6th Upload on DPP4 Inhibitors

“No greater opportunity, responsibility,
or obligation can fall to the lot of a
human being than to become a
physician”
----- Harrison's , 1950

DPP-4 (dipeptidyl peptidase 4)
Inhibitors
Dr Md Main Uddin
MBBS, FCPS
Assistant Professor
(Medicine)
Cox’s Bazar Medical
College
10/5/2018 2Cox's Bazar Medical College

Iso-glycaemic profilesInsulinconcentration
0 10 20 30 40 50 60 70 80 90
minutes
Glucose given orally
Glucose given intravenously to
achieve the same profile
Incretin effect

A recent study published in Diabetes, Obesity and
Metabolism 17: 107–115, 2015. Clearly approves the efficacy
& safety of DPP4 inhibitors in elderly patients with diabetes.
• DPP-4 inhibitors ensure high rates of adequate glycaemic
control, associated with a low risk of hypoglycaemia,
• It appear to have a neutral effect on body weight, and
can potentially improve quality of life .
• A dose adjustment can ensure safe use, even in the
presence of advanced kidney failure.
• Have beneficial effects on cardiovascular events in
patients at high risk, DPP-4 inhibitors could play in
maintaining/improving cognitive function.

Sitagliptin
• 1st approved member of a new class of OAD - DPP-4 inhibitor
• Potent, highly selective, reversible and competitive inhibitor of DPP-4 enzyme
• Approved by the FDA on October 17 2006. EU approval March 2007

Linagliptin, a novel member of the
dipeptidyl peptidase 4 (DPP-4) inhibitor
class, It has a unique profile with a primarily
non renal route of elimination, requiring no
dose adjustment in patients with chronic
kidney disease. Thus safe for renal & hepatic
impaired patients.

A recent study which was published in
American Journal of Kidney Diseases in the
year 2015 shows that, Linagliptin is not
associated with increased kidney disease risk
in patients with type 2 diabetes.
Linagliptin does not undergo major hepatic
metabolism and is mainly excreted unchanged
via bile and gut.
Once-daily dosing with no dose adjustment in
renal or hepatic impairment

Adapted from
SIGN

DIABETES MELLITUS
• Definition
• Etiopathogenesis
• Presenting problems in DM(C/F)
a) Newly discovered hyperglycemia
b) Long term supervision
c) Acute complication
d) Long term complication
e) DM in special situation
• Investigation
• Treatment
• Follow up

• Diabetes mellitus is a clinical syndrome
characterised by hyperglycaemia caused by
absolute or relative deficiency of insulin.
• Hyperglycaemia -- microvascular disease, and
in particular diabetic retinopathy.
• Impaired glucose tolerance -- large vessel
disease (e.g. atheroma leading to myocardial
infarction) and with a greater risk of
developing diabetes in future.

Aetiological classification
Type 1 diabetes
• Immune-mediated
• Idiopathic
Type 2 diabetes Other specific types
• Genetic defects of β-cell function
• Pancreatic disease (e.g. pancreatitis, fibrocalculous
pancreatopathy)
• Excess endogenous production of hormonal antagonists to
insulin
• Drug-induced (e.g. corticosteroids)
• Viral infections (e.g. congenital rubella, mumps, Coxsackie
virus B)
Gestational diabetes

Type 2 diabetes
• Insulin resistance -- Intra-abdominal 'central'
adipose tissue , physical inactivity
• Pancreatic β-cell failure -- deposition of
amyloid
• Genetic predisposition -- Genome-wide
association studies have identified over 65
genes or gene regions that are associated with
type 2 diabetes

• Environmental and other risk factors
1) Diet and obesity -- overeating, especially
when combined with obesity and
underactivity
2) Age -- middle-aged and elderly
3) Pregnancy -- The term 'gestational diabetes'
refers to hyperglycaemia occurring for the first
time during pregnancy

Insulin resistance
(metabolic) syndrome
• Hyperinsulinaemia
• Type 2 diabetes or impaired glucose tolerance
• Hypertension
• Low HDL cholesterol; elevated triglycerides
• Central (visceral) obesity
• Microalbuminuria
• Increased fibrinogen
• Increased plasminogen activator inhibitor-1
• Increased C-reactive protein (CRP)
• Elevated plasma uric acid

Type 1 diabetes
• T cell-mediated autoimmune disease involving
destruction of the insulin-secreting β cells in
the pancreatic islets which takes place over
many years
• Type 1 diabetes is associated with other
autoimmune disorders , including thyroid
disease , coeliac disease , Addison's disease ,
pernicious anaemia and vitiligo.

