DM

1. DIABETES MELLITUS: A
GLOBAL HEALTHCARE
PROBLEM
By: Ika Mulyono, M. Farm-Klin., Apt.
Kuliah dan Praktek Farmasi Klinis II
Semester Genap 2019-2020
Fakultas Farmasi-Universitas Surabaya

2. LEARNING OBJECTIVE
By the end of this topic, each student should know:
1. Classification, risk factors, sign and symptoms, and diagnosis of Diabetes Mellitus
2. Complications of Diabetes Mellitus
3. Management for diabetes patient: OAD and insulin
and will be able to
1. explain the importance of controlling blood glucose and consequences of
uncontrolled blood glucose
2. explain the algorithm used to control blood glucose
3. find DRPs in case study

3. LEARNING OBJECTIVE
This topic will be divided in 3 separate days:
• Topic on 1st day: introduction, overview, complication
• Topic on 2nd and 3rd day: management diabetic patient: oral and
insulin
Note:
• GDM and Diabetes in Critically ill will be excluded from this topic
• Management of each complication is not detailed in this lecture

4. OUTLINE
Introduction
• Epidemiology
• Glucose homeostasis
• Definition
Overview Diabetes
Mellitus
• Classification
• Risk factor
• Clinical presentation
• Diagnosis
Complication
• Macrovascular
• Microvascular

5. INTRODUCTION

6. INTRODUCTION
Why is important to
learn about
Diabetes Mellitus?

7. EPIDEMIOLOGY-global prevalence
WHO global report 2016
The global prevalence rising from 4.7% to
8.5% in the adult population
Diabetes prevalence has risen faster in low-
and middle- income countries than in high-
income countries

8. EPIDEMIOLOGY-global
prevalence
…cont.
Total number of adults
with diabetes (20-79
years)
International Diabetes Federation. IDF diabetes atlas 9th ed.2019

9. PREVALENSI
BERDASARKAN
USIA

12. Prevalence (%) estimates of diabetes (20-79 years) by income group
and age-IDF 2019
EPIDEMIOLOGY-global prevalence
…cont.
International Diabetes Federation. IDF diabetes atlas 9th ed.2019

13. Rural-urban division among people with diabetes
EPIDEMIOLOGY-global
prevalence
…cont.
International Diabetes Federation. IDF diabetes atlas 9th ed.2019

14. EPIDEMIOLOGY-mortality
prevalence
WHO global report 2016

15. EPIDEMIOLOGY-in Indonesia
How about in Indonesia?

16. EPIDEMIOLOGY-in Indonesia
…cont.
RISKESDAS 2013: 1.5 based on diagnosis & 6.9
based on blood glucose laboratory findings
RISKESDAS 2018: 2.0 based on diagnosis & 8.5
based on blood glucose laboratory findings

17. GLUCOSE HOMEOSTASIS
IDF atlas of diabetes 6th edition.2013
Feeding state
Fasting state

18. Feeding State
• ±85% of glucose
taken up by
peripheral tissues is
metabolized in
muscle, and only
small amount being
metabolized by
adipocyte
• Insulin dependent
organ
• Non-insulin
dependent organ
Liver
Conversion glucose !
glycogen and free fatty
acid
INSULIN
Adipose tissue
• Glucose converted to
free fatty acid !
stored as TG
• Prevent TG breakdown
Muscle
• The uptake of glucose !
storage as glycogen
• The uptake of amino acids
! conversion to protein

19. Fasting State
• Oppose the action of
insulin
• Stimulate hepatic
glucose production
Counter regulatory
hormon
Glucagon
No food intake ! no
energy
REMEMBER!!!
Our body always
needs energy

20. GLUCOSE HOMEOSTASIS
…cont.
Glucose production
Liver
(85%)
Kidney
(15%)
• Glycogenolysis
(glycogen – glucose)
• Gluconeogenesis
(amino acids are
transported from
muscle to liver!
converted to glucose)
• Affected by epinephrine
• Inhibited by insulin
• Unaffected by glucagon

