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+THERAPEUTIC

UPDATES-
DIABETES
Pharmacy Refresher Course
Atmiya Institute of Pharmacy

By:
Parth D. Mair (M.Pharm. MBA)
Que Pharma Pvt. Ltd.
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Contents

 What is Diabetes?

 Statistics

 Risk Factors

 Types of Diabetes

 Complications associated with Diabetes

 Management and Treatment of Diabetes

 Recent Advances in Diabetes Treatments

 References
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What is Diabetes?

 Diabetes is a condition where the amount of glucose in your


blood is too high because the body cannot use it properly.

 This is because your pancreas doesn’t produce any insulin,


or not enough insulin, to help glucose enter your body’s cells
– or the insulin that is produced does not work properly
(known as insulin resistance).
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Statistics

 It is estimated that 61.3 million people aged 20-79 years live


with diabetes in India (2011 estimates). This number is expected
to increase to 101.2 million by 2030.

 77.2 million people in India are said to have pre-diabetes.

 About 1 million people died from diabetes in India in 2012

 1 out of 4 people living in urban slums of Chennai suffer from


diabetes, which is more than three times higher than the national
average of about 7%

 Indians get diabetes on average 10 years earlier than their


Western counterparts.

 The annual cost for India due to diabetes was about $38 billion
in 2011
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 8.3% of the U.S. population has Diabetes (25.8 million) & 79


million are Prediabetic.

 India is second only to China which is home to 92.3 million


diabetics.

 Worldwide Diabetes prevalence of 387 million (8.3%) and


predicted to be 592 million by 2035.
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Risk Factors

 Obesity

 Family history of diabetes


 Physical inactivity
 Race/Ethnicity

 History of gestational diabetes


 History
of impaired glucose tolerance or
impaired functional glucose
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 Hypertension

 HDL <35 mg/dl

 Polycystic ovary syndrome

 History of vascular disease

 Acanthosis Nigricans
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Types of Diabetes

 Type 1 Diabetes

(Associated with absolute insulin deficiency)

 Type 2 Diabetes

(Due to Insulin secretory defect/ Insulin Resistance)

 Gestational Diabetes

 Diabetes due to other causues


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Type 1 Diabetes

 Characterized by absolute deficiency of Insulin due


destruction of β- cells in Pancreas.

 Also called as Insulin Dependent Diabetes Mellitus.

 Two etiologies

 Auto-Immune Mediated Diabetes (Also Called Juvenile


Diabetes) (5-10% of Total diabetic Cases)

 Idiopathic Diabetes (Unknown etiologies, mostly due to


genetic makeup, Inherited)
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 Pancreatic islets are infiltrated with lymphocytes


 Antibodies to islet cells
 T lymphocytes
 Activated lymphocytes within peri-pancreatic lymph nodes, islets
and systemic circulation
 Cytokines

 β cell death mechanisms are assumed to include apoptosis,


CD8 T cell toxicity and nitric oxide metabolite formation

 Once the β cells are destroyed the inflammatory process


subsides and the islets become atrophic
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Symptoms

 Urinating often

 Extreme Fatigue

 Feeling very thirsty

 Blurry Vision

 Feeling very hungry even though you are eating

 Slow to heal cuts and bruises

 Weight loss
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Type 2 Diabetes

 Individuals have insulin resistance and usually relative insulin


deficiency.

 Also known as Non Insulin Dependent Diabetes Mellitus


(NIDDM)

 Accounts for ~90% of Diabetic cases.

 Etiology of Type 2 Diabetes is not known fully.

 Risk factors mentioned earlier contribute to increased


occurrence of Type 2 Diabetes.

 Can go unnoticed for many years as hyperglycaemia develops


gradually and it is not severe enough for classic diabetes
symptoms to get noticed.
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 BMI over 25 25 kg/m2 increases the TYPE 2 diabetes risk.

 Obesity itself causes some degree of insulin resistance.

 Certain drugs such as glucocoticoids, thiazide diuretics and


atypical antipsychotics are known to increase the risk of
diabetes.
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Gestational Diabetes

 It was defined as any degree of glucose intolerance that was


diagnosed for first time during pregnancy.
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Other Types of Diabetes

 Monogenic Diabetic Syndrome

- Neonatal Diabetes (Within 6 months of birth)

- Maturity Onset Diabetes of the Young (MODY) (Impaired


insulin secretion due to certain gene mutation)

 Cystic Fibrosis Related Diabetes


+ Complications Associated with Diabetes

 Diabetic retinopathy

 Diabetic nephropathy

 Diabetic neuropathy

 Cardiovascular Risks

 Diabetic Foot
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Ophthalmologic complications of DM

 Leading cause of blindness between 20 to 74 years of age in


the U.S.

 People with DM are 25 times more likely to become blind.

 The development of retinopathy depends on the degree of


glycemic control and the duration of DM.

 Blindness results from progressive diabetic retinopathy and


macular edema.

