Principles of Therapeutics

Oral Anti-diabetic Drugs

(OADs)
Developed by Leslie Quiwa, MD and Cecilia Jimeno, MD
Philippine Society of Endocrinology, Diabetes and Metabolism
Objectives
1. To review to the pathophysiology and diagnosis
of Type 2 diabetes mellitus (T2DM)
2. To enumerate the various classes of locally-
available oral anti-diabetic drugs (OADs) and
describe their characteristics
3. To discuss the general recommendations for
antihyperglycemic therapy in T2DM and the
various factors that influence the choice of OADs
in clinical practice
4. To illustrate a patient-centered approach to
the management of T2DM
 I. Overview of Type 2 DM

II. Oral Medications for T2DM

DM
III. Using OADs in Clinical Practice

IV. Patient-centered
Management of T2DM
Overview of
Type 2 DM
The Spectrum of Glycemia
HYPERGLYCEMIA

NORMAL PREDIABETES DIABETES

< 100 mg/dl 100-125 mg/dl  126 mg/dL*

FBS Impaired Fasting Glucose
< 5.6 mmol/L 5.6-6.9 mmol/L  7.0 mmol/L*

< 140 mg/dL 140-199 mg/dL  200 mg/dL*

OGTT Impaired Glucose Tolerance

2hr, 75g < 7.8 mmol/L 7.8-11.0 mmol/L  11.1 mmol/L*

< 5.7% 5.7-6.4%  6.5%*

HbA1c

Plus classic symptoms of hyperglycemia or hyperglycemic crisis

 200 mg/dL
RBS
 11.1 mmol/L
* In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing.
American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2. In Standards of Medical Care in Diabetes – 2016. Diabetes Care 2016;39(Suppl. 1): S13–S22
 6

Pharmacologic Options for Treatment

Injectable Non-Injectable
Diabetes Therapies
Therapies Therapies

Insulin Therapies • BiguanidesNon-Insulin

(Metformin)
Therapies
• Bile acid sequestrants
• Sulfonylureas (SU)
• Dopamine 2 agonists
•
Intensification Thiazolidinediones
GLP-1 RA
(TZD) GLP-1 RA
Start Regimens
Regimens Therapies Combinations
• DPP-IV Inhibitors
• Meglitinides
Basal
Basal Premix
Bolus• Alpha-glucosidase inhibitors
• SGLT2 inhibitors
 The Ominous Octet

SUs, TZD,
DPP4i, metformin,
GLP1-RA insulin Increased
& insulin
Decreased peripheral hepatic glucose
Decreased insulin glucose uptake output
secretion Metformin, TZD & insulin

Decreased HYPERGLYCEMIA Increased

incretin lipolysis
effect TZDs
DPP4i,
GLP1-RA,
AGI,
metformin Poor appetite
control
Increased
Increased DPP4i & GLP1-RA
glucose
glucagon reabsorption
DPP4i, GLP1-RA & insulin
secretion
SGLT2i

Adapted from DeFronzo, R.A. From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus. Diabetes Care 2009;58:773-795
 General recommendations for
antidiabetic therapy in type 2 DM
Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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 Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy† dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high 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 Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

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 GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin § or 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 Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡

American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes – 2016. Diabetes Care 2016;39(Suppl. 1):S52–S59
 The ADA algorithm emphasizes
that various therapeutic
interventions can be combined to
achieve glycemic control.

Lifestyle interventions form the

base of the “pyramid” followed by
metformin as the recommended
first-line drug. This can
subsequently be combined with a
range of other anti-DM
medications, both oral and
injectable

insulin GLP-1-RA SGLT2-i DPP4-i TZD 3 plus

sulfonylurea 2 plus
Metformin 1
Healthy eating, weight control, physical activity
American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes – 2016. Diabetes Care 2016;39(Suppl. 1):S52–S59
 Initiation of drug therapy among newly
diagnosed type 2 diabetes patients

