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Criteria for the diagnosis of DM
Symptoms of diabetes plus random
blood glucose concentration ≥ 200
mg/dl OR
FPG ≥ 126 mg/dl OR
Two –hour plasma glucose ≥ 200
mg/dl during an oral glucose
tolerance test
MEDICATIONS FOR INITIAL
THERAPY
ADA and EASD recommends that
metformin therapy (in the absence of
contraindications) be initiated, concurrent
with lifestyle intervention, at the time of
diabetes diagnosis .
 Metformin was chosen for initial therapy
because of glycemic efficacy, absence of weight
gain and hypoglycemia, general tolerability,
and favorable cost.
In patients with
contraindications to
metformin, the ADA/EASD
consensus guideline
suggests either insulin or a
sulfonylurea
 In patients with contraindications to
metformin, we suggest a shorter acting
sulfonylurea, such as glipizide.
 Insulin is also a reasonable option for
initial therapy in patients who present
with symptomatic or poorly controlled
diabetes or in patients in whom it is
difficult to distinguish type 1 from type
2 diabetes.
Pioglitazone may be
considered in patients with
lower initial A1C values or if
there are specific
contraindications to
sulfonylureas.
Metformin
 reduces A1C by 1.5 percentage points
 often leads to modest weight reduction or
weight stabilization.
 reductions in the risk of macrovascular
complications
 Gastrointestinal side effects are common
 metformin monotherapy does not usually
cause hypoglycemia.
Metformin
 Metformin can rarely cause lactic acidosis.
 metformin should not be administered when
conditions predisposing to lactic acidosis are
present.
 Such conditions include impaired renal function
(plasma creatinine above 1.4 mg/dL in women and
1.5 mg/dL in men), decreased tissue perfusion or
hemodynamic instability due to infection or other
causes, concurrent liver disease or alcohol abuse,
and heart failure.
Metformin
 Patients who are about to receive intravenous
iodinated contrast material
 or undergo a surgical procedure (with potential
compromise of circulation)
 should have metformin held until renal
function and circulation can be established.
 Serum creatinine is typically assessed two to
three days after contrast administration.
Sulfonylureas
Sulfonylureas are the oldest class
of oral hypoglycemic agents.
They are moderately effective,
lowering blood glucose
concentrations by 20 percent and
A1C by 1 to 2 percent.

Sulfonylureas
 The major adverse effect of sulfonylureas is
hypoglycemia.
 Hypoglycemia induced by long-acting sulfonylureas
may be severe and is often prolonged in the absence of
appropriate therapy.
 Risk factors for hypoglycemia include increasing age,
alcohol abuse, poor nutrition, and renal insufficiency
 Shorter acting sulfonylureas, such as glipizide , are less
likely to cause hypoglycemia than the older, longacting sulfonylureas and therefore are the preferred
sulfonylureas, especially in older patients.
Sulfonylureas
In a patient who is not a
candidate for metformin or
who cannot tolerate
metformin, we suggest a
shorter-duration sulfonylurea,
such as glipizide.
Meglitinides
 Repaglinide short-acting glucose-lowering drug
that act similarly to the sulfonylureas and have
similar or slightly less efficacy in decreasing
glycemia.
 Meglitinides are pharmacologically distinct from
sulfonylureas and may be used in patients who
have allergy to sulfonylurea medications.
 They have a similar risk for weight gain as
sulfonylureas but possibly less risk of
hypoglycemia. However, they are considerably
more expensive than sulfonylureas.
Meglitinides
 Repaglinide is principally metabolized by the
liver, with less than 10 percent renally excreted.
 Dose adjustments with this agent do not
appear to be necessary in patients with renal
insufficiency.
 Repaglinide could be considered as initial
therapy in a patient with chronic kidney
disease who is intolerant of sulfonylureas.
Thiazolidinediones
 The thiazolidinediones ,pioglitazone, lower blood glucose

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concentrations by increasing insulin sensitivity.
lower A1C by 0.5 to 1.4 percentage points
They are also associated with more weight gain and fluid
retention than metformin.
Are considerably more expensive than generic
sulfonylureas and metformin.
Drugs in this class are not recommended in patients with
symptomatic heart failure and are contraindicated in
patients with New York Heart Association class III or IV
heart failure.
Thiazolidinediones
 we do not generally choose
thiazolidinediones for initial therapy
and reserve their use for second-line
treatment in combination with other
anti-diabetic medications where
synergistic effects can lower A1C
substantially.
Alpha-glucosidase inhibitors
Because they act by a different mechanism, the
alpha-glucosidase inhibitors, acarbose and
miglitol, have additive hypoglycemic effects in
patients receiving diet, sulfonylurea,
metformin, or insulin therapy .
 This class of drugs is less potent than the
sulfonylureas or metformin, lowering A1C by
only 0.5 to 0.8 percentage points.

