Diabetes mellitus refers to a group of diseases that affect how the body uses blood sugar (glucose). Glucose is an important source of energy for the cells that make up the muscles and tissues.

2. Diabetes or Diabetes Mellitus
❑ Chronic Metabolic Disorder
❑ Vascular Abnormalities
Characterized by
• Hyperglycemia
• Glycosuria
• Polydipsia
• Polyphagia
• Ketoacidosis

4. Diabetes mellitus
Type 1 Diabetes
- cells that produce
insulin are
destroyed
- results in insulin
dependence
- commonly detected
before 30
Type 2 Diabetes
- blood glucose levels rise
due to 1) Lack of insulin
production 2) Insufficient
insulin action (resistant
cells)
- commonly detected after
40
- effects > 90%
Gestational Diabetes
3-5% of pregnant women develop gestational
diabetes

5. 5
Characteristic Type 1 ( 10% ) Type 2
Onset (Age) Usually < 30 Usually > 40
Type of onset Abrupt Gradual
Nutritional status Usually thin Usually obese
Diet Mandatory with insulin Mandatory with or without
drug
Hypoglycemic drugs Should not be used Clinically indicated
Clinical symptoms Polydipsia, polyphagia,
polyurea, Wt loss
Often asymptomatic
Ketosis Frequent Usually absent
Endogenous insulin Absent Present, but relatively
ineffective
Related lipid
abnormalities
Hypercholesterolemia
frequent, all lipid fractions
elevated in ketosis
Cholesterol & triglycerides
often elevated; carbohydrate-
induced hypertriglyceridemia
common
Insulin therapy Required Required in only 20 - 30% of
patients

8. Liver Muscle Adipose
↓ glucose production ↑ Glucose transport ↑ glucose transport
↑ glycolysis ↑ glycolysis ↑ lipogenesis&
lipoprotein lipase
activity
↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis
↑ Protein synthesis ↑ protein synthesis

9. • In the case of type 1 diabetes, insulin levels
are grossly deficient. Thus type 1 diabetes is
invariably treated with insulin
• Type 2 diabetes is frequently associated with
obesity. Serum insulin levels are normal or
elevated, so this is a disease of insulin
resistance. A number of treatment options
may be employed.

10. • 11th January 1922 - pancreatic islet cell
extract first administered to 14 year old insulin
deficient patient
• Bovine and porcine pancreatic extracts
• 1980 human insulin available
-amino acid modification of porcine insulin
- synthesised by introducing DNA for human
insulin into bacteria or yeast

12. ❑Liver and Kidney are two organ remove insulin
from circulation by hydrolysis of disulfide
connection between A & B chains.
❑ Liver remove 60% of insulin.
❑ Kidney remove 35-40% of insulin.

13. INSULIN RECEPTOR
Binding sites
Cell
membrane
Tyrosin kinase
Intracellular
space

14. • Human insulin: Humulin® (from E.coli),
Novalin® (from yeast)
• NPH - neutral protamine Hagedorn (NPH),
protamine mixed.
• Lente® insulin / Ultralente® insullin- zinc
added
Regular insulins

15. • Fatty Acid Acylated insulins
• Insulin Lispro (Humalog®) (1996)
• Insulin Aspart (NovoLog®) (2000)
• Insulin Glargine (Lantus®) (2002)
• Insulin Detemir (Levemir®) (Jun.,2005)
• Insulin Glulisine (Apidra®) (Jan., 2006)
Insulin Analogs

16. 16
❑ Ultra-short-acting (Rapid acting)-with very fast
onset and short duration
❑ Short-acting (Regular)-with rapid onset of action
❑ Intermediate-acting
❑ Long-acting- with slow onset of action
TYPES OF INSULIN PREPARATIONS

17. 17
Short-acting (regular) insulins
e.g. Humulin R, Novolin R
Uses Designed to control postprandial
hyperglycemia & to treat
emergency diabetic ketoacidosis
Physical
characteristics
Clear solution at neutral pH
Chemical
structure
Hexameric analogue
Route & time of
administration
S.C. 30 – 45 min before meal
I.V. in emergency
(e.g. diabetic ketoacidosis)
Onset of action 30 – 45 min ( S.C )
Peak serum levels 2 – 4 hr
Duration of action 6 – 8 hr
Usual
administration
2 – 3 times/day or more
Ultra-Short acting insulins
e.g. Lispro, aspart, glulisine
Similar to regular insulin but
designed to overcome the
limitations of regular insulin
Clear solution at neutral pH
Monomeric analogue
S.C. 5 min (no more than 15 min)
before meal
I.V. in emergency
(e.g. diabetic ketoacidosis)
0 – 15 min ( S.C )
30 – 90 min
3 – 4 hr
2 – 3 times / day or more