Newly diagnosed T2DM

HbA1c < 9% HbA1c > 9%

FBS < 250 mg/dL FBS > 250 mg/dL

Option for
Combination
Monotherapy combination Insulin therapy
therapy
therapy

UNITE for Diabetes. Philippine Practice Guidelines on the Diagnosis and Management of Diabetes Mellitus. Compendium of Philippine Medicine, 16th ed., 2013.
Oral Medications
for Type 2 DM
Biguanides (Metformin)
Insulin sensitivity
Fasting
blood sugar
Hepatic glucose output

 HbA1c
1-2%
• Dosages: 500, 850, 1000 mg/tab
• Regular or sustained-release (extended release,
“XR”)
• Contraindications: hepatic insufficiency, acidosis,
hypoxia, decompensated CHF, alcohol abuse

J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders.
 Metformin and Renal Function
Traditional creatinine levels where metformin is
contraindicated

≥ 1.5 mg/dL ≥ 1.4 mg/dL

S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
 Metformin and Renal Function
Possible Approach to Metformin Prescribing in the Setting of CKD
Maximum Total
eGFR* Other Recommendations
Daily Dose, mg

≥ 90 2,550
60 to < 90 2,550
Avoid if kidney function is expected to become
unstable
45 to < 60 2,000
Consider more cautious follow-up of kidney
function
Do not initiate therapy at this stage but drug
may be continued
30 to < 45 1,000
Avoid if kidney function is or expected to
become unstable
15 to < 30 Do not use
< 15 Do not use
* mL/min per 1.73 m2

Inzucchi SE et al. Metformin in Patients With Type 2 Diabetes and Kidney Disease: A Systematic Review. JAMA. 2014 Dec 24-31;312(24):2668-75
 Metformin
PROS CONS
• Very cheap • Gastrointestinal
• Low hypoglycemia distress (up to 1/3 of
risk patients)
• Weight neutral or • Lactic acidosis (rare)
weight loss • Can cause vitamin
• Strongest record of B12 deficiency
achievement in
outcome studies

J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders
S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
 Metformin

• Use as the first line drug for Type 2 DM

unless contraindicated
• To avoid gastrointestinal upset start at a low dose (e.g.
500-850 mg OD) and titrate upward slowly to more
effective doses (e.g. 500 to 1000 mg BID)
• Sustained-release formulations (metformin XR) can
lessen upper GI symptoms but can increase the
frequency of diarrhea
• The maximal daily dose of 2550 mg generally does NOT
provide additional benefit beyond that seen at 2000
mg/day
J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders
S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
Sulfonylureas
SU
Beta cells

Fasting
blood sugar
Insulin
secretion

• Gliclazide, glimepiride, glipizide, glibenclamide

• Insulin secretagogues
 HbA1c
• Cheap and cost-effective 1-2%
• Caution: renal insufficiency, elderly
• The maximum marketed dose is 2 to 4 times higher
than the maximum effective dose
J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders
S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
 Sulfonylureas
PROS CONS
• Arguably the most • Hypoglycemia
cost-effective • Weight gain
glucose lowering • Possible
agents cardiotoxicity
• Well-tolerated • Higher rate of β cell
• Good glycemic failure
lowering ability • Less durable
glycemic control

Nathan, David M. et al. “Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy” Diabetes Care
32.1 (2009): 193–203.
S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
 Sulfonylureas

SU Dosing Guide
Sulfonylurea Initial dose Maximum Dose
Glibenclamide 2.5 mg 20 mg divided in 2 doses
Glipizide 2.5-5 mg 40 mg, two doses when > 10 mg
Glipizide ER 2.5-5 mg 20 mg OD
Glimepiride 1-2 mg 8 mg OD
Gliclazide 80 mg BID 320 mg, 2 doses when > 160 mg
Gliclazide MR 30 mg 120 mg

Diamicron and Diamicron MR product monographs (July 13, 2016)

J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders
S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
 Sulfonlyureas
• Do NOT use very high doses because
the maximum effective dose is only half
to a quarter of the maximum marketed
dose
• Most effective when used concomitantly with insulin-
sensitizing therapy

• Glibenclamide (glyburide) is associated with the

highest rates of hypoglycemia

• Glipizide is the best SU to use in patients with

advanced chronic kidney disease

Diabetes Treatment, Part 2: Oral Agents for Glycemic Management. M.J. Fowler. Clinical Diabetes 2007 Oct; 25(4): 131-134.
S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
 Meglitinides
Glinide
Beta cells

