptin (FDA approved 2006)
 Vildagliptin (EU approved 2008)
 Saxagliptin (FDA approved 2009)
 Linagliptin (FDA approved 2011)
Islet -cell
Impaired
Insulin Secretion

TZDs
GLP-1 analogues
DPP-4 Inhibitors
Sulfonylureas/
Meglitinides
Increased
Lipolysis
TZDs
Metformin
TZDs

TZDs
Metformin
Increased
HGP
DPP-4=dipeptidyl peptidase-4.
Decreased Glucose
Uptake
Islet -cell
Impaired Insulin
Secretion
Insulin
Resistance
10 mmol/L
5 mmol/L
Fasting
Plasma Glucose
Increased
HGP
(180 L/day) (900 mg/L)=162 g/day
Glucose
SGLT2
S1
SGLT1
S3
90%
10%
No Glucose

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
Islet -cell
Impaired Insulin
Secretion
Insulin
Resistance
10 mmol/L
Fasting
Plasma Glucose
Increased
HGP
Glucosuria
Islet -cell
Impaired Insulin
Secretion
Insulin
Resistance
10 mmol/L
Increased
HGP
5 mmol/L
Fasting
Plasma Glucose
Glucosuria
Durability
Safety and
tolerability
Renal
impairment
The efficacy of SGLT2 inhibition may wane once
blood glucose falls into the normal range
The long-term safety of this class remains to be
proven
Risk of nocturia and genitourinary infections may limit
use in some patients
SGLT2 inhibition may not be effective in patients with
renal impairment
Multiple
Corrects a Novel
Pathophysiologic
Defects
in Type 2
Defect
Diabetes
Weight
Promotes
Management
Weight
Loss
Adverse
Effects
No Hypoglycemia
of Therapy
Improves
Type 2
Glycemic
Diabetes
Control
CVD
Risk
Improvements
in
(Lipid
and
Glucose
and Weight
Support Other
Hypertension
CVD Interventions
Control)
Complements
Action of Other
Hyperglycemia
Antidiabetic
Agents
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
Healthy eating, weight control, increased physical activity & diabetes education
Monotherapy
Metformin
Efficacy*
Hypo risk
Weight
Side effects
Costs
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Metformin
Metformin
Sulfonylurea
Thiazolidinedione
DPP-4
inhibitor
high
moderate risk
gain
hypoglycemia
low
high
low risk
gain
edema, HF, fxs
low
intermediate
low risk
neutral
rare
high
+
+
Metformin
Metformin
+
Metformin
+
+
Metformin
+
SGLT2
inhibitor
GLP-1 receptor
agonist
Insulin (basal)
intermediate
low risk
loss
GU, dehydration
high
high
low risk
loss
GI
high
highest
high risk
gain
hypoglycemia
variable
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Triple
therapy
Sulfonylurea
+
TZD
Metformin
+
Thiazolidinedione
+
Metformin
Metformin
+
+
DPP-4
Inhibitor
+
SU
SGLT-2
Inhibitor
+
SU
SU
Metformin
+
GLP-1 receptor
agonist
+
Metformin
+
Insulin (basal)
+
TZD
SU
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
TZD
or
DPP-4-i
or
SGLT2-i
or
SGLT2-i
or
SGLT2-i
or
DPP-4-i
or
Insulin§
or
SGLT2-i
or
Insulin§
or
Insulin§
or GLP-1-RA
or GLP-1-RA
or
or
Insulin§
or GLP-1-RA
Insulin§
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
Combination
Figureinjectable
2. An -hyperglycemic therapy
Basal Insulin +
‡
therapy
in T2DM:
General recommenda ons
+
Mealtime Insulin or
GLP-1-RA
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Healthy eating, weight control, increased physical activity & diabetes education
Monotherapy
Metformin
Efficacy*
Hypo risk
Weight
Side effects
Costs
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Metformin
Metformin
Sulfonylurea
Thiazolidinedione
DPP-4
inhibitor
high
moderate risk
gain
hypoglycemia
low
high
low risk
gain
edema, HF, fxs
low
intermediate
low risk
neutral
rare
high
+
+
Metformin
Metformin
+
Metformin
+
+
Metformin
+
SGLT2
inhibitor
GLP-1 receptor
agonist
Insulin (basal)
intermediate
low risk
loss
GU, dehydration
high
high
low risk
loss
GI
high
highest
high risk
gain
hypoglycemia
variable
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Triple
therapy
Sulfonylurea
+
TZD
Metformin
+
Thiazolidinedione
+
Metformin
Metformin
+
+
DPP-4
Inhibitor
+
SU
SGLT-2
Inhibitor
+
SU
SU
Metformin
+
GLP-1 receptor
agonist
+
Metformin
+
Insulin (basal)
+
TZD
SU
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
TZD
or
DPP-4-i
or
SGLT2-i
or
SGLT2-i
or
SGLT2-i
or
DPP-4-i
or
Insulin§
or
SGLT2-i
or
Insulin§
or
Insulin§
or GLP-1-RA
or GLP-1-RA
or
or
Insulin§
or GLP-1-RA
Insulin§
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
Combination
Figureinjectable
2. An -hyperglycemic therapy
Basal Insulin +
