Diabetes mellitus signs symptoms types causes treatment pharmacological non pharmacological

1. PATHOPHYSIOLOGY AND
THERAPEUTICS OF
DIABETES MELLITUS(DM)

2. COURSE LECTURER
• Dr. (Mrs.) Thelma Mpoku Alalbila Aku
talalbila@uhas.edu.gh
tmalalbila@gmail.com
-0244825108
Pharmacy Practice Office
Contact Hours : Any convenient time
-Via Class rep
-Phone call/Email/SMS/Whatsapp.

3. INTRODUCTION
•Diabetes mellitus is derived from the Greek
word diabetes meaning siphon - to pass
through and the Latin word mellitus
meaning honeyed or sweet. This is because in
diabetes excess sugar is found in blood as well
as the urine.

4. INTRODUCTION
Diabetes mellitus is a group of metabolic disorders of
fat, carbohydrate, and protein metabolism that results
from defects in insulin secretion, insulin action
(sensitivity), or both.
This results in chronic complications including
microvascular, macrovascular, and neuropathic
disorders. (1)

5. PREVALENCE OF DM
• Type 1 DM accounts for 5% to 10% of all cases of DM
and is likely initiated by the exposure of a genetically
susceptible individual to an environmental agent(2)
• Sweden, Sardinia, and Finland have the highest
prevalence of islet cell antibody (3% to 4.5%) and are
associated with the highest incidence of type 1 DM, 22
to 35 per 100,000.(3)

6. Prevalence of DM CONT’D
• The prevalence of type 2 DM is increasing. Type 2 DM
accounts for as much as 90% of all cases of DM.(1)
• The prevalence of type 2 DM increases with age, it is more
common in women than in men in the United States and some
groups of Native Americans, Hispanic American, Asian
American, African American, and Pacific Island people.(4)
• Gestational diabetes mellitus (GDM) complicates roughly 7%
of all pregnancies in the United States.(5)

7. PREVALENCE OF DM CONT’D
• The weighted prevalence of diabetes among the adults aged
50 years and above in Ghana is 3.95% (95%) being
insignificantly higher in females than males (6)

8. PREVALENCE OF DM CONT’D

9. ETIOLOGIC CLASSIFICATION OF DM

10. CAUSES OF TYPE 1

11. CAUSES OF TYPE 1 CONT’D
ENVIRONMENTAL FACTORS IMPLICATED IN TYPE 1
DIABETES

12. CAUSES OF TYP2 DM
This form of diabetes is characterized by
insulin resistance and a relative lack of insulin secretion.
Most individuals with type 2 diabetes exhibit abdominal
obesity.
 Hypertension, dyslipidemia and elevated plasminogen
activator inhibitor type 1 (PAI-1) levels.
This clustering of abnormalities is referred to as the insulin
resistance syndrome or the metabolic syndrome

13. CAUSES OF TYP2 DM CONT’D

15. Diagnostic
Criteria
A1c ≥ 6.5%
FBG ≥ 126 mg/dl
2 hour
post
prandial
≥ 200 mg/dl
Random BG ≥ 200 mg/dl with
symptoms of
hyperglycemia
or
hyperglycemic
crisis*
A1c 5.7 – 6.4%
FBG 100 – 125 mg/dl
2 hour post
prandial
140 – 199 mg/dl
PreDiabetes Diabetes

18. TREATMENT OF DM

20. Management
Goals
 Hemoglobin A1c: < 7% or < 8 in select
populations
 Fasting Plasma Glucose: 80-130 mg/dl
 Plasma Glucose (2 hrs after meal): <180 mg/dL
 Blood Pressure (BP)
 JNC8 Guidelines (Released 12/2013); ADA
2017
Standards of Medical Care in Diabetes
BP <140/90 mm/Hg
 Cholesterol:
2013 ACC/AHA Guidelines: Patients age 40-75
years
with:

21. Th
e
ABCs
of
Diabete
s
Manageme
nt
A1c
Blood Pressure Control
Cholesterol and Blood
Lipid
Complication
Prevention
 Smoking cessation
 Aspirin use
 Kidney health




Contr
ol
 Immunizations, annual eye exam, foot
care/health,
dental cleaning/exam
and

22. THERAPEUTIC OBJECTIVES (STG,2017)
• Relieve symptoms and maintain fasting (4−6 mmol/L) and
2−hour post−meal (4−8 mmol/L) blood glucose levels
within the normal limits.
• Prevent acute diabetes complications such as
hypoglycaemia, ketoacidosis and the hyperosmolar state.
• Prevent the chronic complications of diabetes, namely;
blindness, limb amputation, kidney disease, nerve damage,
strokes, heart attacks and neonatal abnormalities.