18. • Insulin lispro, the first monomeric insulin analog to be marketed, is
produced by recombinant technology wherein two amino acids near
the carboxyl terminal of the B chain have been reversed in position:
Proline at position B28 has been moved to B29, and lysine at position
B29 has been moved to B28
• When injected subcutaneously, the
drug quickly dissociates into monomers
and is rapidly absorbed with onset of
action within 5–15 minutes and peak
activity as early as 1 hour. The time to
peak action is relatively constant, regardless
of the dose

19. Regular insulins
e.g. Humulin R, Novolin R
• Short-acting insulin— Regular insulin is a short-acting soluble
crystalline zinc insulin that is now made by recombinant DNA
techniques to produce a molecule identical to that of human
insulin. Its effect appears within 30 minutes, peaks between 2
and 3 hours after subcutaneous injection, and generally lasts
5–8 hours.
• The clinical consequence is that when regular insulin is
administered at mealtime, the blood glucose rises faster than
the insulin with resultant early postprandial hyperglycemia
and an increased risk of late postprandial hypoglycemia.
Therefore, regular insulin should be injected 30–45 or more
minutes before the meal to minimize the mismatching.

20. 20
Intermediate - acting insulins
e.g. Isophane (NPH) - neutral protamine Hagedorn,
protamine mixed
▪ Subcutaneous injection.(Only)
▪ Onset of action 2 - 5 hr
▪ Peak serum level 5 - 7 hr
▪ Duration of action 4 - 12 hr
it is usually mixed with regular, lispro, aspart, or glulisine insulin
and given two to four times daily for insulin replacement.

21. Insulin mixtures
• 75/25 70/30 50/50 (NPH / Regular)
• Intermediate insulins composed of isophane
complexes of protamine with insulin lispro
and insulin aspart have been developed:
• “NPL” (neutral protamine lispro)
- 50%/50% and 75%/25%
• “NPA” (neutral protamine aspart)
- 70%/30%

22. 22
Lente insulin
▪ Mixture of 30% semilente insulin
70% ultralente insulin
▪ Injected S.C. (only)
▪ Onset of action 1 - 3 hr
▪ Peak serum level 4 - 8 hr
▪ Duration of action 13 - 20 hr

23. 23
Long – acting insulins
e.g. Insulin glargine –
long-acting insulin analog
• Onset of action 1-2 hr
• Absorbed less rapidly than NPH & Lente insulins.
• Duration of action - 24 hr (Glargine is usually given once
daily)
Designed to overcome the deficiencies of intermediate acting insulins
Advantages over intermediate-acting insulins:
▪ More safe than NPH & Lente insulins due to reduced risk of
hypoglycemia(esp.nocturnal hypoglycemia).
▪ Clear solution that does not require resuspension before administration.

24. • Insulin detemir— This insulin is the most
recently developed long-acting insulin analog.
• Insulin detemir has a dose-dependent onset of
action of 1–2 hours and duration of action of
more than 12 hours.
• It is given twice daily to obtain a smooth
background insulin level.

25. Insulin degludec
Insulin degludec (INN/USAN) is an
ultralong-acting basal insulin
analogue that was developed by
Novo Nordisk under the brand name
Tresiba.
It is administered via subcutaneous
injection once daily to help control
the blood sugar level of those with
diabetes. It has a duration of action
that lasts up to 42 hours (compared
to 18 to 26 hours provided by other
marketed long-acting insulins such as
insulin glargine and insulin detemir),
making it a once-daily basal insulin,
that is one that provides a base
insulin level, as opposed to the fast-
and short-acting bolus insulins.