N: Postprandial BS
R: fasting and
postprandial BS
Insulin
secretion
 HbA1c
• Repaglinide and nateglinide 0.5-1.5%
• Insulin secretagogues that are taken before
meals due to short duration of action
• Repaglinide: 0.5, 1, 2 mg/tab; maximum of 4
mg prior to meal; nateglinide: 120 mg/tab
prior to meal
• Contraindication/caution: Severe liver disease
Product monographs: GlucoNorm (03 June 2015), Starlix (10 June 2011)
J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders
S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
 Glinides

PROS CONS
• Less hypoglycemia • Frequent dosing can
compared to SUs reduce compliance
• Targets postprandial • Expensive
blood sugar • Weight gain

S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
Thiazolidinediones (TZDs)
fasting blood glucose
triglycerides
+
insulin
PPAR sensitivity
 HbA1c
• Pioglitazone and rosiglitazone
0.5-1.4%
• Delayed onset of effect
• Dosage (Pio): 15 mg, 30 mg, 45 mg OD
• Maximum dose (Pio): 45 mg/day
• Contraindications: NYHA Class I-IV heart failure,
active hepatocellular disease, unexplained ALT >
2.5x the upper limit of normal
Product monographs: Actos (18 May 2012), Avandia (5 March 2012)
J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders
S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
Glitazones /TZDs

PROS CONS
• Low hypoglycemia • Can cause or worsen
risk peripheral edema
• Effective and well- and heart failure
tolerated • Weight gain
• Potential to slow • Increased fracture
down β cell risk
deterioration • Pio:  bladder cancer

S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
-Glucosidase Inhibitors
polysaccharides
AGI
--

-glucosidase postprandial
blood sugar
monosaccharides carbohdyrate
absorption

 HbA1c
• Acarbose, voglibose, miglitol
0.5-0.8%
• Taken before meals
• Start with a low dose and increase gradually
to minimize GI side effects
• Contraindications: renal failure, intestinal
disorders
Product monographs: Glucobay (21 Nov 2014); Volicose
J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders
S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
-Glucosidase Inhibitors

PROS CONS
• Targets postprandial • Only moderately
glucose effective
• Low hypoglycemic • Expensive
risk • GI distress:
• Weight neutral flatulence, diarrhea,
• Possibly decreases abdominal pain
cardiovascular risk

S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
 DPP4 Inhibitors (“gliptins”)
Circulating
GLP-1 incretin
degrades levels Insulin
β cells Blood
L cells DPP4-I secretion sugar
DPP4

 HbA1c
0.5-0.8%
• Sitagliptin, vildagliptin, saxagliptin, linagliptin
• Usual dose is the maximum marketed dose
• Only requires downward titration for renal
insufficiency (except linagliptin)
• Contraindications: prior history of pancreatitis
J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders
S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
DPP4 Inhibitors

PROS CONS
• Remarkably well- • Only modestly
tolerated effective
• No upward titration • Expensive
needed • Increases risk of
• Low hypoglycemia pancreatitis
risk
• Weight neutral

S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
DPP4 Inhibitors

DPP4-I Dosing Guide

DPP4-I Dose Forms Renal Dose Adjustment
CrCl < 30 25 mg OD
25 mg, 50 mg,
Sitagliptin CrCl  30 to < 50 50 mg OD
100 mg
CrCl  50 100 mg OD
CrCl > 50 5 mg OD
Saxagliptin 2.5 mg, 5 mg
CrCl  50 2.5 mg OD
CrCl  50 50 mg BID
Vildagliptin 50 mg
CrCl < 50 50 mg OD
Linagliptin 5 mg No adjustment needed*
*Use with caution in patients with ESRD and those on dialysis

Product monographs of Trajenta (14 May 2015); Januvia (18 Oct 2016); Onglyza; Galvus
SGLT2 Inhibitors
S1 segment of
proximal tubule

SGLT2-I

Glucose
SGLT2

SGLT1
~90% reabsorption

~10% reabsorption

Distal S2/S3 segment

of proximal tubule

No glucose
Glucose
Chao EC, Henry RR. SGLT2 inhibition—a novel strategy for diabetes treatment. Nat Rev Drug Discov. 2010;9(7):551–9.
SGLT2 Inhibitors (“gliflozins”)

