DIABETES MELLITUS: A

GLOBAL HEALTHCARE
PROBLEM
By: apt. Ika Mulyono, M. Farm-Klin.
Kuliah dan Praktek Farmasi Klinis II
Semester Gasal 2022-2023
Fakultas Farmasi-Universitas Surabaya

 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

 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

 OUTLINE

• Epidemiology
Introduction • Glucose homeostasis
• Definition

• Classification
Overview Diabetes • Risk factor
Mellitus •
•
Clinical presentation
Diagnosis

• Macrovascular
Complication • Microvascular

INTRODUCTION
INTRODUCTION

Why is important to
learn about
Diabetes Mellitus?
EPIDEMIOLOGY-global prevalence

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

WHO global report 2016

 EPIDEMIOLOGY-global
prevalence
…cont.

International Diabetes Federation. IDF diabetes atlas 10th ed.2021



PREVALENSI
DUNIA
PREVALENSI BERDASARKAN USIA
PREVALENSI BERDASARKAN JENIS
KELAMIN
 EPIDEMIOLOGY-global prevalence
Prevalence (%) estimates of diabetes (20-79 years) by income group
…cont.

International Diabetes Federation. IDF diabetes atlas 10th ed.2021



 EPIDEMIOLOGY-global
Rural-urban division among people with diabetes prevalence
…cont.

International Diabetes Federation. IDF diabetes atlas 10th ed.2021



 PREVALENSI
UNDIAGNOSED DM
 EPIDEMIOLOGY-mortality
prevalence

WHO global report 2016

 EPIDEMIOLOGY-in Indonesia

How about in Indonesia?

 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



 GLUCOSE HOMEOSTASIS

Feeding state

Fasting state

IDF atlas of diabetes 6th edition.2013

 Muscle

• The uptake of glucose !

storage as glycogen
Feeding State
• The uptake of amino acids
! conversion to protein

• ±85% of glucose
taken up by
peripheral tissues is
metabolized in
INSULIN muscle, and only
small amount being
metabolized by
adipocyte
Adipose tissue Liver
• Insulin dependent
• Glucose converted to
Conversion glucose ! organ
free fatty acid !
glycogen and free fatty • Non-insulin
stored as TG
acid
• Prevent TG breakdown dependent organ

 Fasting State
No food intake ! no
energy
REMEMBER!!!
Our body always
needs energy
Counter regulatory
hormon

• Oppose the action of

insulin
Glucagon • Stimulate hepatic
glucose production

 GLUCOSE HOMEOSTASIS
…cont.

Glucose production

• Glycogenolysis
(glycogen – glucose)
• Gluconeogenesis Liver Kidney
(amino acids are (15%)
transported from (85%)
muscle to liver!
converted to glucose)
• Affected by epinephrine
• Inhibited by insulin
• Unaffected by glucagon



 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

Overview Diabetes Mellitus

 CLASSIFICATION
Pre-DM Diabetes Mellitus

Gestational
Type 1 DM Type 2 DM Others
DM
 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

 Type 1 DM
… CONT.
Staging of type 1 Stage 1 Stage 2 Stage 3
Diabetes

Characteristics - Autoimmunity - Autoimmunity - New onset

- Normoglycemia - Dysglycemia hyperglycemia
- Presymptomatic - Presymptomatic - Symptomatic

Diagnosis criteria - Multiple - Multiple - Clinical symptoms

autoantibodies autoantibodies - Diabetes by
- No IGT or IFG - Dysglycemia: IFG standard criteria
and/or IGT
- FPG: 100-125 mg/dL
- 2-h PG: 140-199 mg/
dL
- A1C: 5,7-6,4% or ≥
10% increase

 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

 Type 2 DM-insulin resistance

…cont.
• Site of insulin resistance:
• Liver
• Muscle
• Adipocyte

• Mechanisms of insulin resistance:

• Obesity
• Metabolic syndrome

 Type 2 DM-insulin resistance

The IDF definition of Metabolic
syndrome:
Central obesity ! waist
circumference of South Asian
(Based on Chinese, Malay, and
Asian-Indians) male ≥ 90cm,
women ≥ 80cm
+ diastolic >85mmHg), or treatment
Plus any two of the following four
factors
…cont.
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
of previously diagnosed
hypertension
• ↑ FPG >100mg/dL, or previously
diagnosed type 2 DM

 Type 2 DM-insulin
resistance
…cont.