26. Dosage Forms & Strengths
injectable solution (prefilled pen, FlexTouch)
• 100 units/mL
• 200 units/mL
Type 1 Diabetes Mellitus
Long-acting basal insulin indicated to improve glycemic
control in patients with diabetes mellitus
Initial dose
For insulin-naïve patients
Start ~1/3 to 1/2 of the total daily insulin dose; use
remaining of total daily insulin dose on short-acting
insulin and divided between each daily meal
Usual initial dose range: 0.2-0.4 units/kg

27. Type 2 Diabetes Mellitus
Long-acting basal insulin indicated to improve
glycemic control in adults with type 2 diabetes
mellitus
Initial dose
• For insulin-naïve patients
• Start 10 units SC qDay

28. Adverse Effects
>10%
• Nasopharyngitis (12.9-
23.9%)
• Severe hypoglycemic
episode (0.3-12.3%)
• Upper respiratory tract
infection (8.4-11.9%)
• Headache (8.8-11.8%)
1-10%
• Diarrhea (6.3%)
• Sinusitis (5.1%)
• Gastroenteritis (5.1%)
• Injection site reactions (3.8%)
• Peripheral edema (0.9-3%)
<1%
• Lipodystrophy

29. Methods of Adminisration
A. Standard Delivery
- The standard mode of insulin therapy is subcutaneous injection using
conventional disposable needles and syringes.
B. Portable Pen Injectors
-These contain cartridges of insulin and replaceable needles.
C. Continuous Subcutaneous Insulin Infusion
Devices (CSII, Insulin Pumps)
-Continuous subcutaneous insulin
infusion devices are external open-loop
pumps for insulin delivery

30. • Hypoglycemia
• Immunopathology of Insulin Therapy
• Lipodystrophy at Injection Sites
• Increased Cancer Risk

32. ❑ Sulfonylurea drugs
❑ Meglitinide analogues
❑ Biguanides
❑ α -glucosidase inhibitors.
❑ Thiazolidinediones.
❑ Dipeptidyl peptidase-4 inhibitors e.g.
Sitagliptin, vildagliptin
❑ GLP1 receptor agonists
❑ SGLT2 inhibitors

33. A closer look at CV effects of 21st century
T2D agents
33
Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315–20. 2. Lantus® SPC. FDA 2015.
1950 1960 1970 1980 1990 2000 2010 2012 2013
Lente class of
insulins
produced
SUs first used
Metformin
introduced
in the UK
Recombinant
human insulin
produced
2nd generation
SUs available
Three new classes introduced:
-glucosidase inhibitors, meglitinides
and TZDs
Glimepiride:
3rd generation SU
DPP4
inhibitors
GLP1 receptor
agonists
SGLT2
inhibitors
Insulin
degludec
 Older T2D agents Newer T2D agents →
Insulin glargine
available2

34. Insulin secretagogues
❑ Sulfonylurea drugs
❑ Meglitinide analogues
❑ GLP1 receptor agonists
❑ Dipeptidyl peptidase-4 inhibitors
Insulin sensitizers
❑ Biguanides
❑ Thiazolidinediones or glitazones
Drugs inhibiting hydrolysis of complex
saccharides :
❑ α-glycosidase inhibitors
Drugs inhibiting reabsorption of glucose in the
kidney
❑ SGLT2 inhibitors

35. SULFONYLUREAS :
First generation Second generation
Tolbutamide Glipizide
Tolazamide Glyburide
Acetohexamide (Glibenclamide)
Chlorpropamide Glimepiride
(Amaryl)

36. 36
MECHANISM OF ACTION OF
SULPHONYLUREAS
1) Release of insulin from β-cells
2) Reduction of serum glucagon concentration
3) Potentiation of insulin action on target tissues

38. Pharmacokinetics of sulfonylureas:
• Orally, well absorbed.
• Reach peak concentration after 2-4 hr.
• All are highly bound to plasma proteins.
• Duration of action is variable.
• Second generation has longer duration
than first generation.
• Metabolized in liver
• excreted in urine
• Cross placenta, stimulate fetal B cells to
release insulin → hypoglycemia at birth.

39. 39
Glipizide
Short-
acting
Glibenclamide
(Glyburide)
Long-acting
Glimepiride
Long-acting
Absorption Well Well Well
Metabolism Yes Yes Yes
Metabolites Inactive Inactive Inactive
Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs
Duration of
action
10 – 16 hrs 12 – 24 hrs 12 – 24 hrs
Excretion Urine Urine Urine
SECOND GENERATION SULPHONYLUREA
COMPOUNDS

40. • Type II diabetes:
monotherapy or in combination with other
antidiabetic drugs.
Uses of sulfonylureas

41. 41
SIDE EFFECTS OF SULPHONYLUREAS
1) Nausea, vomiting, abdominal pain, diarrhea
2) Hypoglycaemia
3) Dilutional hyponatraemia & water intoxication
(Chlorpropamide)
4) Disulfiram-like reaction with alcohol
(Chlorpropamide)
5) Weight gain

42. 42
SIDE EFFECTS OF SULPHONYLUREAS (contd.)
6) Blood dyscrasias
(not common; less than 1% of patients)
- Agranulocytosis
- Haemolytic anaemia
- Thrombocytopenia
7) Cholestatic obstructive jaundice (uncommon)
8) Dermatitis (Mild)
9) Muscle weakness, headache, vertigo
(not common)
10) Increased cardio-vascular mortality with
longterm use ??