 Two stages of diabetic retinopathy


 nonproliferative and proliferative
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Nonproliferative diabetic retinopathy

 It occurs late in first decade or early second decade of the


disease. (ten years after the onset of first signs of diabetes)

 It is associated with retinal vascular microaneurysms, blot


hemorrhages and cotton wool spots.

 Pathophysiology
 There is loss of retinal pericytes, increase in retinal vascular
permeability, change in retinal blood flow and abnormal retinal
microvasculature
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Proliferative diabetic retinopathy

 The hallmark appearance is neovascularization, which occur


at optic nerve and at macula.

 The new blood vessels can easily rupture causing vitreous


hemorrhage, fibrosis and retinal detachment
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Renal complications of Diabetes
Mellitus

 Diabetic nephropathy is the cause of ESRD (End Stage Renal


Disease).

 The pathogenesis of diabetic nephropathy is related to


chronic hyperglycemia.

 Mechanism of chronic hyperglycemia progressing to ESRD


 involve effects of soluble factors such as growth factors,
angiotensin II and endothelin
 Alteration in renal microcirculation like glomerular hyperfiltration
and rise in glomerular capillary pressure.
 And structural changes in glomeruli for example BM thickening,
mesangial expansion, high extracelluar matrix
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Renal complications continued

 The first 5 years of diabetes it involves glomerular BM


thickening and mesangial volume expansion.

 In 5 to 10 years of type 1 DM, individuals excrete small


amounts of albumin in urine.
 Microalbuminuria is 30-300mg/d

 Macroabluminuria occurs over the next 10 years


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Diabetic Neuropathy

 The occurrence of diabetic neuropathy is determined by the


duration of diabetes and the glycemic control.

 This has two types


 symmetric and asymmetric types

 Symmetric neuropathy can present as small fiber


involvement (e.g. dysesthesia)

 Asymmetric neuropathy categorized into acute and gradual


onset.

 Examples of acute onset: oculomotor neuropathy

 Examples of Gradual onset - The loss of sensory input from the


foot
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Cardiovascular Risks

 Hypertension

 Dyslipidemia (Hypercholesterolemia)

 Thrombosis

 Coronary Artery Diseases


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Type 1 Diabetes Treatment

 Insulin Supplement
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Type 2 Diabetes Treatment

 Control through Diet and Weight Loss

 Use of Oral Hypoglycemic Agents


 Sulfonylureas
 Meglitinides
 Biguanides
 Thiazolidinediones
 Alpha-Glucosidase Inhibitors
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SULFONYLUREAS

 Increases Beta cell production of insulin

 First Generation Drugs:


 Tolbutamide, Chlorpropamide

 Second Generation Drugs:


 Glyburide, Glipizide, Glimepiride

 Side Effect: for examples


 Tolbutamide: Tinnitus
 Chlorpropamide: hypoglycemia, Disulfiram-like rxn
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MEGLITINIDES

 Increase Beta Cell production of insulin

 Drug Name: Repaglinide

 Usage: a fast acting premeal therapy to limit postprandial


hyperglycemia

 Side Effect: can cause hypoglycemia when taking together


with gemfibrozil
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BIGUANIDES

 Increases peripheral cell sensitivity to insulin

 Drug Names: Metformin, Phenformin

 Avoid the use of this drug in renal impairment or prior to


radiologic dye procedure for potential acute renal failure

 Adverse Effect: Lactic acidosis, diarrhea


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THIAZOLIDINEDIONES

 Increases tissue sensitivity of peripheral cells and hepatic


cell to insulin

 Drug Names: Rosiglitazone, Pioglitazone

 Metabolized by cytochrome P450 system

 Contraindication:
 Severe heart failure, liver disease

 Adverse Effect: hepatotoxicity


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Alpha-Glucosidase Inhibitors

 Decrease absorption of disaccharides by inhibiting alpha-


glucosidase

 Drug Names: Acarbose, Miglitol

 Have minimal effects on blood sugar-- they do not stimulate


insulin release

 Metabolized within the GI tract by flora

 Adverse effects: Flatulence, diarrhea


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DPP-4 Inhibitors

 a class of oral hypoglycemics that block DPP-4

 Dipeptidyl Peptidase Inhibitors work by inhibiting the action


of this enzyme, thereby prolonging incretin effect in vivo.

 Incretins are a group of metabolic hormonesthat stimulate a


decrease in blood glucose levels.

 E.g. Sitagliptin, Vildagliptin


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Recent Advances

 Synthetic Amylin Analog

 Incretin Mimetics

 Oral Agents

-Insulin Sectretagogues

- Alpha Glucosidase Inhibitors

- Dipeptidyl Peptidase IV Inhibitors

- Insulin Sensitizers
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Synthetic Amylin Analog

 Pramlintide, a synthetic analogue of amylin, is an injectible


antihyperglycemic agents that modulates postprandial
glucose levels and is approved for postprandial use for
persons with type 1 and type 2 diabetes.