21. DEFINITION
• DM is a chronic disease that occurs when the pancreas
does not produce enough insulin, or alternatively, when the
body cannot effectively use the insulin it produces.1
• DM is a group of metabolic disturbances, characterized
mainly by hyperglycemia, and finally resulting in the
appearance of various complication (macro and micro-
angiopathy/vascular).2
• Diabetes is a syndrome that is caused by a relative or an
absolute lack of insulin.3

22. Overview Diabetes Mellitus

23. CLASSIFICATION
Diabetes Mellitus
Type 1 DM Type 2 DM
Gestational
DM
Others
Pre-DM

24. Type 1 DM
• Incidence: 5-10%
•VERY FEW of insulin (negligible) ! absolute
insulin deficiency due to autoimmune β cell
destruction.
• Feature of DM type 1:
• Genetic susceptibility and heritance
• HLA system
• Other gene or gene regions
• Autoimunity
• Environmental factors

25. Staging of type 1
Diabetes
Stage 1 Stage 2 Stage 3
Characteristics - Autoimmunity
- Normoglycemia
- Presymptomatic
- Autoimmunity
- Dysglycemia
- Presymptomatic
- New onset
hyperglycemia
- Symptomatic
Diagnosis criteria - Multiple
autoantibodies
- No IGT or IFG
- Multiple
autoantibodies
- Dysglycemia: IFG
and/or IGT
- FPG: 100-125 mg/dL
- 2-h PG: 140-199 mg/
dL
- A1C: 5,7-6,4% or ≥
10% increase
- Clinical symptoms
- Diabetes by
standard criteria
Type 1 DM
… CONT.

26. Type 2 DM
• Incidence: 90-95%
• Insulin resistance or insulin deficiency due to
progressive loss of β cell insulin secretion
• Feature of DM type 2:
• Inheritance
• Environmental factors (obesity)
• Immunology and inflammation
• Abnormalities of insulin secretion and action

27. • Site of insulin resistance:
• Liver
• Muscle
• Adipocyte
Type 2 DM-insulin resistance
…cont.
• Mechanisms of insulin resistance:
• Obesity
• Metabolic syndrome

28. Type 2 DM-insulin resistance
…cont.
The IDF definition of Metabolic
syndrome:
Central obesity ! waist
circumference of South Asian
(Based on Chinese, Malay, and
Asian-Indians) male ≥ 90cm,
women ≥ 80cm
+
Plus any two of the following four
factors
Four factors:
• ↑ TG level >150mg/dL, or specific
treatment for this lipid abnormality
• ↓ HDL – Cholesterol <40mg/dL
(male) or <50mg/dL (female), or
specific treatment for this lipid
abnormality
• ↑ BP (systolic >130mmHg or
diastolic >85mmHg), or treatment
of previously diagnosed
hypertension
• ↑ FPG >100mg/dL, or previously
diagnosed type 2 DM

29. THE IDF CONSENSUS DEFINITION OF METABOLIC SYNDROME IN CHILDREN & ADOLESCENTS. 2007
Type 2 DM-insulin
resistance
…cont.

30. DM type 1 DM type 2
Epidemiology Younger (<30 y.o)
Lean
Older (>30 y.o)
Overweight
Heredity HLA – DR3 or DR4
30 – 50% concordance in
identical twin
No HLA links
50% concordance in
identical twin
Pathogenesis Autoimmune disease:
❖ Islet cell autoantibodies
❖ Insulin autoantibodies
❖ GAD65
❖ Tyrosine phosphatase
autoantibodies
No immune
disturbance
Insulin resistance
COMPARISON OF TYPE 1 AND TYPE 2 DM