43. 43
CONTRAINDICATIONS OF
SULPHONYLUREAS
1) Type 1 DM ( insulin dependent)
2) Parenchymal disease of the liver or kidney
3) Pregnancy, lactation
4) Major stress

44. 44
DRUGS THAT AUGMENT THE
HYPOGLYCEMIC ACTION OF
SULPHONYLUREAS
WARFARIN
SULFONAMIDES
SALICYLATES
PHENYLBUTAZONE
PROPRANOLOL
ALCOHOL
CHLORAMPHENICOL
FLUCONAZOLE

45. 45
DRUGS THAT ANTAGONIZE THE
HYPOGLYCEMIC ACTION OF
SULPHONYLUREAS
DIURETICS (THIAZIDE, FUROSEMIDE)
DIAZOXIDE
CORTICOSTEROIDS
ORAL CONTRACEPTIVES
PHENYTOIN, PHENOBARB., RIFAMPIN
ALCOHOL ( chronic pts )

46. MEGLITINIDE ANALOGUES
Repaglinide (Prandin)
Nateglinide (Starlix)

47. Mechanism of Action
Stimulate insulin release from functioning
B cells by modulating K efflux via
blocking ATP-sensitive K channels
resulting in depolarization and calcium
influx.

48. 48
MEGLITINIDES
PHARMACOKINETICS
Taken orally
Rapidly absorbed ( Peak approx. 1hr )
Metabolized by liver
t1/2 = 1 hr
Duration of action 4-5 hr

49. 49
MEGLITINIDES
CLINICAL USE
Approved as monotherapy and in combination with
metformin in type 2 diabetes
Taken before each meal, 3 times / day
Does not offer any advantage over sulfonylureas;
Advantage: Pts. allergic to sulfur or sulfonylurea
SIDE EFFECTS:
Hypoglycemia
Wt gain ( less than SUs )
Caution in pts with renal & hepatic impairement.

50. 50
BIGUANIDES
MECHANISM OF ACTION
1. Increase peripheral glucose utilization
2. Inhibits gluconeogenesis
3. Impaired absorption of glucose from the gut
Does not stimulate insulin release.
Metformin

51. 51
BIGUANIDES
PHARMACOKINETICS
Given orally
Not bind to plasma proteins
Not metabolized
Excreted unchanged in urine
t 1/2 2 hr

52. • Obese patients with type II diabetes
• Monotherapy or in combination.
Advantages:
• No risk of hyperinsulinemia or hypoglycemia
or weight gain (anorexia).
Uses of metformin

53. 53
BIGUANIDES (Contd.)
SIDE EFFECTS
1. Metallic taste in the mouth
2. Gastrointestinal (anorexia, nausea, vomiting,
diarrhea, abdominal discomfort)
3. Vitamin B 12 deficiency (prolonged use)
4. Lactic acidosis ( rare – 01/ 30,000-exclusive in renal
& hepatic failure)

54. 54
1. Hepatic impairment
2. Renal impairment
3. Alcoholism
4. Heart failure
BIGUANIDES
CONTRAINDICATIONS

55. 55
Glucovance® (Glyburide & Metformine HCl)
Sulfonylurea & Biguanide Combo drugs

56. Hypoglycemics, Metformins
PRODUCT LIST AND FDA-APPROVED INDICATIONS

57. Hypoglycemics, Metformins

58. Thiazolidinediones (Glitazones)-Tzds
• Insulin Sensitizers
• Activation of Peroxisome Proliferator-Activated Receptor-γ
(PPAR-γ).
• Do not promote Insulin secretion from β-cells
• Two agents are :
Pioglitazone
Rosiglitazone