• Genetic predisposition -- The HLA haplotypes
DR3 and/or DR4 are associated with increased
susceptibility to type 1 diabetes
• Environmental factors -- reduced exposure to
microorganisms, viral infection

Investigations
• Blood – Glucose, HbA1C
• Others – When a diagnosis of diabetes is
confirmed, other investigations should include
plasma urea, creatinine and electrolytes,
lipids, liver and thyroid function tests, and
urine testing for ketones, glucose, albumin.

• Glucose - variation in renal threshold
for glucose, common during pregnancy
and in young people; drugs (such as β-lactam
antibiotics, levodopa and salicylates) may interfere
with urine glucose tests.
• Ketones - fasting or exercising strenuously
for long periods, who have been vomiting repeatedly,
or who have been eating a diet high in fat and low in
carbohydrate
• Albumine - Standard dipstick testing for albumin
detects urinary albumin at concentrations above 300
mg/L

• The World Health Organization (WHO)
guidelines (2011) introduced the use of HbA1c
for diagnosis of diabetes, with an IFCC HbA1c
of more than 48 mmol/mol also being
diagnostic.

Newly discovered hyperglycaemia
• Routine biochemical analysis of asymptomatic
patients, during severe illness ('stress
hyperglycaemia'), chronic symptoms, present
as an emergency with acute metabolic
decompensation.
• The key goals are to establish whether the
patient has diabetes, what type of diabetes it
is and how it should be treated.

Diagnosis of diabetes
Patient complaints of symptoms suggesting diabetes
• Test urine for glucose and ketones
• Measure random or fasting venous blood glucose.
Diagnosis confirmed by:
– Fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dL)
– Random plasma glucose ≥ 11.1 mmol/L (200 mg/dL)
Indications for oral glucose tolerance test
• Fasting plasma glucose 6.1-7.0 mmol/L (110-126
mg/dL)
• Random plasma glucose 7.8-11.0 mmol/L (140-198
mg/dL)
In asymptomatic patients two samples are required to
confirm diabetes.

OGTT
Preparation before the test
• Unrestricted carbohydrate diet for 3 days
• Fasted overnight for at least 8 hrs
• Rest for 30 mins
• Remain seated for the duration of the test,
with no smoking
Sampling
• Plasma glucose is measured before and 2 hrs
after a 75 g oral glucose drink

Fasting 2 hrs after
glucose load
Fasting
hyperglycaemia
6.1-6.9 mmol/L
(110-125 mg/dL)
< 7.8 mmol/L
(< 140 mg/dL)
Impaired glucose
tolerance
< 7.0 mmol/L
(< 126 mg/dL)
7.8-11.0 mmol/L
(140-199 mg/dL)
Diabetes ≥ 7.0 mmol/L
(≥ 126 mg/dL)
≥ 11.1 mmol/L
(≥ 200 mg/dL)
Interpretation (venous plasma glucose)

Symptoms of hyperglycaemia
• Thirst, dry mouth
• Polyuria
• Nocturia
• Tiredness, fatigue, lethargy
• Noticeable change in weight (usually weight loss)
• Blurring of vision
• Pruritus vulvae, balanitis (genital candidiasis)
• Nausea; headache
• Hyperphagia; predilection for sweet foods
• Mood change, irritability, difficulty in concentrating,
apathy

• The classical symptoms are prominent in type
1 diabetes, but are often absent in patients
with type 2 diabetes.
• increased susceptibility to infection -- skin
sepsis (boils) or genital candidiasis
Type 2 diabetes
• Central (truncal or abdominal) obesity
• Hypertension is present in at least 50% of
patients with type 2 diabetes.
• Dyslipidaemia
• Non-alcoholic fatty liver disease

Comparative features of type 1 and
type 2 diabetes
Type 1 Type 2
Typical age at onset < 40 yrs > 50 yrs
Duration of symptoms Weeks Months to years
Body weight Normal or low Obese
Ketonuria Yes No
Rapid death without
treatment with insulin
Yes No
Autoantibodies Yes No
Diabetic complications at
diagnosis
No 25%
Family history of diabetes Uncommon Common
Other autoimmune disease Common Uncommon