Insulin
 Although historically insulin has been used for
type 2 diabetes only when inadequate glycemic
control persists despite oral agents and lifestyle
intervention,
 there are increasing data to support using insulin
earlier and more aggressively in type 2 diabetes.
 By inducing near normoglycemia with intensive
insulin therapy, both endogenous insulin secretion
and insulin sensitivity improve; this results in
better glycemic control, which can then be
maintained with diet, exercise and oral
hypoglycemics for many months thereafter.
Insulin
 Insulin therapy in type 2 diabetes is
initially aimed at increasing basal
insulin concentrations .
 Patients with type 2 diabetes require
relatively large doses of insulin,
compared with those needed for type 1
diabetes.
Management of persistent hyperglycemia
in type 2 diabetes mellitus
 ADA and EASD consensus guideline for
pharmacotherapy to control hyperglycemia in type 2
diabetes recommends testing A1C levels every three
months and addition of a second medication when the
treatment goal of A1C <7 percent with metformin plus
lifestyle intervention is not achieved within three
months .
 In order to achieve the A1C goal, the glucose goals below
are usually necessary:
 • Fasting glucose 70 to 130 mg/dL
 • Postprandial glucose (90 to 120 minutes after a meal)
<180 mg/dL
TREATMENT OPTIONS
 The guidelines favor insulin or sulfonylurea as the
second step, and insulin is preferred for patients whose
A1C is further from target (>8.5 percent) or who have
symptoms related to hyperglycemia.
 If target A1C is not achieved with metformin, and
sulfonylurea or basal insulin, the ADA/EASD suggest
starting or intensifying insulin therapy.
 In patients on sulfonylureas and metformin who are
starting insulin therapy, sulfonylureas are generally
tapered and discontinued.
TREATMENT OPTIONS
 Thiazolidinediones (TZDs) are not
considered first choice agents due to the risk
of CHF and fractures and expense.
 As an example, in a patient who would be at
particularly high risk if hypoglycemia
occurred (eg, a construction worker) and
inadequate glycemic control on metformin
(A1C >7 but <8.5 percent), pioglitazone could
be used.
TREATMENT OPTIONS
 For those close to target, we prefer to add a
shorter-duration sulfonylurea (such as
glipizide, to reduce the risk of hypoglycemia
compared with longer-acting sulfonylureas),
rather than insulin.
 For those further from target (A1C >8.5
percent) we prefer to add insulin, rather
than an oral agent.
Metformin monotherapy failure
 In patients with inadequate glycemic
control on metformin and A1C >8.5
percent, we suggest adding insulin .
 In patients with inadequate glycemic
control on metformin (A1C >7.0 percent),
with A1C close to target (≤8.5 percent), we
suggest adding a short acting
sulfonylurea, such as glipizide .
Metformin monotherapy failure
 The addition of pioglitazone is an alternative option in
individuals without risk factors for heart failure or
fracture, who do not reach glycemic goals with
metformin alone, if there are contraindications to
sulfonylureas or patient preference limits the use of
sulfonylureas or insulin .
 Another reasonable alternative is the addition of
repaglinide, which can be considered in individuals
who do not reach glycemic goals with metformin, if
there are contraindications to sulfonylureas or patient
preference limits the use of insulin .
Contraindications to metformin and
sulfonylurea monotherapy failure
 In individuals with contraindications to metformin,
sulfonylureas are often first-line therapy.
 In patients with inadequate glycemic control on
sulfonylureas, with A1C >8.5 percent, we suggest
switching to insulin .
 In patients with inadequate glycemic control on
sulfonylureas (A1C >7 percent), with A1C close to
target (≤8.5 percent), we suggest adding
pioglitazone .
Dual oral agent failure
 In individuals with inadequate glycemic control (A1C
>7 percent) on two oral agents (usually metformin and
sulfonylurea), we suggest switching to insulin
(discontinue sulfonylurea and continue metformin) .
 alternative that is less likely to work is three oral
agents.
 However, three oral agents (metformin, sulfonylurea,
pioglitazone) can be considered in patients with A1C
values that are not too far from goal (A1C ≤8.5
percent).
Combination oral and insulin
therapy
 While NPH has been used commonly
at bedtime to supplement oral
hypoglycemic drug therapy, longer
acting insulins, such as insulin
glargine (once daily) added to oral
agents are similarly effective for
reducing A1C values and may cause less
nocturnal hypoglycemia.
Insulin therapy in type 2
diabetes mellitus
If once per day insulin is added to
oral hypoglycemic therapy in
patients with type 2 diabetes,
insulin NPH given at bedtime or
insulin glargine given in the
morning or at bedtime is a
reasonable initial regimen.
Insulin therapy in type 2
diabetes mellitus
 When switching to insulin
monotherapy, it is reasonable to begin
with a similar regimen consisting of
basal insulin (NPH or glargine insulin)
given once or twice daily .
 Subsequent modifications can be made
according to blood glucose and A1C
values.
Insulin therapy in type 2
diabetes mellitus
 Insulin can be considered initial
therapy for all patients with type 2
diabetes, particularly patients
presenting with A1C >10 percent,
 fasting plasma glucose >250 mg/dL
 random glucose consistently >300
mg/dL
 or ketonuria.
Insulin therapy in type 2
diabetes mellitus
A potential problem is that patients who are
initially thought to have type 2 diabetes may
actually have type 1 diabetes, and therefore
require insulin as initial therapy.
 In patients in whom it is difficult to
distinguish type 1 from type 2 diabetes
(patients who are underweight, are losing
weight, or are ketotic), initial treatment
with insulin is required.

Insulin therapy in type 2
diabetes mellitus
 Although we do not
recommend premixed insulin
for the treatment of type 1
diabetes, it is a reasonable
option for patients with type 2
diabetes who are doing well on a
stable, fixed ratio.