23. MONITORING COMPLICATIONS -
ADA
• Yearly dilated eye examinations in type 2 DM, and an initial eye
examination in the first 3 to 5 years in type 1 DM, then yearly
thereafter.
• The feet should be examined and the blood pressure assessed at
each visit.
• A urine test for microalbumin once yearly is appropriate.
• Yearly testing for lipid abnormalities

24. SELF-MONITORING OF BLOOD GLUCOSE
• The optimal frequency of SMBG for patients with type 2 DM is
unresolved.
• Frequency of monitoring in type 2 DM should be sufficient to
facilitate reaching glucose goals.
• The role of SMBG in improving glycemic control in type 2 DM
patients is controversial but has shown to reduce the HbA1c
~0.4%(6)

25. NONPHARMACOLOGIC THERAPY
• Diet
All patients (and close relations who cook or control their
meals) must be referred to a dietician or diet nurse for
individualized meal plans.
 In general, patients must avoid ‘free’ or refined sugars, such as
in soft drinks, or adding sugar to their beverages. Complex
carbohydrates are to be encouraged.

26. NONPHARMACOLOGIC THERAPY CONT’D
Diet
Most of a day’s diet must consist of carbohydrates (60%),
protein (15%) and fat (25%) mostly of plant−origin and low in
animal fat.
The total caloric content (portions) of meals must be reduced
and the amount of fibre in the meal increased in those who are
also overweight or obese.
 Some healthcare professionals advice patients to eat only
unripe plantain (‘apem’ in the Twi language). This practice is
improper and must be discouraged.

27. NONPHARMACOLOGIC THERAPY CONT’D
• Aerobic exercise improves
 insulin resistance and glycemic control in the majority of individuals
reduces cardiovascular risk factors
contributes to weight loss or maintenance, and improves well-being.
 Start exercise slowly in previously sedentary patients. Older patients,
patients with long-standing disease (age >35 years, or >25 years with DM
≥10 years)
 patients with multiple cardiovascular risk factors, presence of microvascular
disease, and patients with previous evidence of atherosclerotic disease
should have a cardiovascular evaluation, probably including an
electrocardiogram and graded exercise test with imaging, prior to beginning
a moderate to intense exercise regimen

28. PHARMACOLOGIC THERAPY
Classes of Antidiabetic Medications
α-glucosidase inhibitors.(acabose,miglitol)
Biguanides ( Metformin)
DPP-IV inhibitors (Sitagliptin , vildagliptin)
Meglitinides.(repaglinide,nateglinide)
Thiazolidinediones [TZDs] or glitazones)(Peroxisome
proliferator-activated receptor γ-agonists )
Sulfonylureas.( glipiZIDE, glimepiride, glyburide)Insulin (regular, NPH, lispro, aspart,
glargine,degludec)

29. Pathophysiology and Drug Therapy
(Peripheral tissue liver, fat cells)
SGLT-2 = Sodium glucose co-transporter 2, GLP-1 = glucagonlike peptide-1,
DPP-4 = dipeptidylpeptidase-4
SGLT-2 Inhibitors
(kidneys)
Thiazolidinediones
Alpha-glucosidase
inhibitors
(GI tract)
Biguanides
(liver, colon?)
Sulfonylureas,
Meglitinides
(pancreas – β cells)
GLP-1 agonists
(GI tract-stomach/small
intestine, colon?; liver,
pancreas-α & β cells, brain)
DPP-4 Inhibitors
(liver, pancreas-α & β cells)
Dopamine agonists
(brain)
Amylinomimetics
(brain)

30. PHARMACOLOGIC THERAPY CONT’D
GLP-1 Therapies (exenatide, liraglutide, albiglutide,
dulaglutide)
DPP-IV Inhibitors (sitagliptin, saxagliptin, linagliptin,
alogliptin
Amylin Analog (pramlintide)
SGLT2 (Sodium glucose co-transporter2 inhibitor)
(canaglifozin, dapagliflozin, empagliflozin).
 Dopamine agonist (bromocriptine)
Bile acid sequestrants (cholestyramine