31. DM type 1 DM type 2
Clinical Insulin deficiency
Risk of ketoacidosis
ALWAYS need insulin
Partial insulin
deficiency initially
Risk of hyperosmolar
state
Many come to need
insulin
Biochemical Eventual disappearance
of
C-peptide
C-peptide persists
COMPARISON OF TYPE 1 AND TYPE 2 DM

32. GESTATIONAL DM(GDM)
• ± 7% of all pregnancies
• Glucose intolerance that is first recognized during
pregnancy diagnosed in the 2nd or 3rd trimester of
pregnancy
• Diagnosis criteria and management approach of GDM
≠ “usual” Diabetes Mellitus
• GDM is risk factor for DM type 2
• Screening OGTT using FPG and 2hPP at 24-48 weeks
gestation

33. OTHER SPECIFIC TYPE
Caused by:
• Genetic defects of β - cell function
• Genetic defects in insulin action
• Disease of the exocrine pancreas
• Endocrinopathies
• Drug or chemical induced
• Infections (CMV, congenital rubella)
• Uncommon forms of immune – mediated diabetes
• Other genetic syndromes

34. Pre-DM
FPG 100 – 125 mg/dL (6 – 6.9 mmol/L)
2-h plasma glucose 140-199 mg/dL (7.8 – 11 mmol/L)
A1C 5.7 – 6 .4%
IFG (Impaired Fasting Glucose)
IGT (Impaired Glucose Tolerance)
HbA1C
Or
Or

35. RISK FACTOR for type 2 DM
• Overweight (≥ 25kg/m2)
• First – degree relative of diabetes mellitus
• Physical inactivity
• Ethnic predisposition
• Previous IFG and IGT, HBA1c ≥ 5,7%
Adult

36. RISK FACTOR for type 2 DM
…cont.
• History of PCOS, GDM, macrosomia
• Clinical conditions associated with insulin
resistance, e.g:
• Severe obesity
• Acanthosis nigricans
• Hypertension
• Dyslipidemia
• Cardiovascular disease
Adult

37. RISK FACTOR for type 2 DM
…cont.
• Overweight
• First or second degree relative of diabetes
• Ethnic predisposition
• Maternal history of diabetes include GDM
• Signs of insulin resistance (e.g: acanthosis nigricans)
• Conditions associated with insulin resistance (e.g hypertension,
dyslipidemia, PCOS)
Children
(< 18 y o)

38. RISK FACTOR for type 2 DM
…cont.

39. CLINICAL PRESENTATION
Clinical
presentation
Acute
Sub-acute
Asymptomatics

40. CLINICAL PRESENTATION-acute
Due to the resulting loss of calories
and non optimal use of glucose as
energy source
Polyphagia
Due to the resulting loss of fluid and
electrolytes
Polydypsia
Due to the osmotic diuresis ! blood
glucose levels exceed the renal threshold
Polyuria

41. CLINICAL PRESENTATION-sub-acute
• Lack of energy
• Visual blurring
• Pruritus vulva
• Balanitis
• Weight loss

42. CLINICAL PRESENTATION-
asymptomatic
No symptoms of ill – health
There is glucosuria or raised blood glucose
But

43. DIAGNOSIS CRITERIA
A1C ≥ 6.5%
FPG ≥ 126mg/dL ! no caloric intake for at least 8 hours
2-h-pp ≥ 200mg/dL ! during an OGTT
(WHO: 75g anhydrous glucose)
Patient with classic triad symptoms of hyperglycemia or
hyperglycemic crisis, random plasma glucose ≥ 200mg/dL
OR
OR
OR
Ambulatory
Glucose
Monitoring

44. Complication

45. Macrovascular
Microvascular
Metabolic
Complications

46. MACROVASCULAR COMPLICATIONS
• Diabetes is a risk factor of atheroslerosis

47. MACROVASCULAR COMPLICATIONS
…cont.
• People with diabetes have excess risk
compared with general population in
certain condition, include:
• Cardiovascular death ! 3 – 4 times
likely
• MI ! 3 – 4 times likely
• HF ! 2 times likely
• Stroke ! 2 – 4 times likely
• Other cardiovascular risk factors which
tend to have multiplicative effect on CVD:
• Hypertension
• Smoking
• Lipid abnormalities

