Lili Indrawati

Treatment algorithm for management of type 2 diabetes

mellitus.
 Patients diagnosed with type 2 diabetes, either by fasting glucose,
oral glucose tolerance testing, or A1C, should have diabetes
education that includes instruction on medical nutrition therapy
and physical activity.
Treatment algorithm for management of type 2
diabetes mellitus
 Most patients newly diagnosed with type 2
diabetes have had subclinical or undiagnosed
diabetes for many years previously
and
 should be evaluated for diabetic complications
(retinal exam, test for excess protein or albumin
excretion in the urine, and clinical evaluation for
peripheral neuropathy and vascular insufficiency);
common comorbidities (hypertension and
dyslipidemia) should be treated.
 Metformin is the consensus first line of therapy and should
be started at the time of diagnosis.
 Failure to reach the glycemic target, generally a A1C ≤7%
within 3-4 months, should prompt the addition of a second
oral agent.
 Reinforce lifestyle interventions at every visit and check
A1C every 3 months.
 Treatment may escalate to metformin plus two oral agents
or metformin plus insulin, if necessary
Sulphonylurea
 The sulphonylureas (r) and repaglinide close KATP
channels (middle), causing depolarization of the
β-cells and increased insulin release.
Sulphonylurea
 The increased release of insulin continues while
there is ongoing drug stimulation, provided the β
cells are fully functional.
 Sulphonylureas can cause hypoglycaemia since
insulin release is initiated even when glucose
concentrations are below the normal threshold for
glucose-stimulated insulin release (approximately
5 mmol/L).
Sulphonylurea
 Sulphonylureas are indicated in patients (especially
those near their ideal weight) in whom diet fails to
control the hyperglycaemia, but in about 30% control
is not achieved with these drugs.
 These agents stimulate insulin release from the
pancreatic islets and so the patient must have partially
functional β-cells for these drugs to be of use.
Sulphonylurea
 Glipizide and glicazide have relatively short half-
lifes and are commonly tried flrst.
 Glibenclamide has a longer duration of action and
can be given once daily.
 However, there is more chance of hypoglycaemia
and glibenclamide should be avoided in patients at
risk from hypoglycaemia (e.g. the elderly). These
patients may be more safety given tolbutamide,
which has the shortest duration of action.
 Biguanide
Fig. 4. Actions of
metformin.
lnhibition of hepatic
↓ glycogenolysis glucose production is
regarded as the
principal mechanism
through which
metformin lowers
blood glucose
FA = fatty acids
Mode of Action
 Metformin has a variety of metabolic effects, some of
which may confer clinical benefits that extend beyond
glucose lowering (table V). However, the molecular
mechanisms of metformin have yet to be fully identified.
 At the cellular level, metformin improves insulin
sensitivity to some extent, an action mediated via post-
receptor signalling pathways for insulin.
 Recent data have suggested that adenosine 5'-
monophosphate-activated protein kinase (AMPK)
is a possible intracellular target of metformin.
 Through phosphorylation of key proteins, AMPK
acts as a regulator of glucose and lipid metabolism
and cellular energy regulation.
 Since metformin lowers blood glucose concentrations
without causing overt hypoglycaemia it is most
appropriately classed as an anti-hyperglycaemic – as
distinct from hypoglycaemic - agent.
 The clinical efficacy of metformin in patients with type 2
diabetes requires the presence of insulin.
 The drug does not stimulate insulin release and a small
decrease in fasting insulin concentrations is typically
observed in patients with hyperinsulinaemia.
 The predominant glucose-lowering mechanism of action of
metformin is to reduce excessive rates of hepatic glucose
production.
 Metformin reduces gluconeogenesis by increasing hepatic
sensitivity to insulin and decreasing the hepatic extraction
of certain gluconeogenic substrates (e.g. lactate).
 Hepatic glycogenolysis is also decreased by
metformin.
 Insulin-stimulated glucose uptake in skeletal muscle
is enhanced by metformin→ increase in the activity of
the enzyme glycogen synthase promotes synthesis of
glycogen.
 Metformin also acts in an insulin-independent
manner to suppress oxidation of fatty acids and to
reduce triglyceride levels in patients with
hypertriglyceridaemia.
 This reduces the energy supply for hepatic
gluconeogenesis and has favourable effects on the
glucose-fatty acid (Randle) cycle (in which fatty
acids are held to compete with glucose as a cellular
energy source).
 Glucose metabolism in the splanchnic bed is
increased by metformin through insulin-
independent mechanisms. This may contribute to
the blood glucose-lowering effect of the drug, and
in turn may help to prevent gains in bodyweight.
 Collectively the cellular effects of metformin serve
to counter insulin resistance and to reduce the
putative toxic metabolic effects of hyperglycaemia
(glucose toxicity) and fatty acids (lipotoxicity) in
type 2 diabetes.
Metabolic and vascular effects of metformin
Antihyperglicemic action
suppresses hepatic glucose output
increases insulin-mediated glucose utilisation
decreases fatty acid oxidation
increases splanchnic glucose turnover
Weight stabilisation or reduction
lmproves lipid profile
reduces hypertriglyceridaemia
lowers plasma fatty acids and LDl-cholesterol; raises HDLcholesterol
in some patients
No risk of serious hypoglycaemia
Counters insulin resistance
decreases endogenous or exogenous insulin requirements
reduces basal plasma insulin concentrations
Vascular effects
increased fibrinolysis
decreases PAI-I levels
improved endothelial function
l19L = hign-density lipoprotein; LDL = low-density lipoprotein;
PAI-1 = plasminogen activator inhibitor-1.
Pharmacokinetics
 Metformin is a stable hydrophilic biguanide that is quickly
absorbed and eliminated unchanged in the urine.
 It is imperative that metformin is only prescribed to
patients with renal function that is sufficient to avoid
accumulation of the drug.
 Renal clearance of metformin is achieved more by tubular
secretion than glomerular filtration, the only significant
drug interaction being competition with cimetidine,
which can increase plasma metformin concentrations.
 Thiazolidinedione