‡
therapy
in T2DM:
General recommenda ons
+
Mealtime Insulin or
GLP-1-RA
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Healthy eating, weight control, increased physical activity & diabetes education
Monotherapy
Metformin
Efficacy*
Hypo risk
Weight
Side effects
Costs
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Metformin
Metformin
Sulfonylurea
Thiazolidinedione
DPP-4
inhibitor
high
moderate risk
gain
hypoglycemia
low
high
low risk
gain
edema, HF, fxs
low
intermediate
low risk
neutral
rare
high
+
+
Metformin
Metformin
+
Metformin
+
+
Metformin
+
SGLT2
inhibitor
GLP-1 receptor
agonist
Insulin (basal)
intermediate
low risk
loss
GU, dehydration
high
high
low risk
loss
GI
high
highest
high risk
gain
hypoglycemia
variable
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Triple
therapy
Sulfonylurea
+
TZD
Metformin
+
Thiazolidinedione
+
Metformin
Metformin
+
+
DPP-4
Inhibitor
+
SU
SGLT-2
Inhibitor
+
SU
SU
Metformin
+
GLP-1 receptor
agonist
+
Metformin
+
Insulin (basal)
+
TZD
SU
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
TZD
or
DPP-4-i
or
SGLT2-i
or
SGLT2-i
or
SGLT2-i
or
DPP-4-i
or
Insulin§
or
SGLT2-i
or
Insulin§
or
Insulin§
or GLP-1-RA
or GLP-1-RA
or
or
Insulin§
or GLP-1-RA
Insulin§
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
Combination
Figureinjectable
2. An -hyperglycemic therapy
Basal Insulin +
‡
therapy
in T2DM:
General recommenda ons
+
Mealtime Insulin or
GLP-1-RA
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Healthy eating, weight control, increased physical activity & diabetes education
Monotherapy
Metformin
Efficacy*
Hypo risk
Weight
Side effects
Costs
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Metformin
Metformin
Sulfonylurea
Thiazolidinedione
DPP-4
inhibitor
high
moderate risk
gain
hypoglycemia
low
high
low risk
gain
edema, HF, fxs
low
intermediate
low risk
neutral
rare
high
+
+
Metformin
Metformin
+
Metformin
+
+
Metformin
+
SGLT2
inhibitor
GLP-1 receptor
agonist
Insulin (basal)
intermediate
low risk
loss
GU, dehydration
high
high
low risk
loss
GI
high
highest
high risk
gain
hypoglycemia
variable
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Triple
therapy
Sulfonylurea
+
TZD
Metformin
+
Thiazolidinedione
+
Metformin
Metformin
+
+
DPP-4
Inhibitor
+
SU
SGLT-2
Inhibitor
+
SU
SU
Metformin
+
GLP-1 receptor
agonist
+
Metformin
+
Insulin (basal)
+
TZD
SU
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
TZD
or
DPP-4-i
or
SGLT2-i
or
SGLT2-i
or
SGLT2-i
or
DPP-4-i
or
Insulin§
or
SGLT2-i
or
Insulin§
or
Insulin§
or GLP-1-RA
or GLP-1-RA
or
or
Insulin§
or GLP-1-RA
Insulin§
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
Combination
injectable
therapy‡
+
Basal Insulin +
Mealtime Insulin or
GLP-1-RA
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Healthy eating, weight control, increased physical activity & diabetes education
Monotherapy
Metformin
Efficacy*
Hypo risk
Weight
Side effects
Costs
Me ormin
intolerance or
contraindica on
Dual
therapy†
HbA1c
≥9%
Efficacy*
Hypo risk
Weight
Side effects
Costs
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
Metformin
Sulfonylurea
Thiazolidinedione
DPP-4
inhibitor
high
moderate risk
gain
hypoglycemia
low
high
low risk
gain
edema, HF, fxs
low
intermediate
low risk
neutral
rare
high
+
+
Metformin
Metformin
+
Metformin
+
+
Metformin
+
SGLT2
inhibitor
GLP-1 receptor
agonist
Insulin (basal)
intermediate
low risk
loss
GU, dehydration
high
high
low risk
loss
GI
high
highest
high risk
gain
hypoglycemia
variable
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Triple
therapy
Sulfonylurea
+
TZD
Uncontrolled
hyperglycemia
(catabolic features,
BG ≥300-350 mg/dl,
HbA1c ≥10-12%)
Metformin
+
Thiazolidinedione
+
Metformin
Metformin
+
+
DPP-4
Inhibitor
+
SU
SGLT-2
Inhibitor
+
SU
SU
Metformin
+
GLP-1 receptor
agonist
+
Metformin
+
Insulin (basal)
+
TZD
SU
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
TZD
or
DPP-4-i
or
SGLT2-i
or
SGLT2-i
or
SGLT2-i
or
DPP-4-i
or
Insulin§
or
SGLT2-i
or
Insulin§
or
Insulin§
or GLP-1-RA
or GLP-1-RA
or
or
Insulin§
or GLP-1-RA
Insulin§
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
Combination
injectable
therapy‡
+
Basal Insulin +
Mealtime Insulin or
GLP-1-RA