48. Atherosclerotic cardiovascular disease (ASCVD):
- coronary heart disease (CHD)
- cerebrovascular disease
- peripheral arterial disease
The leading cause of morbidity and mortality for individuals with diabetes and
results in an estimated $37.3 billion in cardiovascular-related spending per year
associated with diabetes
Recent studies —> rates of incident heart failure hospitalization were two
fold higher inpatients with diabetes compared with those without.
Hypertension is often a precursor of heart failure of either type, and ASCVD
can coexist with either type

49. MACROVASCULAR COMPLICATIONS
…cont.
• Diabetes is the leading cause of new cases of blindness
among adults aged 20–74 years.
• Diabetes is the leading cause of kidney failure,
accounting for 44% of new cases in 2011.
• About 60% to 70% of people with diabetes have mild to
severe forms of nervous system damage.
• More than 60% of nontraumatic lower-limb amputations
occur in people with diabetes.

50. MACROVASCULAR COMPLICATIONS
…cont.
• Diabetic risk factors for macrovascular
complications:
• Duration of illness
• Increasing age
• Systolic hypertension
• Hyperinsulinemia ! due to metabolic syndrome
• Hyperlipidemia
• Proteinuria
• Smoking

51. MACROVASCULAR COMPLICATIONS –
Hypertension
• Increasing microvascular and macrovascular risk in diabetic
patients
• Target therapy: should be individualized
• Lower 10-year cardiovascular risk (<15%): < 140/90mmHg (A)
• Higher 10-year cardiovascular risk (>15%): < 130/80 mmHg (C)
• Elderly patients less stringent: < 140/90mmHg or < 150/90 mmHg
(poor health status)
Evidence:
• Randomized clinical trials showed < 140/90 mmHg reduces
cardiovascular events as well as microvascular complications.
• Intensive BP control (< 130/80 mmHg) have been evaluated in larger
RCT and meta analyses of RCT

53. MACROVASCULAR COMPLICATIONS –
Hypertension
…cont.
• First line therapy: ACE Inhibitors or ARBs in patient with:
• Albumin to creatinine ratio ≥ 300 mg/g creatinine, or
• Albumin to creatinine ratio 30-299 mg/g creatine
• Evidence:
• The high CVD risks in diabetic patients and the high
prevalence of undiagnosed CVD ! favor use these
agents as first line therapy
• Use of RAS inhibitors in diabetic patients with albuminuria or
renal insufficiency provide compelling benefits

54. MACROVASCULAR COMPLICATIONS –
Hypertension
…cont.
• Many patients require three or more drugs to reach
target
• Diuretics, CCBs, β-blockers ! useful as second
and third agents
• The National Kidney Foundation recommends
diuretics as second line therapy in patients with
DKD:
• Thiazides if GFR ≥ 30 ml/min per 1.73 m2
• Loop diuretics if GFR < 30 ml/min per 1.73 m2

55. MACROVASCULAR COMPLICATIONS – Dyslipidemia
• Diabetic patients should be screened annualy for: TG, LDL,
HDL, TC.
• Target therapy:
• Individual without overt CVD: primary goal is an LDL
cholesterol <100mg/dL
• Individual with overt CVD ! lower LDL cholesterol <
70mg/dL
• Therapy: Statins, reasons:
• Statins have good efficacy in lowering LDL cholesterol
• Statins have good evidence for its use in diabetic
population