59. Mechanism of Action

60. 60
MECHANISM OF ACTION
- Increase target tissue sensitivity to insulin by:
reducing hepatic glucose output & increase glucose
uptake & oxidation in muscles & adipose tissues.
They do not cause hypoglycemia (similar to
metformin and acarbose ) .
THIAZOLIDINEDIONE DERIVATIVES

61. 61
PHARMACOKINETICS
- 99% absorbed
- Metabolized by liver
- 99% of drug binds to plasma proteins
- Half-life 3 – 4 h
- Eliminated via the urine 64% and feces 23%
THIAZOLIDINEDIONE DERIVATIVES

62. 62
INDICATIONS
Type II diabetes alone or in combination with
metformin or sulfonylurea or insulin in patients
resistant to insulin treatment.
Pioglitazone may be taken once daily; the usual
starting dose is 15–30 mg/d, and the maximum is
45 mg/d.
THIAZOLIDINEDIONE DERIVATIVES

63. 63
ADVERSE EFFECTS
- Mild to moderate edema
- Increase the risk of heart failure
- Wt gain
- Headache
- Myalgia
- Hepatotoxicity ? (liver function tests for 1st year of
therapy).
THIAZOLIDINEDIONE DERIVATIVES

64. α-Glucosidase Inhibitors
• Competitive inhibitor of Intestinal α- Glucosidase .
• Delays carbohydrate absorption
• Reducing postprandial increase in blood glucose
• Agents are :
- Acarbose
- Miglitol

65. Acarbose
Acarbos
e
Acarbose
Mechanism of Action

66. Acarbose
• Given orally, poorly absorbed.
• Metabolized by intestinal bacteria.
• Excreted in stool and urine.
Kinetics of -glucosidase inhibitors

67. 67
INDICATIONS
Patients with Type II inadequately controlled by
diet with or without other agents( SU, Metformin)
Can be combined with insulin
may be helpful in obese Type II patients
(similar to metformin)
α-GLUCOSIDASE INHIBITORS

68. 68
SIDE EFFECTS
Flatulence
Loose stool or diarrhea
Abdominal pain
Alone does not cause hypoglycemia
α-GLUCOSIDASE INHIBITORS

69. CONTRAINDICATIONS
• patients with inflammatory bowel disease or
any intestinal condition that could be worsened
by gas and distention
• patients with renal impairment
• acarbose has been associated with reversible
hepatic enzyme elevation and should be used
with caution in the presence of hepatic disease.

70. Incretin mimetics
• Incretins are GI hormones secreted in
response to food, carried through circulation
to the beta cells to stimulate insulin secretion
& decrease glucagon secretion.

71. Incretins
• Two main Incretin hormones:
– GLP-1 (glucagon-like peptide-1)
– GIP (gastric inhibitory peptide or glucose-
dependent insulinotropic peptide)
Both are inactivated by dipeptidyl peptidase-4
(DPP-4).

72. Incretin mimetics
- Exenatide
- Liraglutide
• is glucagon-like peptide-1 (GLP-1) agonist.
• Therapy of patients with type 2 diabetes.
who are not controlled with oral medicine.

73. GLP1 has various potential effects on the CV system:
Data derived from non-clinical and mechanistic proof-of-concept studies
73
1. Jax. Clin Res Cardiol 2009;98:75–9. 2. Grieve. Br J Pharmacol 2009;157:1340–51 (modified).
3. Robinson et al. BMJ Open 2013;3:pii e001986.
↑ Insulin sensitivity
(direct or indirect?)
↑ Insulin secretion
↓ Glucagon secretion
↑ Insulin biosynthesis
↑ β-cell proliferation
↓ β -cell apoptosis
↓ Appetite
↑ Neuroprotection
↓ Glucose output
Brain
Pancreas
Liver Muscle and
adipose tissue
↑ Endothelial function
↑ Nitric oxide production
↑ ↓ Myocardial contractility (data conflict)
↑ Systolic function in myocardial infarction
↑ Systolic function in cardiomyopathy
↓ Infarct size
↑ Ischaemic pre-conditioning
↑ Post-ischaemic recovery
↑ Myocardial glucose uptake
Heart
Incretin
hormone1,2
Clinical trial data show that GLP1 receptor agonists are associated with small increases in heart
rate and modest reductions in body weight and blood pressure3

74. GLP 1 Mimetic - Exenatide
Effects:
• Stimulates post-prandial insulin secretion
(Stimulation of GLP-1 secretion from intestine
which in turn stimulate insulin secretion from β
cells).
• Slows gastric emptying
• Reduces appetite
Administered:
• Subcutaneous injection
• Twice daily

