anti diabetic drugs

1. AN OVERVIEW OF ANTI-DIABETIC
DRUGS AND MANAGEMENT OF
DIABETIC COMPLICATIONS

2. OUTLINE
OVERVIEW OF DIABETES MELLITUS
DRUGS USED IN MANAGEMENT OF
DIABETES MELLITUS
MANAGEMENT OF DIABETIC
COMPLICATIONS
CONCLUSION

3. DIABETES MELLITUS
 Diabetes Mellitus is a group of metabolic
disorders of fat, carbohydrate and protein
metabolism, that results from defects in insulin
secretion, insulin action (sensitivity), or both.
 It is characterized by hyperglycemia, and
results in chronic complications including
microvascular, macrovascular, and neuropathic
disorders.

4. . Insulin is a polypeptide hormone that facilitates the
conversion of glucose, the end-product of
carbohydrate metabolism, into the storage form,
glycogen, thereby mopping up excess glucose from
the blood stream.
 CLASSES
 The two major classifications of DM are:
 1. type 1, that is insulin deficient, and
 2. type 2, that is combined insulin resistance and
relative deficiency in insulin secretion.
 Other types include,
 Gestational Diabetes, which is a glucose intolerance
that is first recognized during pregnancy.

5.  Maturity onset diabetes of the young (MODY),
which is characterized by impaired insulin
secretion with minimal or no insulin resistance,
caused by genetic defects.
 Type 1 and type 2 DM differ in clinical
presentation, onset, etiology and progression of
disease. Both are associated with microvascular
and macrovascular complications.
 Type 1 results from autoimmune destruction of
beta cells of the pancreas, whereas type 2 is
due to insulin resistance and a relative lack of
insulin secretion, with progressive lack of
insulin secretion over time.

6.  Diagnosis of DM is made by 3 criteria:
 A. a fasting plasma glucose >= 126 mg/dl or
 B. a 2-hr value from a 75-g oral glucose
tolerance test >= 200mg/dl or
 C. a casual or random plasma glucose level of
>= 200 mg/dl with symptoms of diabetes,
 with results confirmed by any of the 3 criteria
on a separate day.
 Common clinical presentation include:
 The triple Ps ( polyuria, polydipsia and
polyphagia) which are marked in type 1,
 Fatigue, marked weight loss.

7.  Goals of therapy in DM are directed towards:
 Attaining normoglycemia,
 Reducing the onset and progression of
retinopathy, nephropathy, and neuropathy
complications,
 Intensive therapy for associated cardiovascular
risk factors,
 Improving quality and quantity of life.

8. DRUGS USED IN MANAGEMENT OF
DIABETES MELLITUS
A. TYPE 1
 INSULIN
 Human Insulin is now recommended in standard
practice, which has been developed using
recombinant DNA technology, either with a non-
disease producing strain of E.coli ( Eli Lilly, Pfizer,
and Sanofi-Aventis ) or Saccharomyces cerevisiae,
baker’s yeast ( Novo Nordisk ), to synthesis insulin.
 Various preparations are available which differ in
onset of action, time to peak effect and duration of
action.
 The different classes of insulin preparations
available include:

9.  a. Fast or Rapid-acting:
 These are the soluble, neutral or regular insulins
and their analogues.
 Their onset is within 10 mins after SC injection, they
peak after about 2 hrs, then decline over a further
4-8 hrs.
 Their analogues include Insulin lispro, aspart and
glulisine. examples are Human Actrapid, Humalog
(insulin lispro), Novorapid (insulin aspart), Apidra
(insulin glulisine), Humulin S, etc
 The analogues are more flexible and convenient.
They can be given immediately before a meal,
rather than the 30 min before recommended for
human soluble insulin.
 Another benefit is that there is reduced risk of
hypoglycaemia because of the shorter duration of
action.

10.  They are insoluble, cloudy suspensions of
insulin complexed with either:
 Protamine (also known as Isophane or NPH
insulin) or
 Zinc (also known as Lente insulin).
 Their onset is usually 1-2 hrs with peak effect
being seen at 4-8 hrs.
 Examples include human insulatard, Humulin I,
Novolin N, etc.
 They have extended duration of action, but
actually requires twice-daily admin to
adequately cover a 24-hr period.