Mechanism of action or a thiazolidinedione on an adipocyte

aP2 = adipocyte fatty acid protein; CoA = coenzym A, FATP= fatty acid
transporter protein; GLUT4 = glucose transporter-4; PPAR= peroxisome
proliferator-activated receptor-ɣ; RxR = rerinoid X receptor; vLDL = very low-
density lipoprotein
Mode of Action

 Stimulation of PPARɣ is regarded as the principal

mechanism through which thiazolidinediones
enhance insulin sensitivity.
 PPARɣ is expressed at highest levels in adipose
tissue, and less so in muscle and liver.
Mode of Action

 PPARɣ operates in association with the retinoid X receptor.

The resulting heterodimer binds to nuclear response
elements, thereby modulating transcription of a range of
insulin-sensitive genes, in the presence of necessary
cofactors
Mode of Action
 Many of the genes activated or suppressed by
thiazolidinediones are involved in lipid and carbohydrate
metabolism (table VI). Stimulation of PPARy by a
thiazolidinedione promotes differentiation of pre-
adipocytes with accompanying lipogenesis, effects that
promote or enhance the local effects of insulin.
 Thiazolidinediones increase glucose uptake via glucose
transporter-4 in skeletal muscle, and some reports
indicate that rates of gluconeogenesis in the liver are
reduced.
 Stimulation of lipogenesis via PPARɣ reduces circulating
non-esterified fatty acid (NEFA) concentrations through
cellular uptake and triglyceride synthesis
Mode of Action

 The reduction in plasma NEFA concentrations is

associated with increased glucose utilisation &
reducing gluconeogenesis by reducing operation of the
glucose-fatty acid cycle; reductions in ectopic lipid
deposition in muscle and liver may contribute to the
improvements on glucose metabolism.
 Thiazolidinediones also reduce the production and
activity of the adipocyte-derived cytokine tumour
necrosis factor (TNF)-α has been implicated in the
development of impaired insulin action in muscle
.
 The glitazones improve sensitivity to insulin.Type II
diabetics not controlled by diet and oral antidiaberic drugs
require insulin injdctions.
.
α-Glucosidase lnhibitors
α-Glucosidase lnhibitors
 The α-glucosidase inhibitors competitively inhibit the
activity of α-glucosidase enzymes in the brush border of
enterocytes lining the intestinal villi (figure 3).
 High affinity binding prevents these enzymes from
cleaving their normal disaccharide and oligosaccharide
substrates into monosaccharides prior to absorption.
 This defers the completion of carbohydrate digestion until
further along the intestinal tract, in turn causing glucose
absorption to be delayed.
α-Glucosidase lnhibitors
 The α -glucosidase inhibitors should be taken with meals
containing digestible carbohydrates, not
monosaccharides; these drugs generally do not
significantly affect the absorption of glucose.
 Since α-glucosidase inhibitors move glucose absorption
more distally along the intestinal tract they alter glucose-
dependent release of intestinal hormones that enhance
nutrient-induced insulin secretion.
α-Glucosidase lnhibitors
 Release of gastric inhibitory polypeptide, which
occurs mainly from the jejunal mocosa, may be
reduced by α-glucosidase inhibitors, whereas
glucagon like peptide-l (7-36 amide) secretion (mostly
from the ileal mucosa) is increased.
 Overall, α-glucosidase inhibitors reduce postprandial
insulin concentrations through the attenuated rise in
postprandial glucose levels.
Pharmacokinetics
 Acarbose is absorbed only to a trivial degree (<2%).
 The drug is degraded by amylases in the small
intestine and by intestinal bacteria; some of these
degradation products are systemically absorbed,
subsequently to be eliminated in the urine over about
24 hours.
Adverse effects
 Gastrointestinal disturbances and rashes occur, but are
rare.
 Hypoglycaemia and hypoglycaemic coma may be induced
by longer-acting drugs, especially in elderly patienrs.
 Sulphonylureas are contraindicated in severe (especially
ketotic) hyperglycaemia, surgery and major illness, when
insulin should be given.
Adverse effects
 Repaglinide is a benzamido derivative with a rapid onset
and short duration of action. It is taken at the onset of a
meal to provide a surge of insulin release during digestion
with a reduced risk of interprandial hypoglycaemia.
 Biguanides. Metformin acts peripherally to increase
glucose uptake by an unknown mechanism. As it does not
increase insulin release, it rarely causes hypoglycaemia.
Adverse effects include nausea, vomiting, diarrhoea and,
very occasionally, fatal lactic acidosis.
Adverse effects
 Acarbose inhibits intestinal α-glycosidases, delaying the
digestion of starch and sucrose. It is taken with meals and
lowers the postprandial increase of blood glucose. Its main
side-effect is flatulence.
 Glitazones (thiazolidinediones). These new drugs increase
sensitivity to insulin by binding to the nuclear ppAR-ɣ
recepror and. By derepression, increase transcription of
certain insulin-sensitive gcncs.
 They are given in combination with metformin or
sulphonylureas.
 The glitazones have no demonstrated advantages over
older therapies and their long-term safety is unknown.
References
 Andrew J. Krentz1 and Clifford J. Bailey. Oral
Antidiabetic Agents Current Role in Type 2
Diabetes Mellitus. Drugs 2005; 65 (3): 385-411
 Goodman and Gilman’s 12th ed
 Pharmagology at a glance