75. Exenatide
• Less hypoglycemic compared to insulin
• BIG benefit of weight loss
• Only licensed to lower blood sugars, not as
weight loss agent
• S.E: Nausea (about 44% of users), vomiting and
diarrhea
• Pancreatitis (liraglutide)

76. Dipeptidyl peptidase-4 (DPP- 4 )
inhibitors
• e.g. Sitagliptin, Vildagliptin
• Orally
• Given once daily
• half life 8-14 h
• Dose is reduced in pts with renal
impairment

77. Mechanism of action of sitagliptin
Inhibit DPP-4 enzyme and leads to an
increase in incretin hormones level.
This results in an increase in insulin
secretion & decrease in glucagon secretion.

78. Mechanism of
action

79. DPP4 inhibitors: Mechanism of action
Adapted from Drucker. Expert Opin Invest Drugs 2003;12:87–100 and Ahrén Curr Diab Rep. 2003;3:365–372.
Food intake
Glucose-dependent
insulin secretion
Increases glucose utilisation
by muscle and adipose tissue
Decreases hepatic glucose
release improving overall
glucose control
Glucose-dependent
glucagon
suppression
β-cells
α-cells
DPP4
Active
GLP1 (7-36)
Inactive
GLP1 (9-36)
amide
2 amino acids
cleaved from
amino terminus
Pancreas
DPP4
inhibitors
Intestine
79

80. Selected mechanistic trials indicate
potential CV effects of the DPP4
inhibitor class
80
1. Ye et al. Am J Physiol Heart Circ Physiol 2010;298:H1454–65. 2. Hocher et al. Int J Cardiol 2013;167:87–93.
3. van Poppel et al. Diabetes Care 2011;34:2072–77. 4. Kröller-Schön et al. Cardiovasc Res 2012;96:140–9.
5. Ta et al. J Cardiovasc Pharmacol 2011;58:157–66. 6. Sauvé et al. Diabetes 2010;59:1063–73.
7. Read et al. Circ Cardiovasc Imaging 2010;3:195–201. 8. Matikainen et al. Diabetologia 2006;49:2049–57.
Endothelial
function3
Atherosclerotic
plaque volume5
Left
ventricular
function6,7
Myocardial
infarct size1,2
Triglycerides8
Inflammation and
oxidative stress4

81. Clinical uses
Type 2 DM as an adjunct to diet & exercise as
a monotherapy or in combination with other
antidiabetic drugs.
Adverse effects
-Nausea, diarrhea
- Headaches
-Nasopharyngitis, upper respiratory infections
-Hypoglycemia
-Allergic and hypersensitivity reactions

82. Sodium-glucose Cotransporter-2
(SGLT2) Inhibitors
• SGLT2 inhibitors, also called gliflozins, are a class of
medications that alter essential physiology of the
nephron; unlike SGLT1 inhibitors that modulate
sodium/glucose channels in the intestinal mucosa.
• The foremost metabolic effect appears to show that
this pharmaceutical class inhibits reabsorption of
glucose in the kidney and therefore lower blood sugar.
• They act by inhibiting sodium-glucose transport protein
2 (SGLT2). SGLT2 inhibitors are used in the treatment of
type II diabetes mellitus (T2DM)

83. Urinary glucose excretion via SGLT2
inhibition1
83
1. Bakris et al. Kidney Int 2009;75;1272–7.
SGLT2
SGLT2
inhibitor
SGLT1
SGLT2 inhibitors
reduce glucose
reabsorption
in the proximal
tubule, leading to
urinary glucose
excretion* and
osmotic diuresis
Filtered glucose load >
180 g/day

84. SGLT2 Inhibitors
• The SGLT2 inhibitors are
efficacious agents in
reducing HbA1c,
postprandial glucose, and
fasting plasma glucose,
as well as reducing
systolic blood pressure
and weight
• Medicines in the SGLT2
inhibitor class include
canagliflozin,
dapagliflozin, and
empagliflozin.