11.  Pre-mixed preparations.
 Also called Biphasic Insulins.
 These are a mixture of either a short-acting and
an intermediate-acting insulin, for instance,
Protamine insulin and soluble insulin do not
interact when mixed together; OR 2 insulin
analogues, example NPH and lispro.
 Examples include Novomix 30, Humulin M3,
Humalog mix 75/25, Novolin 70/30, etc.
 They are most suitable for twice-daily insulin
regimens, which offers more convenience.

12.  Long-acting insulins
 These analogues have been modified for more
extended DOA.
 Their onset is 2-5 hrs; they peak at 6-9 hrs, and duration
of action covers 14-24 hrs.
 Examples include Lantus ( insulin glargine ) and Levemir
( insulin detemir ).
 EXUBERA.
 This was the first Human insulin inhalation powder
developed by rDNA technology, formulated to easily
reach the alveoli space and get absorbed through the
alveoli. The onset and peak of Exubera insulin after
inhalation is similar to that of rapid-acting insulin
analogues, but the duration of action is similar to
regular insulin.
 However, Exubera use was recently discontinued due
to poor sales.

13.  Adverse effect of insulin.
 Hypoglyceamia
 Lipohypertrophy, thickening of subcutaneous
tissues at injection site due to recurrent injection
at the same site.
 Occasionally, localized skin reactions.

14.  TYPE 2
 Six classes or oral agents are currently
available for treatment of DM type 2 :
 A. Biguanides. e,.g Metformin
 B. Sulphonylureas. E.g Glibenclamide,
glimepiride, tolbutamide, chlorpropamide,etc
 C. thiazolidinediones, E.g pioglitazone
 D. alpha-glucosidase inhibitors, E.g, Acarbose,
Miglitol
 E. Dipeptidyl-peptidase-4 (DPP-4) inhibitors, E.g
Saxagliptin, Sitagliptin, Vildagliptin.
 F. Meglitinides. e,.g Repaglinide, Nateglinide.
 Eventually, type 2 DM patients would require
Insulin, due to progressive beta-cell destruction.

15.  A. Metformin.
 It remains the cornerstone of oral treatment of
DM type 2. Due to a major advantage that it
remains beneficial even when beta-cell function
has declined, because its action does not
involve stimulation of pancreatic insulin
secretion.
 Does not cause hypoglycaemia or weight gain,
thus useful in obese patients.
 Maximum licenced dose is 3g/day in divided
doses, but doses of more than 2g/day often
cause intolerance.
 Should be given with or after meals to minimize
G.I side effects, which is the most common.

16.  Contraindiactions to metformin use include:
 Renal impairement, eGFR<45 ml/min/1.73m^2. OR
serum creatine of 1.4 mg/dl in females, and 1.5
mg/dl in males.
 Severe liver disease
 Uncontrolled cardiac failure
 Severe pulmonary insufficiency.
 Cimetidine increases metformin serum conc.
When given concomitantly.

17.  B. Sulphonylureas (insulin secretagogues)
 They enhance insulin secretion from pancreatic beta
cells,.
 All sulphonylureas are equally effective at
lowering plasma glucose when given at equipotent
doses.
 First-gen agents are no longer used routinely due
to side effects. Eg Chlorpropamide.
 Max daily dose of glibenclamide is 15 mg once, but
can be given 2 x daily; that of glimepiride is 6 mg
once daily. They should be given 30 mins before the
first main meal of the day.
 Their major side effects are hypoglycaemia and
weight gain.
 Ingestion of alcohol can prolong the hypoglycemic
effects of sulphonylureas.

18.  Meglitinides
 They have more rapid action and shorter
duration than the sulphonylureas.
 Repaglinide is licenced for use as a single agent
when diet control, weight reduction and
exercise have failed to regulate glucose levels,
or im combination with metformin.
 Nateglinide is only licenced for combination
therapy with metformin, when metformin alone
is inadequate.
 Max daily dose of repalinide is 16 mg, in 3
divided doses, and that of nateglinide is 540 mg
in 3 divided doses, with each main meal.
 Side effects include hypoglycaemia, weight
gain, visual disturbances, NVD, constipation.