56. MACROVASCULAR COMPLICATIONS – Dyslipidemia
…cont.
• Start with low dose to prevent side effect:
• Myopathy
• Rhabdomyolisis
• Increase SGOT/SGPT !new evidence don’t have to
check routinely
• In higher dose ! pleiotropic effect
• Statin should be added for diabetic patients
(regardless of baseline lipid levels):
• With overt CVD
• Without CVD ! over 40 y.o and have one or more
other CVD risk factors

57. MACROVASCULAR COMPLICATIONS
– Dyslipidemia
…cont.
• If target is not reached on MAXIMAL TOLERATED statins
therapy (<30% target reduction of LDL cholesterol from
baseline) ! consider adding additional LDL-lowering
therapy (ezetimibe) for secondary prevention
• Statin+Fibrate or Statin+Niacin have not been shown to
improve atherosclerotic cardiovascular outcomes,
generally not recommended
• Target therapy for other lipid profile:
• TG <150mg/dL
• HDL >40mg/dL (men) and >50mg/dL (women)

58. AMERICAN DIABETES ASSOCIATION
STANDARD OF MEDICAL CARE IN DIABETES
2019

59. MACROVASCULAR COMPLICATIONS – the
use of antiplatelet
…cont.
• Highly recommended: use low dose aspirin
(75-162mg) as a SECONDARY prevention in
diabetic patients with a history of CVD
• CONSIDER use of low dose aspirin as a PRIMARY
prevention in diabetic patients at increased CV
risk (10 year risk >10%)
• For patients with aspirin allergy !clopidogrel
should be used (75mg/day)

60. MICROVASCULAR COMPLICATIONS
• Nephropathy
• Retinopathy
• Neuropathy

61. MICROVASCULAR COMPLICATIONS-
Nephropathy
• Prevalence 20-40%
• Diabetes may damage the kidney in three main ways:
• Glomerular damage
• Ischaemia ! due to hyperthropy of afferent and
efferent arterioles
• Ascending infection
• Hyperglycemia ! intraglomerular hypertension and
renal hyperfiltration.
Early detection of nephropathy
Persistent albuminuria with
minimal glomerulosclerosis

62. MICROVASCULAR COMPLICATIONS-
Nephropathy
…cont.
• Screening:
• Urine albumin excretion
• Serum creatinine
• Definition of abnormalities in albumin excretion:
• Normal: < 30 mg/24h
• Persistent albuminuria (microalbuminuria) 30-299
mg/24h → earliest stage of diabetic nephropathy
in DM type 1; marker for development of
nephropathy in DM type 2; marker of increased
CVD risk
• Persistent albuminuria (macroalbuminuria) ≥ 300
mg/24h

63. MICROVASCULAR COMPLICATIONS-
Nephropathy
…cont.
• Conditions can accelerate progression of renal
disease:
• Hypertension
• Proteinuria
• Lipid abnormalities ! contribute progression of
glomerulosclerosis
• Management:
• Aggressive treatment of hypertension
• Optimize blood glucose control
• Reduction of protein intake: 0,8 – 1,0g/kg body
weight

64. MICROVASCULAR COMPLICATIONS-
Nephropathy
…cont.
• Treatment of hypertension:
• Based on evidence: ACEIs for type 1 diabetic
patients
• Based on evidence: both ACEIs or ARBs for type
2 diabetic patients
• ACEIs and ARBs reduce loss of kidney function in
diabetic nephropathy patients ! above and
beyond any such effect attributable to
reduction in BP

65. Stages of CKD
Description
GFR (mL/min per
1.73 m2 body
surface area
Stage 1
Kidney damage with normal
or increased GFR
≥90
Stage 2
Kidney damage with mildly
decreased GFR
60-89
Stage 3 Moderately decreased GFR 30-59
Stage 4 Severely decreased GFR 15-29
Stage 5 Kidney failure < 15 or dialysis

66. MICROVASCULAR COMPLICATIONS-
Retinopathy
• Diabetes affects the eye in several ways:
• Diabetic retinopathy ! lessions in the
retina and in the iris
• Cataract ! due to fluctuation in
blood sugar ! osmotic changes in
the lens ! with the absorption of
water into the lens ! eye become
hypermetropic

