FARMAKOTERAPI DIABETES

MELLITUS
Dewi Rahmawati
 Outline
 Definisi Diabetes Mellitus
 Etilogi
 Sign & symptoms
 Diagnosa
 Patofisiolgi
DEFINISI DIABETES MELLITUS (DM)
gangguan
metabolik

abnormalitas pd
hiperglikemia metabolisme KH,
lemak dan protein

menurunnya sekresi insulin,

sensitivitas insulin atau bahkan
keduanya
Plasma glucose levels
Etiologi
 Typical type 1 DM is an autoimmune disorder
developing in childhood or early adulthood,
although some latent forms do occur.
 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
 The prevalence of type 2 DM is increasing. Type 2
DM accounts for as much as 90% of all cases of
DM, and the overall the prevalence of type 2 DM in
the United States is approximately 9.6% in persons
age 20 years or older
 Multiple risk factors for the development of type 2
DM have been identified, including family history (i.e.,
parents or siblings with diabetes); obesity (i.e., ≥20%
over ideal body weight, or body mass index [BMI]
≥25 kg/m2); habitual physical inactivity; race or
ethnicity; previously identified impaired glucose
tolerance or impaired fasting glucose (see Diagnosis
of Diabetes section); hypertension (≥140/90 mm Hg
in adults); high-density lipoprotein (HDL) cholesterol
≤35 mg/dL and/or a triglyceride level ≥250 mg/dL;
history of gestational DM (see Classification of
Diabetes section) or delivery of a baby weighing >4
kg (9 lb); history of vascular disease; presence of
acanthosis nigricans; and polycystic ovary disease
Sign & Symptomps
 Poliuria (peningkatan pengeluaran urin) karena air
mengikuti glukosa yang keluar melalui urin
 Polidipsia (peningkatan rasa haus) akibat volume yang
sangat besar dan keluarnya air yang menyebabkan
dehidrasi ekstrasel dehirasi intrasel menstimulasi
pengeluaran hormon antidiuretik dan menimbulkan rasa
haus
 Polifagia (peningkatan rasa lapar) akibat keadaan
pascaabsorptif yang kronis, katabolisme protein lemak,
kelaparan relatif sel
 Rasa lelah dan kelemahan otot akibat katabolisme
protein diotot dan ketidakmampuan sebagian sel untuk
menggunakan glukosa sebagai energi.
Patofisiologi
Con’t
Con’t
Con’t
Con’t
Con’t
 Defisiensi Insulin/sel beta pankreas
Disfungsi sel beta mengakibatkan ketidakmampuan
sel pulau (sel islet) pankreas menghasilkan insulin
yang memadai untuk mengompensasi resistensi insulin
dan untuk menyediakan insulin yang cukup setelah
sekresi insulin dipergunakan.
Con’t
 Resistensi Insulin
1. Mengakibatkan penurunan ambilan glukosa seluler
yang dimediasi oleh insulin.
2. Hepar juga menjadi resistensi terhadap insulin, yang
biasanya berespon terhadap hiperglikemia dengan
menurunkan produksi glukosa. Pada diabetes tipe 2,
produksi glukosa hepar terus berlangsung meskipun
terjadi hiperglikemia, mengakibatkan peningkatan
keluaran glukosa hepar basal secara tidak tepat.
3. Obesitas, terutama obesitas abdomen, berhubungan
langsung dengan peningkatan derajat resistensi
insulin.
Insulin secretion
Diagnosa

1. Jika keluhan klasik ditemukan, maka pemeriksaan glukosa

plasma sewaktu >200 mg/dL sudah cukup untuk
menegakkan diagnosis DM.
2. Pemeriksaan glukosa plasma puasa ≥ 126 mg/dL dengan
adanya keluhan klasik
3. .Tes toleransi glukosa oral (TTGO). Meskipun TTGO
dengan beban 75 g glukosa lebih sensitif dan spesifik
dibanding dengan pemeriksaan glukosa plasma puasa,
namun pemeriksaan ini memiliki keterbatasan tersendiri.
TTGO sulit untuk dilakukan berulang-ulang dan dalam
praktek sangat jarang dilakukan karena membutuhkan
persiapan khusus
Apabila hasil pemeriksaan tidak memenuhi kriteria normal
atau DMmaka dapat digolongkan ke dalam TGT atau
GDPT