85. Pharmacological properties of
available
SGLT2 inhibitors
85
*For the 300 mg dose.
Data from http://www.ema.europa.eu/ (Jardiance SPC, Forxiga SPC , Invokana PI, Invokana SPC, all accessed June 2015); 1. Sha et al. Diab Obes
Metab 2015;17:188–97.
Empagliflozin Dapagliflozin Canagliflozin
Therapeutic dose (mg/day)
Starting dose
10–25
10
5–10
10
100–300
100
Administration QD
With or without food
QD
With or without food
QD
Before first meal
Peak plasma concentration
(hours post-dose) 1.5 Within 2 1–2
Absorption
(mean oral bioavailability)
≥ 60% ~ 78% ~ 65%
Metabolism  Primarily glucuronidation - no active metabolite →
Elimination
(half-life, hours)
Hepatic:renal 43:57
[12.4]
Hepatic:renal 22:78
[12.9]
Hepatic:renal 67:33
[13.1]*
Selectivity over SGLT1 1:5000 > 1:1400 > 1:1601
Glucose excretion with higher
dose (g/day)
78 ~ 70 119
Link to SGLT2
clinical data

86. 86
Hypoglycemics, SGLT2
Reaching across Arizona to provide comprehensive
quality health care for those in need
Drug Manufacturer Indications
canagliflozin
(Invokana®)
Janssen ▪ Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
mellitus (T2DM)
▪ To reduce the risk of major adverse cardiovascular events (MACE) in adults with T2DM and
established cardiovascular disease (CVD)
▪ To reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular
death, and hospitalization for heart failure in adults T2DM and diabetic nephropathy with
albuminuria > 300 mg/day
canagliflozin/ metformin
(Invokamet®)
Janssen ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when
treatment with both canagliflozin and metformin is appropriate
▪ To reduce the risk of MACE in adults with T2DM and established CVD*
canagliflozin/ metformin
(Invokamet® XR)
Janssen ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when
treatment with both canagliflozin and metformin is appropriate
▪ To reduce the risk of MACE in adults with T2DM and established CVD*
dapagliflozin (Farxiga®) AstraZeneca ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM
▪ To reduce the risk of hospitalization for heart failure in adults with T2DM and established
CVD or multiple cardiovascular (CV) risk factors

87. 87
Hypoglycemics, SGLT2
Reaching across Arizona to provide comprehensive
quality health care for those in need
dapagliflozin/ metformin
ER (Xigduo® XR)
AstraZeneca ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment
with both dapagliflozin and metformin is appropriate
▪ Dapagliflozin is indicated to reduce the risk of hospitalization for heart failure in adults with
T2DM and established CVD or multiple CV risk factors.
empagliflozin (Jardiance®) Boehringer Ingelheim ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM
▪ To reduce the risk of cardiovascular death in adults with T2DM and established CVD
empagliflozin/ metformin
(Synjardy®)
Boehringer Ingelheim ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment
with both empagliflozin and metformin is appropriate
▪ To reduce the risk of cardiovascular death in adults with T2DM and established CVD*
empagliflozin/ metformin
ER (Synjardy® XR)
Boehringer Ingelheim ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when both
empagliflozin and metformin is appropriate
▪ To reduce the risk of cardiovascular death in adults with T2DM and established CVD*
ertugliflozin (Steglatro™) Merck, Sharp & Dohme ▪ Adjunct to diet and exercise to improve glycemic control in adults T2DM
ertugliflozin/ metformin
(Segluromet™)
Merck, Sharp & Dohme ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM who are not
adequately controlled on a regimen containing ertugliflozin or metformin, or in patients who are
already treated with both ertugliflozin and metformin

88. 88
Potential Adverse Effect Practical Considerations
Adverse drug-drug
Interaction
Pharmacokinetic drug-drug interactions are minimal
Canagliflozin is a P-glycoprotein substrate (modest inhibition);
co-administration with digoxin may increase plasma levels of
digoxin;
monitor digoxin levels and for signs and symptoms of toxicity
when both are used together
Genital and urinary
infections
Mycotic infections more common among females and in
uncircumcised males
Reinforce importance of adequate hygiene
Counsel patients to urgently report genital/perineal
tenderness, redness, or swelling
No significant increase in risk of urinary tract infections
Hypoglycemia Uncommon; risk increased with concomitant use of
sulfonylureas and insulin

89. 89
Potential Adverse Effect Practical Considerations
Diabetic ketoacidosis Avoid pre-emptive substantial reductions in insulin dose
Hold dose if acutely ill with limited oral intake, and 3 days
before major surgery
Use caution with low carbohydrate diets to minimize
excessive ketosis
Discourage excessive alcohol intake
Counsel patients regarding potential symptoms of diabetic
ketoacidosis (fruity odor on breath, thirst, polyuria, nausea,
vomiting,
abdominal pain, confusion, and fever)
Renal injury Baseline and periodic monitoring of renal function is
recommended, especially if used in chronic kidney disease
Cases of acute kidney injury are rare, except in concert with
volume depletion