67. MICROVASCULAR COMPLICATIONS-
Retinopathy
…cont.
• Control of blood glucose and blood
pressure → to reduce the risk and slow
the progression of retinopathy
• Eye examination doing by
ophthalmologist or optometrist
• Treatment: laser photocoagulation
therapy

68. Distal symmetric
polyneuropathy
Diabetic
autonomic
neuropathy
Cardiovascular
autonomic
neuropathy
Gastrointestinal
neuropathy
Genitourinary
tract disturbance
MICROVASCULAR COMPLICATIONS-
Neuropathy

69. MICROVASCULAR COMPLICATIONS-Neuropathy
…cont.
Distal symmetric polyneuropathy (DPN) & diabetic
autonomic neuropathy
• Drug used to treat symptomatic DPN:
• Tricyclic drugs, ex: amitriptyline
• Opioid, ex morphine sulphate, tramadol,
oxycodone
• Anticonvulsants, ex: gabapentin
• 5-hydroxytryptamine & norepinephrine uptake
inhibitor, ex: duloxetin
• GABA analogue, ex: pregabalin
• Substance P inhibitor, ex topical capsaicin

70. MICROVASCULAR COMPLICATIONS-Neuropathy
…cont.
• Consequences of diabetic neuropathy:
• Amputation
• Foot ulceration
• Risk factor for ulcers and amputation:
• Poor glycemic control
• Amputation
• history of foot ulcer
• Foot deformity
• Peripheral neuropathy with LOPS
• Visual impairment
• Diabetic nephropathy
• Peripheral arterial disease
• Cigarette smoking
• Preulcerative callus or corn

71. MICROVASCULAR COMPLICATIONS-
Neuropathy
…cont.
• Foot examination:
•Inspection
•Assessment of foot pulses
•Testing for loss of protective
sensation

72. REFERENCES
1. World Health Organization. Diabetes fact sheet. 2013
2. World Health Organization. Diabetes fact sheet. 2015
3. International Diabetes Federation. IDF diabetes atlas 7th ed.2015
4. International Diabetes Federation. IDF diabetes atlas 8th ed.2017
5. American Diabetes Association. Diabetes statistics [Internet]. 2013 [updated
August 2013].avalilable from: http://www.diabetes.org/diabetes-basics/
diabetes-statistics/
6. National Diabetes Information Clearinghouse. National diabetes statistic.
2011
7. Katsilambros N, Diakoumopoulou E, Ioannidis I, Liatis S, Makrilakis K, Tentolouris
N, et al. Diabetes in clinical practice. John Wiley & sons Ltd. 2006
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Williams BR. Applied therapeutics the clinical use of drugs. 10th ed.
Philadelphia: Lippincott Williams & Wilkins; 2013. p. 1223-1300
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Matzke GR, Wells BG, Posey LM. Pharmacotherapy a pathophysiologic
approach. 8th ed. USA: McGraw-Hill Companies,Inc; 2011. p. 1255 - 1302

73. REFERENCES
10. Marieb EN, Hoehn K. Human anatomy & physiology. 7th ed. Pearson Education Inc;
2010.
11. Kumar P, Clark M. Clinical Medicine. 7th ed. Spain: Saunders Elsevier; 2009.
12. American Diabetes Association. Standards of medical care in diabetes – 2014.
Diabetes Care 37: S14-80
13. American Diabetes Association. Standards of medical care in diabetes – 2017.
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14. International Expert committee report on the role of A1C assay in the diagnosis of
diabetes. 2009; Diabetes Care 32(7): 1327-1334.
15. International Diabetes Federation. The consensus definition of metabolic syndrome
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[updated 2014 July 28; cited 2014 August 21]. Available from: http://www.cdc.gov/
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