1. TGT: Diagnosis TGT ditegakkan bila setelah

pemeriksaan TTGO didapatkan glukosa plasma 2
jam setelah beban antara 140 – 199 mg/dL (7,8-
11,0 mmol/L).
2. GDPT: Diagnosis GDPT ditegakkan bila setelah
pemeriksaan glukosa plasma puasa didapatkan
antara 100 – 125 mg/dL (5,6 – 6,9 mmol/L) dan
pemeriksaan TTGO gula darah 2 jam < 140 mg/dL.
Management
Ada 2015
31
 SULFONYLUREA
 The first class of oral antidiabetic agents.
 Increased pancreatic insulin secretion through interaction with the
sulfonylurea receptor on islet cells.
 Target pancreatic secretory dysfunction and raise serum insulin levels
high enough to overcome insulin resistance in peripheral tissues.
 Increased insulin levels flow directly into the portal vein, decreasing
hepatic glucose production
 All members of this drug class appear to be equally efficacious, with a
decrease in fasting plasma glucose concentration of about 60 to 70
mg/dL (3.3 to 3.9 mmol/L) and a drop in HbA1c levels of about 1.5%
to 2% compared with placebo when maximal doses are used
Sulfonylurea
 Can lead to hypoglycemia and weight gain,
particularly in elderly, renal & liver disfunction
 Unfortunately, as evidenced by the UKPDS, most
patients treated with sulfonylurea monotherapy show
a progressive decline in blood glucose control (17). It
has been postulated that this failure is due to
sulfonylurea-induced "exhaustion" of beta cells
Biguanide
 Improve peripheral insulin sensitivity, but it appears
to exert most of its effect on the liver i.e. decrease
hepatic glucose production
 Problems with metformin include several
gastrointestinal distress which prominent during
initiation of therapy.
 Tends to induce modest weight loss
Biguanide
 The UKPDS revealed that the subgroup of overweight patients taking metformin
under the intensive protocol had a reduction in microvascular risk similar to
sulfonylureas or insulin.
 Greater reductions in all diabetes-related end points, all-cause mortality rate, and
stroke when compared with the groups taking sulfonylureas or insulin.
 The additional nonglycemic benefit of metformin may, theoretically, be related to its
insulin-lowering effect or, more generally, to the improvement in insulin resistance;
both of these effects may directly or indirectly attenuate the atherosclerotic process.
Modest beneficial effects on plasma lipids (24) and fibrinolysis also have been
demonstrated.
 Studies have consistently shown that metformin also lowers fasting plasma glucose
levels by about 60 to 70 mg/dL (3.3 to 3.9 mmol/L) and HbA1c by about 1.5% to
2.0% (24).
 It appears to be equally efficacious in non-obese patients (24). It may, therefore,
be an appropriate first-line therapy for patients of any weight.
Contraindications to metformin therapy

 Renal dysfunction
 Serum creatinine level >1.5 mg/dL in men, >1.4 mg/dL in women
 Metformin should be temporarily discontinued in patients undergoing
radiologic studies involving intravascular administration of iodinated
contrast materials. Treatment may be restarted 48 hours after the
procedure when normal renal function is documented.
 Treatment should be carefully initiated in patients >80 years of age after
measurement of creatinine clearance demonstrates that renal function is not
reduced.
 Congestive heart failure that requires pharmacologic therapy, or other
form of acute or chronic hemodynamic impairment
 Hepatic dysfunction
 Dehydration
 Acute or chronic metabolic acidosis (including diabetic ketoacidosis)
 Known hypersensitivity to metformin
Alpha-glucosidase inhibitors

 Retard the rate of absorption of carbohydrates through the intestine by

inhibiting the enzyme in the brush border of enterocytes that cleave
oligosaccharides to monosaccharides.
 Mild efficacy and the high frequency of gastrointestinal distress
 Suitable for patients with mild diabetes or those taking other oral agents
who continue to have large postprandial blood glucose excursions.
 Do not cause hypoglycemia when used as monotherapy, and their use does
not lead to weight gain.
 Decrease postprandial plasma glucose levels by 40 to 60 mg/dL (2.2 to
3.3 mmol/L), fasting plasma glucose levels by 20 to 30 mg/dL (1.1 to 1.7
mmol/L), and HbA1c levels by 0.5% to 1.0% when compared with placebo
 There are no long-term data on the protective effects against diabetic
complications.
Thiazolidinediones