31. PHARMACOLOGIC THERAPY CONT’D

32. PHARMACOLOGIC THERAPY CONT’D

33. PHARMACOLOGIC THERAPY CONT’D

34. PHARMACOLOGIC THERAPY CONT’D

35. PHARMACOLOGIC THERAPY CONT’D

36. PHARMACOLOGIC THERAPY CONT’D

37. PHARMACOLOGIC THERAPY CONT’D

38. PHARMACOLOGIC THERAPY CONT’D

39. PHARMACOLOGIC THERAPY CONT’D

40. PHARMACOLOGIC THERAPY CONT’D

41. Meglitinide
s
Contraindication
s:
 Diabetic
ketoacidosis,
with or without
coma;
 Type 1 diabetes (insulin
dependent,
 Concurrent gemfibrozil therapy
Significant Adverse Effects:
 Hypoglycemia (Less than with
SFU)
 Headache
 Upper Respiratory Tract Infection
IDDM
)

42. PHARMACOLOGIC THERAPY CONT’D

43. PHARMACOLOGIC THERAPY CONT’D

44. PHARMACOLOGIC THERAPY CONT’D

45. Thiazolidinediones
(TZDs)
U.S. Boxed Warning
(Rosiglitazone):
 Increased risk of
MI
or
death
 Exacerbation of heart
failure
Contraindications:
NYHA Class III/IV heart failure
(initiation
of
therapy)

46. Treatment
Considerations
 A1c –
lowering
 Blood
Glucose
 Weight
Effect:

Hypoglycemia
potential:
1.5%
Target
:
Gain
FP
G
&
PPG
risk:
Low
 Only antidiabetic class that
directly
counteracts insulin resistance

47. Insuli
n
 Protein
produced
pancreas
by the beta cells of
the
 Allows body to take glucose from the blood
and
convert it to useful energy in the cells
 Many patients with Type 2 diabetes will
need insulin alone or in combination with
oral
medicatio
ns
to
maintain
A1C < 7 %, 10 yrs
post
diagnosis
(UKPDS Research Group. JAMA
1999;251:2006-12)

48. Types
of
Insuli
n
Rapid-acting
insulin:
Long-acting (basal)
insulin:
 Lispro
(Humalog),
(NovoLog),
 glulisine
(Apidra)
aspar
t

glargine
100units/ml
(Lantus),
300 units/ml
(Toujeo)
 detemir (Levemir)
 degludec (Tresiba)
FDA
approved, 9/2015
Premixed insulin:
short-acting insulin:
 Humulin R, Novolin R
Intermediate-acting
(basal)
insulin:
 NPH (Humulin N, Novolin
N)
NovoLog Mix 70/30,
Humalog
70/30
Humalog Mix75/25
Humulin 70/30,Novolin
70/30



Degludec/aspa
rt
70/30

(Ryzodeg) FDA
approved,

49. Insulin Combination
Products
FDA Approved in 11/2016
 Soliqua(R) 100/33 (insulin glargine &
lixisenatide
injection) 100 Units/mL & 33 mcg/mL
 Xultophy® 100/3.6 (insulin degludec and
liraglutide injection) 100 units/mL and
3.6 mg/mL

50. Benefits
of
Early Addition
of
Insuli
n
 Beta cell preservation
 Reduction in micro/macrovascular
complications
 Fewer hospitalizations and associated costs
 Improved treatment satisfaction and quality-
of-life
(QOL)
 Early addition improves glycemic control

51. Insuli
n
Significa
nt
Adverse
Effects:

Hypoglycemia
 Weight gain

52. Treatment
Considerations
 A1c –
lowering
potential
 Blood
Glucose
 Weight
Effect:

Hypoglycemia
basal
potential: best A1c
lowering
Target
:
Gain
FPG &
PPG
risk: high (rapid acting),
lower
for

53. Role
of
Incretins in Glucose
Homeostasis

54. Pathophysiology and Drug Therapy
GLP-1=glucagonlike peptide-1, DPP-4 = dipeptidylpeptidase-4
DPP-4 Inhibitors
(liver, pancreas-α & β cells)
GLP-1 agonists
(GI tract-stomach/small
intestine, colon?; liver,
pancreas-α & β cells, brain)
Amylinomimetics
(brain)

55. GLP-
1
Analog
s

Exenatide

Exenatide
(Byetta)
XR
(Bydureon)
 Liraglutide (Victoza)
 Albiglutide
(Tanzeum)]
 Dulaglutide
(Trulicity)
 Lixisenatide
(Adlyxin),
MoA:
FD
A
approved 7/2016
 Augments glucose-dependent insulin
secretion
Effects diminish at lower plasma glucose
range