MANAGEMENT OF DIABETES
Diet and lifestyle
• Composition of the diet (diet chart)
• Weight management
• Exercise -- walking, gardening, swimming or
cycling, for approximately 30 minutes daily.
• Alcohol

Anti-diabetic drugs
OHA
• Biguanides -- Metformin
• Sulphonylureas – Tolbutamide, chlorpropamide ,
gliclazide, glimepiride and glipizide
• Meglitinides – Repaglinide, Nateglinide
• Alpha-glucosidase inhibitors -- Acarbose
• Thiazolidinediones -- Pioglitazone
• Incretin-based therapies -- sitagliptin, vildagliptin
and saxagliptin

• Metformin – given with
food, irrespective of body
weight, 1-3 gm/day, 2-3
devided doses.
A/E – GI upset, lactic
acidosis.
• Gliclazide, glimepiride –
nonobese; differences
among these are potency,
duration of action and
cost

• It should not be used in CKD (GFR below of 30
mL/min).
• Its use is also contraindicated in patients with
impaired hepatic function and in those who drink
alcohol in excess, in whom the risk of lactic acidosis
is significantly increased.
• It should be discontinued, at least temporarily, if any
other serious medical condition develops, especially
one causing severe shock or hypoxia.
Metformin

Insulin
• Type 1 DM
• Type 2 DM
Severe weight loss
Renal or hepatic disease
In individuals who are hospitalized or acutely ill; e.g.
acute stroke, AMI, septicemia
During major surgery

• There is little consensus regarding the optimal
insulin regimen in type 2 diabetes, but an
intermediate insulin given at night with
metformin during the day is initially as
effective as multidose insulin regimens in
controlling glucose levels, and is less likely to
promote weight gain.

• Insulin is usually initiated in a single dose of
long-acting insulin (0.3–0.4 U/kg per day),
given either before breakfast and in the
evening (NPH) or just before bedtime (NPH,
glargine, detemir).
• Metformin is a useful adjunct to insulin in
those able to tolerate it. A second morning
dose of insulin may become necessary to
control postprandial hyperglycaemia.

• Twice-daily injections of premixed soluble and
isophane insulins (i.e. biphasic isophane
insulin) are widely used and reasonably
effective
• Once-daily insulin glargine showed good
control of blood glucose in one study. More
aggressive treatment, with multiple injections
or continuous infusion pumps, is increasingly
being used in younger patients with type 2
diabetes.

Insulin
Side-effects of insulin therapy
• Hypoglycaemia
• Weight gain
• Peripheral oedema (insulin treatment causes
salt and water retention in the short term)
• Lipodystrophy at injection sites

Choice of Initial Glucose-Lowering
Agent
• The level of hyper-glycemia should influence
the initial choice of therapy.
• Assuming maximal benefit of MNT and
increased physical activity has been realized,
patients with mild to moderate hyperglycemia
[FPG <11.1–13.9 mmol/L (200–250 mg/dL)]
often respond well to a single, oral glucose-
lowering agent.

• Patients with more severe hyperglycemia [FPG
>13.9 mmol/L (250 mg/dL)], a stepwise approach
that starts with a single agent and adds a second
agent to achieve the glycemic target can be used
• Insulin can be used as initial therapy in individuals
with severe hyperglycemia [FPG >13.9–16.7
mmol/L (250–300 mg/dL)] or in those who are
symptomatic from the hyperglycemia.
• Rapid glycemic control with insulin will reduce
"glucose toxicity" to the islet cells, improve
endogenous insulin secretion

Adapted from
SIGN

Long term supervision of DM
How to review a patient in the diabetes clinic
Smoking, Exercise, Alcohol
Body weight and BMI
Blood pressure (130-140/70-
80 mmHg)
Eye examination
• Visual acuities
• Fundoscopy or digital
photography
Lower limbs and feet
• Peripheral pulses
• Tendon reflexes
• Perception of vibration
sensation, light touch
and proprioception
• Ulceration

Hypoglycaemic episodes
• Number and cause of severe (requiring
assistance for treatment) events and
frequency of mild (self-treated) episodes
• Time of day when 'hypos' are experienced
• Nature and intensity of symptoms
• Ability to identify onset (awareness)