90. 90
Potential Adverse Effect Practical Considerations
Volume depletion Increased risk with concomitant diuretic use; consider diuretic
dose adjustment
Educate patient about potential for orthostatic hypotension
and necessity to monitor daily weights and blood pressure,
particularly in the
first week of therapy
Lower limb amputations Predominantly toe and metatarsal
More apparent with canagliflozin
Increased risk among those with previous amputations or in
patients with peripheral artery disease
Remind patients to perform regular foot exams and to see a
podiatrist annually

91. Hypoglycemics, SGLT2
• Per the AACE/ACE guidelines, agents for monotherapy are recommended in the following order
(highest to lowest recommendation):
1.metformin,
2.GLP-1 receptor agonists,
3.SGLT2 inhibitors,
4.DPP-4 inhibitors,
5.TZDs,
6.Alpha-glucosidase inhibitors, and sulfonylureas/secretagogue glinides
• AACE/ACE recognizes that empagliflozin and canagliflozin are associated with significantly
reduced cardiac mortality, hospitalization for heart failure, as well as secondary renal endpoints
• Additionally, dapagliflozin demonstrated reduced all-cause mortality and the composite of CV
death and HF hospitalization; however, it did not significantly lower the combined risk of CV
death and nonfatal MI and stroke
• The American College of Physicians’ (ACP) revised 2017 guidelines for T2DM recommend
metformin as first-line therapy, and a sulfonylurea, TZD, SGLT-2 inhibitor, or a DPP-4 inhibitor
as preferred second-line treatments

92. Hypoglycemics, SGLT2
• Per the 2019 American Diabetes Association (ADA)
Standards of Medical Care in Diabetes, metformin is
recommended as initial therapy for the treatment of
T2DM, along with lifestyle interventions at the time of
diagnosis, unless metformin is contraindicated

93. Hypoglycemics, SGLT2
• If metformin fails to produce the target HbA1c after 3 months of therapy, a
thiazolidinedione (TZD), sulfonylurea (SU), dipeptidyl peptidase-4 (DPP-4) inhibitor, SGLT2
inhibitor, glucagon-like peptide-1 (GLP-1) receptor agonist, or basal insulin should be
added in patients without atherosclerotic cardiovascular disease (ASCVD) or chronic kidney
disease (CKD)
• In patients with ASCVD or CKD, the addition of an agent with known cardiovascular (CV)
or renal benefit (select GLP-1 agonist or select SLGT2 inhibitor) is preferred
• The selection of medications should be patient-centric and prescribers should consider
potential issues such as HbA1c target, impact on weight and hypoglycemia, side effects,
the frequency and mode of administration, patient adherence, patient preference, and cost
• Thiazolidinediones and sulfonylureas are generally considered less safe than glucagon- like
peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter type 2 (SGLT2)
inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, or alpha-glucosidase inhibitors

94. Hypoglycemics, SGLT2
• If there is a compelling need to minimize weight gain or promote weight loss, a GLP-1
agonist or SGLT2 inhibitor are recommended
• In patients with atherosclerotic cardiovascular disease (ASCVD), the addition of
empagliflozin (Class A recommendation), liraglutide (Class A recommendation), or
canagliflozin (Class C recommendation) is preferred
• In patients with heart failure (HF) or chronic kidney disease (CKD), empagliflozin,
canagliflozin, or dapagliflozin is preferred
• The American Association of Clinical Endocrinologists (AACE) and American College of
Endocrinology (ACE) 2019 diabetes management algorithm and 2015 clinical practice
guidelines for developing a diabetes care plan include the use of SGLT2 inhibitors as an
alternative to metformin for monotherapy and as an appropriate add-on to metformin in
dual therapy and triple therapy

95. Insulin Th in DM type II.
• Insufficient glycaemic control despite of maximal
doses of PAD in combination
• Decompensation during intercurrent diseases
(infections, trauma, stress)
• Perioperative period
• Pregnancy and lactation
• Vital organs failure (stroke, IM)
• Allergy
• Contraindications and adverse effects
• Significant hyperglycaemia at admission