 Increase insulin sensitivity in muscle and, therefore, augment peripheral glucose disposal, resulting in lower
circulating glucose concentrations
 Exert most of its effect on peripheral skeletal muscle, with relatively smaller effects on hepatic glucose
production (inverse to metformin).
 Concomitant use of metformin and troglitazone has been found to be additive, providing further support for
the relatively distinct proposed mechanisms of action.
 Do not cause hypoglycemia when used as monotherapy; however, their addition to sulfonylureas, other
secretagogues, or insulin therapy can precipitate a hypoglycemic episode.
 The currently available thiazolidinediones, rosiglitazone maleate (Avandia) and pioglitazone hydrochloride
(Actos), are not known to contribute to idiosyncratic hepatocellular injury.
 Decrease fasting plasma glucose level of about 30 to 60 mg/dL (1.7 to 3.3 mmol/L) and a 1% to 1.5%
decrease in HbA1c level compared with placebo
 Pioglitazone is given once daily and rosiglitazone once or twice daily. Both agents have been shown to
lower serum free fatty acid levels and increase high-density lipoprotein cholesterol levels.
 Contraindicated in advanced forms of congestive heart failure.
 Augmenting insulin sensitivity, lowering insulin levels, improving lipid profiles, and enhancing fibrinolysis, the
reduction in vascular disease with thiazolidinediones might be expected to be larger than with other agents
(or at least as great as with metformin).
 New Modalities in DM Treatment
 Incretins are insulinotropic hormones secreted from specialized
neuroendocrine cells in the small intestinal mucosa in response to
carbohydrate ingestion and absorption
 The two hormones accounting for most incretin effects are glucose-
dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-
1 (GLP-1).
 GIP and GLP-1 stimulate pancreatic β-cells in a glucose-dependent
manner, contributing to the early phase insulin response. GLP-1 also
inhibits pancreatic α-cells, thus reducing glucagon secretion and hepatic
glucose production. Incretin action is efficient, but short lived
 Adverse Effects: nausea, vomiting and/or diarrhea, severe abdominal
pain
 Efficacy: menurunkan HbA1c : 0.8-1,0% pd 30 minggu, menurunkan BB
4-5kg pd 80 minggu
 New Modalities in DM Treatment (cont.)
 Exenatide
Exenatide is the only GLP-1 mimetic that is approved by
the FDA and is available as a sterile solution for
subcutaneous injection. has a half-life of 12 to 14 hours,
thus requiring twice daily administration within 60
minutes prior to the morning and evening meals.
 Pharmacologic Effect: improve A1c values and decreased
weight,
 Dose 2 x 10-mg,
 The main adverse effect (AE) was nausea

40
Nonsulfonylurea secretagogue

 The mechanism of action of the meglitinides, represented by

repaglinide (Prandin), is similar to that of the sulfonylureas.
 Unlike sulfonylureas, however, meglitinides have a "quick on-
quick off" action that, theoretically, offers improved
postprandial control and reduces the incidence of late
postprandial hypoglycemia
 Taken shortly before each meal doses ranging from 0.5 to 4
mg, up to three or four times a day.
 It may benefit patients with unpredictable meal schedules or
large postprandial glucose excursions.
Nonsulfonylurea secretagogue
 The efficacy of the meglitinides is similar to that of
the sulfonylureas, leading to a decrease in the fasting
plasma glucose level of about 60 mg/dL (3.3
mmol/L) and in HbA1c of 1.7% to 1.9% compared
with placebo
 The main disadvantages of the meglitinides are their
frequent dosing requirements and the risk for
hypoglycemia and hyperinsulinemia, which is the same
as with the sulfonylureas.
 No long-term data are available on nonsulfonylurea
secretagogues and their effects on diabetic
complication rates.
 EXENATIDE

 Adalah: AA peptida sintetik yg berikatan dg reseptor GLP-

1 di seluruh bagian tubuh dan memberikan aksi
glukoregulatori.
 Me↑ sekresi glukosa dependent insulin serta menekan
sekresi glukagon PP yang menyebabkan produksi glula di
liver ↓
 Mengurangi intake makanan sehingga me ↓ BB
 Efektivitas:reduksi HbA1c 0,9%, signifikan menurunkan
gula PP, namun efek menengah pada FPG
 ESO: mual, muntah, diare
 Dosis: awal 2 x 5mg titrated to 2x10mg , secara s.c. 30min-
1jam sebelum makan
Dipeptidyl peptidase IV inhibitor