Urinalysis
• Analyse fasting specimen for glucose, ketones,
albumin
Biochemistry
• Lipid profile and renal, liver and thyroid function
Glycaemic control
• F, 2ABF
• Glycated haemoglobin (HbA1c) (Target 48-58
mmol/mol)
• Inspection of home blood glucose monitoring
record

Acute complication
• Diabetic ketoacidosis
• Hyperglycaemic hyperosmolar state
• Hypoglycaemia

• Mortality in DKA is most commonly caused in adults by
hypokalaemia, acute respiratory distress syndrome and
comorbid conditions such as acute myocardial
infarction, sepsis or pneumonia.
• The cardinal biochemical features are:
hyperketonaemia (≥ 3 mmol/L) and ketonuria
(more than 2+ on standard urine sticks)
hyperglycaemia (blood glucose ≥ 11 mmol/L (~200
mg/dL))
metabolic acidosis (venous bicarbonate < 15 mmol/L
and/or venous pH < 7.3).

Potassium loss
• Osmotic diuresis
• Secondary hyperaldosteronism as a result of
reduced renal perfusion.
• Metabolic acidosis

Investigations
• Venous blood:
for urea and
electrolytes,
glucose and
bicarbonate
• Urine or blood
analysis for
ketones
• ECG
• Infection screen: full blood count, blood and urine
culture, C-reactive protein, chest X-ray

Hyperglycaemic hyperosmolar state
• Plasma osmolarity =
2[Na+] + [glucose] +
[urea]
• The normal value is
280–290 mmol/L and
consciousness is
impaired when it is
high (> 340 mmol/L),
as commonly occurs in
HHS.

Hypoglycaemia
• Hypoglycaemia (blood glucose < 3.5 mmol/L
(63 mg/ dL)) in diabetes results in most
circumstances from insulin therapy
• When hypoglycaemia develops in non-diabetic
people, it is called ‘spontaneous’
hypoglycaemia
• Hypoglycaemia is defined as ‘severe’ while
requiring assistance for recovery.

Hypoglycaemia in
diabetes
Common causes
• Missed, delayed or
inadequate meal
• Unexpected or unusual
exercise
• Alcohol
• Errors in oral anti-diabetic
agent(s) or insulin
dose/schedule/administra
tion
Risk factors for severe hypoglycaemia
• Strict glycaemic control • Impaired awareness of
• Age (very young and elderly) hypoglycaemia
• Long duration of diabetes

Long
term

Preventing diabetes complications
• Glycaemic control -- No single factor other than
glycaemic control had a significant effect on
outcome.
• Low target HbA1c is appropriate in younger
patients with earlier diabetes who do not have
underlying cardiovascular disease
• Aggressive glucose-lowering is not beneficial in
older patients with long duration of diabetes and
multiple comorbidities.
• Control of other risk factors – ACE inhibitors,
statins

Diabetic retinopathy
• Diabetic retinopathy (DR) is one of the most
common causes of blindness in adults
between 30 and 65 years of age in developed
countries.

Screening
Management
• Good glycaemic (HbA1c around 7%) control
and an appropriate blood pressure (< 130/80
mmHg) should be maintained to prevent
onset and delay progression of diabetic eye
disease.
• Retinal photocoagulation (laser treatment)
• Monoclonal antibody -- ranibizumab

Nephropathy
• Microalbuminuria -- ACE or ARB
Neuropathy
• Peripheral nervous system
• Classification
• Management

Diabetes in pregnancy
• Gestational diabetes is
defined as diabetes
with first onset or
recognition during
pregnancy.
• Women at high risk for
gestational diabetes
should have an oral
glucose tolerance test
at 24–28 weeks

• Aiming for pre-meal blood glucose levels of less
than 5.5 mmol/L or postmeal blood glucose levels
of less than 7.0 mmol/L
• Metformin or glibenclamide is considered safe to
use in pregnancy.
• Insulin may be required, especially in the later
stages of pregnancy
• Woman should be tested at least 6 weeks post-
partum with an oral glucose tolerance test.

• A woman with diabetes should, if possible, be
helped to achieve excellent glycaemic control
before becoming pregnant.
• In addition, high-dose folic acid (5 mg, rather
than the usual 400 μg, daily) should be
initiated before conception to reduce the risk
of neural tube defects.

Conclusion
• Discipline
• Diet
• Drug
FAQs

• I am here for last few minutes
because I do not know too much.
• But because, I can remember too
little.

6th Upload on DPP4 Inhibitors

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