• Dapagliflozin (Forxiga), canagliflozin

(Invokana), empagliflozin (Jardiance)  HbA1c
0.9-1.2%
• 70-100 grams of glucose per day is
lost through the urine
• Becomes ineffective as kidney function declines
(GFR < 45-60 mL/min/1.73m2)
• Caution: elderly, volume-depleted patients, those
at risk for recurrent urogenital tract infections

Product monographs: Invokana (22 May 2014); Forxiga (10 Dec 2014); Jardiance (12 Sept 2016)
J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders
SGLT2 inhibitors

PROS CONS
• Low risk of • Expensive
hypoglycemia • Increases risk of
• Consistently causes genital infections
weight loss (around • Decrease in efficacy in
2-3 kg over 6 months) those with advanced
• Lowers blood kidney disease
pressure

S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
 SGLT2 Inhibitors

SGLT2-I Dosing Guide

SGLT2-I Dose Forms Recommended Dose*
eGFR ≥ 60 100 to 300 mg OD
Canagliflozin 100 mg, 300 mg eGFR 45 to < 60 100 mg OD
eGFR < 45 Do not use
eGFR ≥ 60 5 to 10 mg OD
Dapagliflozin 5 mg1, 10 mg
eGFR < 60 Do not use
eGFR ≥ 45 10 to 25 mg OD
Empagliflozin 10 mg, 25 mg
eGFR < 45 Do not use
* Dose in boldface is the recommended starting dose
1 Not available locally

Product monographs: Invokana (22 May 2014); Forxiga (10 Dec 2014); Jardiance (12 Sept 2016)
Using OADs in
Clinical Practice
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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 Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy† dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high 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 Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

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 GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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 Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡
American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes – 2016. Diabetes Care 2016;39(Suppl. 1):S52–S59
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Metformin
Costs low
intolerance or 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):
contraindication
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy† dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
HbA1c Weight gain gain neutral loss loss gain
≥9% Side effects If HbA1c target not achieved after ~3 months of monotherapy,
hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high variable
proceed
If HbA1c totarget
2-drugnot combination
achieved after (order ~3 not months meant of totripledenotetherapy any and
specific
patient preference
If HbA1c target –~3choice
not achieved after dependent
months of dual therapy, proceed to on
3-drugacombination
variety ofnotpatient-
(order &
meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
disease-specific
Metformin 1) On oral Metforminfactors Metformin
combination  moveMetformin to injectables Metformin Metformin
+ + + + + +
Triple Sulfonylurea2) On GLP-1
Thiazolidine-RA  add
DPP-4 basal insulin
SGLT-2 GLP-1 receptor Insulin (basal)
dione Inhibitor Inhibitor agonist
therapy + 3) On optimally
+ titrated
+ basal insulin +  add +GLP-1 RA or +
TZD SU SU SU SU TZD
mealtime insulin
If HbA1c
or InDPP-4-i target
refractory not achieved
DPP-4-i
or patients, or after
considerTZD ~3 or
adding months TZD of monotherapy,
TZD or
or SGLT2-i TZD or DPP-4-i

proceed
or SGLT2-i to 3-drug or SGLT2-i combination or SGLT2-i (orderor not meant or
DPP-4-i to denote
Insulin §
any or SGLT2-i
Uncontrolled specific
or GLP-1-RA preference
or GLP-1-RA – choice dependent
or Insulin §
or on a variety of patient-or&GLP-1-RA
Insulin §

hyperglycemia
(catabolic features, disease-specific
or Insulin §
factors
or Insulin §

BG ≥300-350 mg/dl,
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
HbA1c ≥10-12%) 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 Basal Insulin + Mealtime Insulin or GLP-1-RA 36
therapy‡ Diabetes Care 2016;39(Suppl. 1):S52–S59
Agents for the Management
of Type 2 Diabetes
• Increase insulin secretion (secretagogues):
sulfonylureas, meglitinides, incretins
• Decrease insulin resistance (insulin sensitizers):
biguanides, thiazolidinediones
• Retard nutrient absorption: alpha-glucosidase
inhibitors
• Inhibit alpha-cell secretion of glucagon: incretins
• Increased renal excretion of glucose: SGLT2-I