19.  Thiazolidinediones or Glitazones.
 They are insulin sensitizers
 Only pioglitazone is available following
withdrawal of troglitazone and rosiglitazone
from the market in 1997 and 2000 respectively.
 Pioglitazone has been shown to have
significant benefit on macrovascular morbidity
and mortality. (Dormandy et al.,2005)
 Max daily dose is 45 mg once daily, given
without regard to meals.
 They are recommended as 3rd-line therapy after
lifestyle modification and the use of metformin
or a sulphonylurea as monotherapy.

20.  Owing to their mode of action involving
changes in gene transcription, the glitazones
take up to 3 months to have their maximum
effect on glycemic control.
 Adverse effects include weight gain and
oedema, particularly in patients with
hypertension and CHF.

21.  Dipeptidyl peptidase-4-inhibitors or Gliptins
 They are incretin-based.
 They are licenced for use as dual therapy with
metformin, a sulphonylurea or glitazone.
 Recommended as 3rd-line therapy in those who
still do not have adequate glucose control or
cannot tolerate metformin and/or a
sulphonylurea.
 Max daily dose of vildagliptin is 50 mg once or
twice daily, sitagliptin is 100 mg, and saxagliptin
is 5 mg, both once daily.
 Adverse effects include GI effects and URTI.
They do not cause hypoglycaemia, and are also
weight neutral.

22.  Alpha-glucosidase inhibitors.
 Acarbose is most commonly in use.
 It reduce carbohydrate digestion.
 Also an option when there is poor glucose
control with diet alone or with other oral
agents.
 Its major side effect is abdominal discomfort
associated with flatulence and diarrhoea. This
has limited its use in clinical practice.

23.  The incretin mimetics
 The 2 currently licensed are Exenatide and
Liraglutide, only available as SC injections
 They have been demonstrated to cause weight
loss.
 It is recommended that exenatide be added to
metformin and a sulphonylurea as 3rd line
therapy ( as an alternative to insulin, glitazones
or DPP-4 inhibitors )bfor patients with a BMI >=
35 kg/m^2.
 Also an alternative in patients with a BMI <= 35
kg/m^2, who are not able to take insulin.

24. MANAGEMENT OF DIABETIC
COMPLICATIONS

25.  Diabetic complications are 2 types:
 A. Microvascular complications; long-term
complications that affect small blood vessels.
They include retinopathy, nephropathy, and
neuropathy
 Macrovascular complications; these are primary
diseases of the coronary arteries, peripheral
arteries, and cerebrovasculature, due to
damage to large blood vessels.

26.  RETINOPATHY
 The development of microaneurysms, retinal or
vitreous haemorrhages, hard and soft exudates,
especially with advanced disease. Also, the
presence of blurred or loss of vision.
 Diabetics should be screened regularly, at least
every 6 months, for retinopathy, especially with
concormitant hypertension of pregnancy.
 Early background retinopathy can reverse with
tight glycemic, as well as blood pressure control,
but more advanced disease will not regress with
improved glycemia.
 Patients with established retinopathy are
properly managed by an ophthalmologist, or an
optometrist trained in diabetic eye disease.

27.  NEPHROPATHY
 Diabetic nephropathy is defined as persistent
proteinuria, or microalbuminuria.
 Microalbuminuria is defined as > 30 mg albumin per
gram of creatinine.
 The earliest sign of nephropathy is hypertension,
which progressively may lead to edema,
arrhythmias and symtoms of renal failure.
 Tight control of both plasma glucose and blood
pressure reduces the risk of developing
nephropathy.
 ACEIs or ARBs are first-line agents recommended in
diabetic retinopathy. They have been
demonstrated to provide renal protective effects,
and delay progression to proteinuria in patients
with microalbuminuria.

28.  However, when creatinine is >2 or 3 mg/dl,
these drugs should be discontinued, because
overt renal failure or renovascular disease can
result.
 Some CCBs, such as verapamil or diltiazem
have also been shown to decrease
microalbuminuria.
 Diuretics are frequently necessary because of
the volume-expanded state of the patient and
are recommended as 2nd line therapy.