THE IDF CONSENSUS DEFINITION OF METABOLIC SYNDROME IN CHILDREN & ADOLESCENTS. 2007

 COMPARISON OF TYPE 1 AND TYPE 2 DM

DM type 1 DM type 2
Epidemiology Younger (<30 y.o) Older (>30 y.o)
Lean Overweight

Heredity HLA – DR3 or DR4 No HLA links

30 – 50% concordance in 50% concordance in
identical twin identical twin

Pathogenesis Autoimmune disease: No immune

❖ Islet cell autoantibodies disturbance
❖ Insulin autoantibodies Insulin resistance
❖ GAD65
❖ Tyrosine phosphatase
autoantibodies

 COMPARISON OF TYPE 1 AND TYPE 2 DM

DM type 1 DM type 2

Clinical Insulin deficiency Partial insulin

deficiency initially
Risk of ketoacidosis
ALWAYS need insulin Risk of hyperosmolar
state

Many come to need

insulin

Biochemical Eventual disappearance C-peptide persists

of
C-peptide

 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

 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

Pre-DM
IFG (Impaired Fasting Glucose)
FPG 100 – 125 mg/dL (6 – 6.9 mmol/L)

Or

IGT (Impaired Glucose Tolerance)

2-h plasma glucose 140-199 mg/dL (7.8 – 11 mmol/L)
Or
HbA1C
A1C 5.7 – 6 .4%
 Adult 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%

 RISK FACTOR for type 2 DM

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



 Children
RISK FACTOR for type 2 DM
(< 18 y o) …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)

 RISK FACTOR for type 2 DM

…cont.



 CLINICAL PRESENTATION
Acute

Clinical
presentation
Sub-acute

Asymptomatics

 CLINICAL PRESENTATION-acute
Due to the osmotic diuresis ! blood
Polyuria glucose levels exceed the renal threshold

Due to the resulting loss of fluid and

Polydypsia
electrolytes

Due to the resulting loss of calories

Polyphagia and non optimal use of glucose as
energy source
 CLINICAL PRESENTATION-sub-acute

• Lack of energy
• Visual blurring
• Pruritus vulva
• Balanitis
• Weight loss

 CLINICAL PRESENTATION-
asymptomatic
No symptoms of ill – health

But

There is glucosuria or raised blood glucose

 DIAGNOSIS CRITERIA
A1C ≥ 6.5%
Ambulatory
OR Glucose
Monitoring

FPG ≥ 126mg/dL ! no caloric intake for at least 8 hours

OR

2-h-pp ≥ 200mg/dL ! during an OGTT

(WHO: 75g anhydrous glucose)

OR
Patient with classic triad symptoms of hyperglycemia or
hyperglycemic crisis, random plasma glucose ≥ 200mg/dL

Complication
 Microvascular

Complications
Macrovascular Metabolic
 MACROVASCULAR COMPLICATIONS

• Diabetes is a risk factor of atheroslerosis

 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

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
 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.

 MACROVASCULAR COMPLICATIONS
…cont.

• Diabetic risk factors for macrovascular

complications:
• Duration of illness
• Increasing age
• Systolic hypertension
• Hyperinsulinemia ! due to metabolic syndrome
• Hyperlipidemia
• Proteinuria
• Smoking



 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

 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

 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

 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

 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



 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)

 AMERICAN DIABETES ASSOCIATION

STANDARD OF MEDICAL CARE IN DIABETES
2019





 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)



 MICROVASCULAR COMPLICATIONS

• Nephropathy
• Retinopathy
• Neuropathy

 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.
Persistent albuminuria with
Early detection of nephropathy
minimal glomerulosclerosis

 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

 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

 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

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

 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



 MICROVASCULAR COMPLICATIONS-
Neuropathy

Diabetic Cardiovascular
Distal symmetric
autonomic autonomic
polyneuropathy
neuropathy neuropathy

Gastrointestinal Genitourinary
neuropathy tract disturbance
 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



 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



 MICROVASCULAR COMPLICATIONS-
Neuropathy
…cont.

• Foot examination:
• Inspection
• Assessment of foot pulses
• Testing for loss of protective
sensation



 REFERENCES
1. World Health Organization. Diabetes fact sheet. 2013
2. World Health Organization. Diabetes fact sheet. 2015
3. International Diabetes Federation. IDF diabetes atlas 10th ed.2021
4. National Diabetes Information Clearinghouse. National diabetes statistic. 2011
5. Katsilambros N, Diakoumopoulou E, Ioannidis I, Liatis S, Makrilakis K, Tentolouris N,
et al. Diabetes in clinical practice. John Wiley & sons Ltd. 2006
6. Kroon LA, William C. Diabetes Mellitus. In: Koda-Kimble MA, Young LY, Alldredge
BK, Corelli RL, Ernst ME, Guglielmo BJ, Jacobson PA, Kradjan WA, Williams BR.
Applied therapeutics the clinical use of drugs. 10th ed. Philadelphia: Lippincott
Williams & Wilkins; 2013. p. 1223-1300
7. Trujillo J, Haines S. Diabetes Mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM. Pharmacotherapy a pathophysiologic approach. 11th ed.
USA: McGraw-Hill Companies,Inc; 2020. p. 3570 - 3675
8. Marieb EN, Hoehn K. Human anatomy & physiology. 7th ed. Pearson Education
Inc; 2010.
9. Kumar P, Clark M. Clinical Medicine. 7th ed. Spain: Saunders Elsevier; 2009.
10. American Diabetes Association. Standards of medical care in diabetes – 2022.
Diabetes Care. 2022 Jan;45 Suppl 1:S4-5