S. Melmed, K.S. Polonsky,P.R. Larsen, H.M. Kronenberg (2016). Pharmacotherapy for Type 2 Diabetes Mellitus. In Williams Textbook of Endocrinology. Philadelphia, PA: Elservier
 EFFICACY: Comparative Efficacy of
Anti-diabetic Agents
Antidiabetic agents

SU MET Glinides DPP-4 TZDs GLP-1 SGLT2-i Insulin

inhibitors RAs
0.0

0.5
1.5 1.5 1.0-1.5 0.5-1.0 0.8-1.0 0.5-1.0 0.9 -1.2
HbA1c reduction (%)a

1.0
≥2.5
1.5

2.0

2.5

3.0

aEfficacy
as monotherapy.
DPP-4, dipeptidyl peptidase-4; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; MET, metformin; TZDs, thiazolidinediones.

Nathan DM et al. Diabetes Care. 2009;32:193-203.

J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus. In Endocrinology: Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders.
 ADR’s of Anti-diabetic Medications
ADVERSE
SU Meg Big AGI TZD DPP4i SGLT2i
EFFECTS

Hypoglycemia ++ + - - - - -
Weight gain + + LOSS
- + - LOSS

Edema - - - - + - -
GI symptoms - - + + - - -
Genital
Other Lactic
problems acidosis
CHF mycotic
infections

Adapted from T2D Algorithm, Executive Summary,Endocr Pract. 2016;22(No.1) and J.L. Jameson and L.J. De Groot (2016). Management of Type 2 Diabetes Mellitus (Table 48-2). In Endocrinology:
Adult and Pediatric 7th Edition. Philadelphia, PA: Elservier Saunders
Contraindications to the use
of OADs
CONTRAINDICATIONS SU Meg Big AGI TZD

Renal insufficiency   

Liver disease     

Inflammatory bowel disease 

Congestive heart failure

(CHF)  

Known hypersensitivity     
Antihyperglycemic Agents and Renal Function
CKD Stage: 5 4 3 2 1
GFR (mL/min): <15 15-29 30-59 60-89 ≥90

Acarbose 25
Metformin 30 60
Safe
Alogliptin 6.25 mg 30 12.5 mg 50 25 mg
Not recommended Linagliptin 15 5 mg
Caution/reduced dose Saxagliptin 15 2.5 mg 50 5 mg

Sitagliptin 25 mg 30 50 mg 50 100 mg
Contraindicated
Exenatide 30 5 mcg BID 50 10 mcg BID

Liraglutide 50 100 mg

Gliclazide/Glimepiride 15 30
Glyburide 30 50
Nateglinide/Repaglinide
Canagliflozin 45 100 mg 60 100-300 mg

Empagliflozin 45 60 10-25 mg

Dapagliflozin 60 5-10 mg

Thiazolidinediones 30

Adapted from: Product Monographs as of Nov 2016; Harper W et al. Can J Diab 2015;39:250-252; and Yale JF. J Am Soc Nephrol 2005; 16:S7-S10.
Issues of Suitability and Cost

Patient-centered
Management
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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 Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy† dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high 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 Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

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 GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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 Basal Insulin + Mealtime Insulin or GLP-1-RA 44
therapy‡ Diabetes Care 2016;39(Suppl. 1):S52–S59
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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 Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy† dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high 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 Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

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 GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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
Anti-hyperglycemic
injectable therapy in T2DM:
Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy ‡
Avoidance of hypoglycemia Diabetes Care 2016;39(Suppl. 1):S52–S59
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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 Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy† dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high 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 Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

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 GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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
Anti-hyperglycemic
injectable therapy in T2DM:
Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy ‡
Avoidance of weight gain Diabetes Care 2016;39(Suppl. 1):S52–S59
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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 Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy† dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high 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 Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

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 GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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 therapy in T2DM:
Anti-hyperglycemic
injectable Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy
Minimization
‡
of Cost Diabetes Care 2016;39(Suppl. 1):S52–S59