29.  NEUROPATHY
 The most common complication seen in patients with type 2
DM.
 A progressive loss in peripheral nerve fibres, resulting in
nerve dysfunction.
 Paresthesias, numbness and pain can be predominant
symptoms. The feet are usually more involved than the hands.
 Regular feet examination and prompt report of any loss of
sensation is recommended, to prevent development of
diabetic-foot ulcer.
 For painful neuropathy, symptomatic therapy is empiric, and
includes low-dose TCADs, anticonvulsants (gabapentin,
pregabalin, carbamazepine), duloxetine, tramadol and some
NSAIDs.

30.  Diabetic autonomic neuropathy presents as
resting tarchycardia, exercise intolerance,
orthostatic hypotension, constipation, erectile
dysfunction, gastroparesis, etc.
 Gastroparesis can be improved by improved
glycemic control, avoiding or stopping
medications that slow GI motility, short-term
use of metoclopramide or erythromycin.
 The hallmark of Diabetic diarrhea is its
nocturnal occurrence. Its frequently responds to
a 10-to-14 day course of doxycycline or
metronidazole.
 Erectile dysfunction is managed with phosphor
diesterase inhibitors, such as sildenafil or
tadenafil.

31.  CARDIOVASCULAR
 A. CORONARY HEART DISEASE.
 The risk for CHD is 2 t0 4 x greater in diabetics
than non-diabetics.
 Regular lipid profile screening is recommended.
 Treatment of dyslipidaemia is necessary to
reduce the risk of CHD.
 The statins and other cholesterol-lowering
agents are mostly indicated.
 Smoking cessation, increased physical activity
and diet have all been shown to be beneficial.
 The American Diabetes Association (ADA)
recommends low-dose Aspirin as primary
prevention of CVD in diabetics.

32.  HYPERTENSION
 Hypertension is twice as common among the
diabetic population compared to the general
population.
 Studies have demonstrated the benefit of tight
BP control reducing the risks of both micro- and
macrovascular complications.
 ACEIs or ARBs are recommended as 1st line
agents, with diuretics and other
antihypertensives introduced as 2nd line agents.
 BP goals are generally more difficult to achieve
than glycemic goals or lipid goals in most
diabetic patients.

33.  PERIPHERAL VASCULAR DISEASE
 PVD affects blood vessels outside the heart.
 In diabetics, it often affects the arteries of the legs,
and may give rise to intermittent claudication, a
cramping pain experienced on walking.
 Smoking cessation, correction of lipid
abnormalities, and antiplatelet therapy are
important strategies in treating claudicants.
 Pentoxifylline or Cilostazol has shown benefits in
some patients.
 Appropriate footwear and foot care are necessary.
 Diabetic foot care is an excellent example of the
adage, ‘’ an ounce of prevention is worth a pound
of cure ‘’.

34. CONCLUSION
 Prevention strategies for type 1 DM have
unsuccessful.
 Prevention strategies for type 2 DM are
established. Lifestyle changes, dietary
restriction of fat, aerobic exercise for 30 mins 5 x
weekly, and weight loss, form the backbone of
successful prevention. No medication is
currently FDA approved for prevention of
diabetes, although several, including metformin
and rosiglitazone , have evidence of potential
delay of the onset of diabetes.

35.  Patient education and ability to demonstrate
self-care and adherence to therapeutic lifestyle
and pharmacologic intervention are crucial to
successful outcomes.
 Multi-disciplinary teams of healthcare
professionals including physicians ( primary
care, endocrinologists, ophthalmologists ),
pharmacists, nurses, dieticians, behavioural
health specialists, certified diabetes educators,
are needed to optimize these outcomes in
persons with DM.

36. REFERENCES
 Curtis Triplitt et al. ( 2008 ) Endocrinologic disorders: Diabetes
Mellitus. Pharmacotherapy, A Pathophysiologic Approach. 7th
edition, 2008.
 Elizabeth Hackett & Stephen Jackson (2012). Diabetes Mellitus.
Clinical Pharmacy and Therapeutics, 5th edition, 2012.
 Robert S. Zimmerman ( 2016 ). Diabetes Mellitus: Management of
Microvascular and Macrovascular complications. Disease
management. Cleveland Clinic, Center for Continuing Education.

37. ….NAA
GOO
DE …..