56. GLP-1
Analogs
Adverse Effects:
 Pancreatitis (exenatide)
 risk factors - (ETOH, ↑TG,
gallstones)

Nausea:
dose limiting side
effect
 Upper respiratory tract infection (14%)
 Hypoglycemia (combination therapy)
 Injection site reactions – (extended
release
Contraindications:
formulation
s)
 History of or family history of medullary
thyroid carcinoma (MTC);
 Patients with multiple endocrine neoplasia
syndrome type
2 (MEN2)

57. Treatment
Considerations
 A1c –
lowering
 Blood
Glucose
long acting
 Weight
Effect:
potential: 0.8 –
1.9%
Target
:
PPG (short-
acting),
FP
G
–
Los
s
 reductions in body weight 2 to 3 kg/6
months
 Hypoglycemia risk: Low
 Injectable only (cost may be high)
 Use with caution in pts with GI diseases
e.g.
(IBD
)

58. Dipeptidyl
Peptidase
Inhibitors
IV (DPP-
IV)
 Sitagliptin (Januvia)
 Saxagliptin (Onglyza)
 Linagliptin (Tradjenta)
 Alogliptin (Nesina)
MoA
 inhibits dipeptidyl
peptidase resulting in
prolonged active
IV (DPP-IV)
enzyme
GLP-1 and GIP
levels.
 Increased insulin release in response to
elevated glucose
 Decreases glucagon release, reduced hepatic
glucose output
 Delayed gastric emptying

59. Dipeptidyl
Peptidase
Inhibitors
IV (DPP-
IV)
Adverse Effects

Nasopharyngitis
 Diarrhea
 Peripheral
edema

60. Treatment
Considerations
 A1c –
lowering
 Blood
Glucose
 Weight
Effect:

Hypoglycemia
potential:
0.5
– 0.7%
Target:
Neutra
l
PP
G
risk:
Low
 Minimal adverse effects
 Monitor for signs and
symptoms
pancreatitis - severe
abdominal
of acute
pain
(possibly
radiating to the back) with/without
vomiting.

61. Pramlintid
e
(Symlin
)
 Amylin analog (injectable)
 FDA approved for
combination
Type I or Type 2 diabetes
 Weight neutral
therap
y
withinsuli
n
in
MoA
:
 Slows down food transit through gut
 Inhibits gluconeogenesis
 causes early satiety via its effects on the
central nervous system

62. Pramlintid
e
Adverse
Effects
 Nausea
 Hypoglycemia
Precautions:
Use with caution
in
in patients with history
of:
 Delayed gastric emptying
 Severe hypoglycemia, more than once in past 6
month

63. Sodium-glucose Co-
transporter
(SLGT-2) Inhibitors
2
 Canagliflozin
(Invokana)
 Dapagliflozin
(Farxiga)

Empagliflozin
MoA
(Jardianc
e)
Inhibits sodium-glucose
cotransporter
proximal renal tubules thereby:
2 (SGLT2) in
the
 Reduces reabsorption of filtered glucose
from the
tubular lumen
 Lowers the renal threshold for glucose
(RTG).
 Increases urinary excretion of glucose

64. Sodium-glucose Co-
transporter
(SLGT-2) Inhibitors
2
Adverse Effects:
 Genitourinary
infection
 Increased serum
potassium
 Dehydration
 Hypotension
 Renal insufficiency
 Increased LDL
cholesterol,
cholesterol (non-HDL),
increase
d
seru
m
 Increased serum
phosphate

65. Sodium-glucose Co-
transporter
(SLGT-2) Inhibitors
2
Precautions:
 Avoid in patients with a history of genital
mycotic infections or uncircumcised males.
 Use with caution in the elderly or
patients
on antihypertensives
 Use with caution in patients predisposed to
hyperkalemia, monitor serum
potassium

66. Sodium-glucose Co-
transporter
(SLGT-2) Inhibitors
2
Contraindications:
 Severe renal
impairment
mL/minute/1.73 m2)
(eGFR
<30
 End-stage renal disease or
patients on
dialysis
.