 Pramlintide lowers glucagon during a meal, slows food


emptying from the stomach and curbs the appetite.
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Glucagon like Polypeptide- 1
Receptors Agonists
 Incretins are intestinal factors that are released in response
to nutrients, contributing to blood glucose lowering.

 In type 2 Diabetes, the release of glucagon like polypepide is


diminished postprandially, which leads to inadequate
glucagon suppression and excessive hepatic glucose output.

 Two synthetic analogues of glucagon like polypeptide


Exenatide and Liraglutide are commercially available to
help restore GLP-1 activity.

 Exenatide and Liraglutide, along with DPP-4 inhibitors, are


currently available to treat patients with T2DM by addressing
decreased concentrations of GLP-1.
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Insulin Pumps

Insulin pumps are small computerized devices that


deliver insulin in two ways:

 In a steady measured and continuous dose (the "basal"


insulin)

 As a surge ("bolus") dose, at your direction, around mealtime.

This USFDA Approved Insulin delivery system most closely


mimics the body's normal release of insulin.
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Combination Therapy

 GLP-1 (Glucagon like Polypeptide) Receptor agonist with


Insulin Secretagogue or with Insulin.

 DPP-4 (Dipeptidyl Peptidase IV) Inhibitor Sitagliptin or


Vidagliptin (Glavusmet) in combination with metformin.

 Pramlintide in combination with Insulin, Metformin or


Sulphonylurea.
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Sodium Glucose Cotransporter 2
Inhibitors (SGLT-2)

 SGLT-2, a low-affinity but high-capacity transporter found in the


brush border of the proximal tubule, is a mediator of glucose
reabsorption in the kidneys.

 In hyperglycemia, the kidneys may play an exacerbating role by


reabsorbing excess glucose, ultimately contributing to chronic
hyperglycemia, which in turn contributes to chronic glycemic
burden and the risk of microvascular consequences.
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 SGLT-2 inhibitors exert their effects by causing the kidneys to


excrete glucose into the urine. The effects are also independent of
insulin secretion.

 These proposed mechanisms make SGLT-2 a viable target to help


combat hyperglycemia in patients with T2DM. These agents
decreased A1C anywhere from 0.5 to 1.5%, and demonstrated low
incidences of hypoglycemia with minimal side effects.
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SGLT-2 Inhibitors (Phase III) include:

 Canagliflozin

 Empagliflozin

 Dapagliflozin
+ Long Acting Basal Insulin Analogue

 LY2605541 is a long-acting basal insulin analogue that is currently


being evaluated in phase III studies in T2DM patients.

 The primary aim of insulin therapy is to replace endogenous


insulin secretion in patients with type 1 or type 2 diabetes in a
physiologic manner, mimicking normal secretion patterns to
adequately regulate glucose metabolism.
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 The currently available human insulins for basal therapy - neutral


protamine Hagedorn (NPH), - and analogs such as insulin glargine,
differ in pharmacokinetic properties.

 Clinical trial data indicate that insulin glargine may satisfy basal
insulin requirements, with an improved safety profile relative to
other available insulins used for basal supplementation.
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11-β-Hydroxysteroid Dehydrogenase
Type 1 Inhibitors (11-β-HSD1)

 11-β-Hydroxysteroid Dehydrogenase or cortison reductase


convert cortison to cortisol. Overexpression of this enzyme can
lead to obesity insulin resistance.

 Preclinical evidence indicates that 11-β-HSD1 has a function in


both obesity and metabolic disease in rodents, which suggests
that inhibiting this catalyst in liver and adipose tissues may lead
to enhanced hepatic and peripheral insulin sensitivity, thus
improving overall glucose levels and possibly decreasing overall
macrovascular risk.
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Vitamin D In DM

 Recent studies have found that deficiency of Vitamin D results in


reduction in insulin secretion and thus in hyperglycemia.

 Both insulin secretion and sensitivity depends upon intracellular


calcium concentration also and Vitamin D is one of the hormone
which has been found to regulate calcium flux within the cells.

 In both observational and case-control studies, an


inverse relationship has been reported with level of 25(OH)Vit D
and degree of glycemic control.
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Stem Cell Therapy
A newly created method of

placing stem cell-derived

pancreatic cells in capsules

under the skin to replace

insulin is tested in diabetic

disease models. The method is successful without producing likely


complications. The study confirms the viability of combining stem
cells and 'encapsulation' technology to treat insulin-dependent
diabetes.
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Betatrophin

 Scientists at Harvard Stem Cell Institute (HSCI) found that a


hormone called betatrophin plays a significant role in enhancing
the production of insulin by beta cells in mice.

 If the study also shows similar results in humans, it will be a huge


leap forward in the treatment of diabetes.
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Islet Cell Transplantation

In islet cell

transplantation,

beta cells are

removed from

a donor's pancreas

and transferred

into a person

with diabetes.
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 Beta cells are found in the islets of the pancreas and produce
insulin, which regulates blood sugar levels. Once transplanted, the
donor islets begin to make and release insulin.

 As with all organ and tissue transplants, rejection of the donor cells
is the greatest challenge.
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