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Healthy eating, weight control, increased physical activity & diabetes education
Monotherapy
Metformin
Efficacy*
Hypo risk
Weight
Side effects
Costs
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Metformin
Metformin
Sulfonylurea
Thiazolidinedione
DPP-4
inhibitor
high
moderate risk
gain
hypoglycemia
low
high
low risk
gain
edema, HF, fxs
low
intermediate
low risk
neutral
rare
high
+
+
Metformin
Metformin
+
Metformin
+
+
Metformin
+
SGLT2
inhibitor
GLP-1 receptor
agonist
Insulin (basal)
intermediate
low risk
loss
GU, dehydration
high
high
low risk
loss
GI
high
highest
high risk
gain
hypoglycemia
variable
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Triple
therapy
Sulfonylurea
+
TZD
Metformin
+
Thiazolidinedione
+
Metformin
Metformin
+
+
DPP-4
Inhibitor
+
SU
SGLT-2
Inhibitor
+
SU
SU
Metformin
+
GLP-1 receptor
agonist
+
Metformin
+
Insulin (basal)
+
TZD
SU
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
TZD
or
DPP-4-i
or
SGLT2-i
or
SGLT2-i
or
SGLT2-i
or
DPP-4-i
or
Insulin§
or
SGLT2-i
or
Insulin§
or
Insulin§
or GLP-1-RA
or GLP-1-RA
or
or
Insulin§
or GLP-1-RA
Insulin§
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Figure 2A. An -hyperglycemic
Combination
therapy
in T2DM:
injectable
‡
therapy
Avoidance
of hypoglycemia
Metformin
+
Basal Insulin +
Mealtime Insulin or
GLP-1-RA
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Healthy eating, weight control, increased physical activity & diabetes education
Monotherapy
Metformin
Efficacy*
Hypo risk
Weight
Side effects
Costs
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Metformin
Metformin
Sulfonylurea
Thiazolidinedione
DPP-4
inhibitor
high
moderate risk
gain
hypoglycemia
low
high
low risk
gain
edema, HF, fxs
low
intermediate
low risk
neutral
rare
high
+
+
Metformin
Metformin
+
Metformin
+
+
Metformin
+
SGLT2
inhibitor
GLP-1 receptor
agonist
Insulin (basal)
intermediate
low risk
loss
GU, dehydration
high
high
low risk
loss
GI
high
highest
high risk
gain
hypoglycemia
variable
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Triple
therapy
Sulfonylurea
+
TZD
Metformin
+
Thiazolidinedione
+
Metformin
Metformin
+
+
DPP-4
Inhibitor
+
SU
SGLT-2
Inhibitor
+
SU
SU
Metformin
+
GLP-1 receptor
agonist
+
Metformin
+
Insulin (basal)
+
TZD
SU
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
TZD
or
DPP-4-i
or
SGLT2-i
or
SGLT2-i
or
SGLT2-i
or
DPP-4-i
or
Insulin§
or
SGLT2-i
or
Insulin§
or
Insulin§
or GLP-1-RA
or GLP-1-RA
or
or
Insulin§
or GLP-1-RA
Insulin§
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Figure 2B. An -hyperglycemic
Combination
therapy
in T2DM:
injectable
‡
therapy
Avoidance
of weight gain
Metformin
+
Basal Insulin +
Mealtime Insulin or
GLP-1-RA
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Healthy eating, weight control, increased physical activity & diabetes education
Monotherapy
Metformin
Efficacy*
Hypo risk
Weight
Side effects
Costs
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Metformin
Metformin
Sulfonylurea
Thiazolidinedione
DPP-4
inhibitor
high
moderate risk
gain
hypoglycemia
low
high
low risk
gain
edema, HF, fxs
low
intermediate
low risk
neutral
rare
high
+
+
Metformin
Metformin
+
Metformin
+
+
Metformin
+
SGLT2
inhibitor
GLP-1 receptor
agonist
Insulin (basal)
intermediate
low risk
loss
GU, dehydration
high
high
low risk
loss
GI
high
highest
high risk
gain
hypoglycemia
variable
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Triple
therapy
Sulfonylurea
+
TZD
Metformin
+
Thiazolidinedione
+
Metformin
Metformin
+
+
DPP-4
Inhibitor
+
SU
SGLT-2
Inhibitor
+
SU
SU
Metformin
+
GLP-1 receptor
agonist
+
Metformin
+
Insulin (basal)
+
TZD
SU
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
TZD
or
DPP-4-i
or
SGLT2-i
or
SGLT2-i
or
SGLT2-i
or
DPP-4-i
or
Insulin§
or
SGLT2-i
or
Insulin§
or
Insulin§
or GLP-1-RA
or GLP-1-RA
or
or
Insulin§
or GLP-1-RA
Insulin§
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Figure 2C. An -hyperglycemic
Combination
therapy
in T2DM:
injectable
‡
therapy
Minimiza
on of costs
Metformin
+
Basal Insulin +
Mealtime Insulin or
GLP-1-RA
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

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
52