 Aksi: memperlama T1/2 GLP-1 endogen,

menghambat enzim dipeptidy peptidase sehingga
GLP-1 tidak tereleminasi dengan cepat
INSULIN USE IN DM TYPE 2
 Indication: when glucose control can no longer be maintained with oral
combination
 Insulin therapy overcome insulin resistance and provide adequate insulin
even in the presence of islet beta-cell dysfunction
 Indications for insulin therapy of type 2 diabetes :
o Hyperglycemia despite maximum doses of oral agents
o Acute Cases
o Uncontrolled weight loss
o Pregnancy
o Renal disease
o A preference for insulin therapy by the patient or physician.

45
Type/Duration of Action Brand Name Manufacturer
Rapid Acting
Insulin lispro Humalog Lilly
Insulin aspart NovoLog Novo Nordisk
Insulin glulisine Apidra Sanofi-Aventis
Short Acting
Regular Humulin R Lilly
Novolin R Novo Nordisk
Intermediate Acting
NPH (isophane insulin suspension) Humulin N Lilly
Novolin N Novo Nordisk
Long Acting
Insulin glargine Lantus Sanofi-Aventis
Insulin detemir Levemir Novo Nordisk
Combination Insulins
NPH/regular mixture Humulin 70/30 Lilly
(70%/30%)
Novolin 70/30 Novo Nordisk
NPH/regular mixture Humulin 50/50 Lilly
(50%/50%)
Insulin aspart protamine/insulin Novolog Mix 70/30 Novo Nordisk
aspart mixture (70%/30%)
Insulin NPL/insulin lispro mixture Humalog Mix 75/25 Lilly
(75%/25%)
Insulin Onset (hr) Peak (hr) Duration (hr) Appearance
Rapid acting 5–25 min 30–90 min <5 Clear
(insulin lispro,
aspart and
glulisine)

Regular 0.5–1 2–3 5–8 Clear

NPH 2–4 4–12 12–18 Cloudy

Insulin glargine 1.5 No pronounced 20–24 Clearb

peak
Insulin detemir 3–8 Relatively flat 5.7–23.2 Clearb
aThe onset, peak, and duration of insulin activity may vary considerably from times listed in
this table. See text and Table 50-12.
bShould not be mixed with other insulins or administered IV. Some patients require twice-

daily dosing.
Complication
 Acute complication
The most common acute complications are
disturbances in glycaemic control. Optimal
management of diabetes aims for a delicate balance,
preventing excessive glucose levels but not forcing
glucose levels too low.
Complication
Complication
 Acute complication
1. Hiperglikemia
2. Hiperglikemia ketoasidosis
3. Hipoglikemia
 Management therapy
 Diabetic ketoacidosis is a medical emergency with
about a 15% mortality rate. Close monitoring and very
careful attention to the patient’s fluid and electrolyte
balance and blood biochemistry are essential
 IV soluble insulin is essential. An initial bolus of about 6
units is followed by continuous infusion (6 units/h). Fluid
replacement needs are estimated from measurements
of the CVP and plasma sodium level
 Hypoglikemia
hypoglycaemia (blood glucose 3 mmol/L) is much more
commonthan symptomatic hyperglycaemia, and it
develops very rapidly, sometimes within minutes.
 Insulininduced hypoglycaemia is usually associated with
injections of short-acting insulin. Deliberate overdosing
is not unknown.
 Hypoglycaemia induced by sulphonylurea antidiabetic
drugs is rarer but more prolonged, more severe and
more difficult to treat than insulin-induced
hypoglycaemia.
 Management therapy
 The conscious patient must take glucose tablets, or
sugar, chocolate, sweet tea, etc. Semiconscious or
comatose patients require IV glucose 20% or IM
glucagon (1 mg) response is usually satisfyingly
prompt, occurring within minutes.
 Glucagon injection can usually be managed easily
by patients’ relatives, who should be fully informed
on how to recognize and deal with hypoglycaemic
episodes.
 In many patients, even before diagnosis,
widespread damage occurs in the kidney, nerves,
eyes or vascular tree
 These long-term complications are to different
degrees common to both types of diabetes, and
their prevention or treatment are the real
challenges for diabetes management.
 Cronic complication
1. Microvaskular retinophaty, nephropathy,
neurophaty
2. Makrovaskular kardiovaskular (jantung)