67. Treatment
Considerations
 A1c –
lowering
 Blood
Glucose
 Weight
Effect:

Hypoglycemia
potential: 0.6
–
Target:
FPG
Neutral
risk: Low
1%
 ADEs; (genitourinary
infections,
 Inconvenient frequent
urination
dehydration
)

68. Self-monitoring
of
Bloo
d
glucos
e
Importance:
 Medication therapy
management
 Dietary management
Testing frequency
depends
regimen.
 All patients should
check
daily.
on patient’s
medication
at least fasting blood
sugar
 Patients on oral medications may test less
frequently
 Patients on insulin therapy usually have
increased

70. Case
1.
52 y/o female with newly
diagnosed
T2DM (3 months
ago)
with A1c of 8.5, presents for f/u today. PMH is
nonsignificant. All labs are WNL. She has no
known drug
allergies
.
Pt is not on any
medications.
BP is 152/91, repeat BP 148/95, Fasting blood
glucose
145.
What is your assessment of this pt’s diabetes and
HTN ?
What medication/(s) would be appropriate for this
pt?
How would you monitor therapy for effectiveness
1.
2.
3.

71. Case
2.
Sweet Sugar, a 60 y/o pt with history of
T2DM
to your clinic for f/u. Her medications
include:
present
s
Lantus 20 units sc 1xd (at 8
pm)
2xd
and
Metformin
1000
mg
Fasting blood glucose (FBG) results from
her log
book
are
as follows: 192, 174, 188, 204, 182, 210,
195
1. What is your assessment of Sugar’s BG control
from her
results?
What adjustments would you make to her insulin
regimen?
2.

72. Case
3
Which of the following class of anti-diabetes agents
is the
most appropriate add-on therapy to metformin for
your
45 y/o patient with an A1c of
7.6% The patient is scared of
needles and normal kidney and
liver function.
(goal of less than
7%). hypoglycemia,
has
GLP-1
Agonist
Sulfonylurea
DPP-4
Inhibitor
Insulin
a.
b.
c.
d.
 What is another reasonable alternative class of
medication for this pt?
 How would you monitor for
effectiveness
medication suggested?
and safety
of

73. Case
4
R.D. is a 32 y/o professional model with Type 2
diabetes. Her
A1c has been fluctuating
between
7.5 and 7.7 for the past
12
months. She has been on metformin ER 2000 mg 1xd,
during
that
period.
R.D. has a history of irritable bowel syndrome
and
also frequent UTI urinary tract infections. She agrees
to the
addition of a second medication
on
condition that it will
not
cause her to gain
weight.
What will be thebes
t
optio
n
for R.D.
?
GLP-1 agonist
Insulin
DPP-4
inhibitor
SGLT-2
a.
b.
c.
d.

74. Practice
Points
A. Considerations for patient-centered
selection of
drug therapy:
How much A1c-lowering effect is required to
achieve
goal?
What coexisting conditions does the patient
have?
Which blood glucose level is not at goal?
What is the patient’s preference for route of
administration?
1.
2.
3.
4.
5.

75. Practice
Points
B
.
Second line options: SFU, TZDs, GLP-1
agonists,
DPP
-
IV inhibitors, SGLT-2 Inhibitors and
basal
insulin
Always initiate basal insulin, titrate to optimum
dose
determined by FBG results (target 80 – 130)
before
1.
adding pre-meal
insulin
regular insulin)
(rapid-acting preferred
to
2. Management of pre-meal insulin based on 2-
hour
post prandial BG (target: < 180)
Self Monitoring of Blood Glucose (SMBG).
Testing
3.

76. Comparison of Antidiabetic Classes
Drug Class Weight Hypogly- Β-cell CVD Targets Use in
Effect cemia Risk protection benefits Insulin
prediabetes
Resistance
α-glucosidase Neutral Low Possible Possible No Yes
Inhibitor
Amylinomimetic Loss Low Possible Yes No No
Bile acid Neutral/loss Low Possible Yes No
No
sequestrant
Biguanide Loss Low Possible Yes Maybe Yes
DPP-4 inhibitor Neutral Low Possible Possible No No
Dopamine Neutral/loss Low Unknown Yes/no No
No
agonist
GLP-1agonist Loss Low Possible Yes No Yes
Insulin Gain High Yes Possible No No
Sulfonylurea, Gain High No No No No
Meglitinide
SGLT-2 Loss Low Unknown Yes Maybe
No
inhibitor

77. REFERENCES
1. American Diabetes Association. Diabetes facts and figures. 2007, http://
www.diabetes.org/diabetes-statistics.jsp
2. Daneman D. Type 1 diabetes. Lancet 2006;367:847–858.
3. Marian Rewers nd Johnny Ludvigsson
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571740/
4. American Diabetes Association. Standards for medical care in diabetes—2007.
Diabetes Care 2007;30(Suppl 1):S4–S41.
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117548/citedby/

78. •THANK YOU