Sales Certification Knowledge Module Diabetes Oral

LEARNING MODULE- Diabetes Oral team

What happens to the food we eat?

Food Carbohydrates Digestion Absorption as

glucose in blood

Glucose
reaches
various
cells

Glucose is used for various functions in the body.

Extra glucose stored in a different form

What are the steps in utilization of glucose?

Entry of glucose in cell(small amount of glucose can directly enter into

peripheral cells through facilitated diffusion even without insulin. But presence
of insulin increases glucose entry by 10 folds. Brain cells, retina & nephrons
can take up glucose without the help of insulin)

Phosphorylation of glucose through enzymes Glucokinase(liver & beta

cells)/Hexokinase(muscle)

Krebs Cycle(series of chemical reactions/oxidation)

Release of energy

Definitions...
Glycolysis: Breakdown of glucose to release energy
Glycogenesis: Formation of glycogen for storage from unutilized
glucose
Glycogenolysis: breakdown of stored glycogen into glucose

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Gluconeogenesis: formation of glucose from sources other than

carbohydrate (fat/protein) to meet energy requirement during fasting
stage.
Lipolysis- Breakdown of fats(triglycerides) into fatty acids & glycerol.
Lipogenesis- Storage of fats
Proteolysis- Breakdown of proteins into amino acids.

What is the physiology of Pancreas?

Pancreas is both an endocrine as well as exocrine organ.

Endocrine function- Insulin is a hormone released by the beta cells of the
pancreas in 2 phases in response to glucose entry into beta cells through
GLUT 2. The rapid first phase which occurs within 5 to 10 mins of food intake
& the delayed second phase which starts from beyond 20 mins. of food
intake. This happens primarily due to stimulation of gut hormones(Gastric
Inhibitory peptide-GIP, Glucagon like polypeptide-GLP) & cholinergic
mechanisms.

The rapid first phase of insulin secretion(peak) is of primary importance since

this directly inhibits hepatic glucose production.
The alpha cells of the pancreas secrete glucagon which increases hepatic
glucose production. Delta cells secrete somatostatin.

Exocrine function- Pancreas secretes enzymes which aid in digestion.

How is insulin secreted from the beta cells of the Pancreas?

Mechanism of insulin secretion from Beta cells of Pancreas

Explanation

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State the physiology of insulin secretion?

Rapid 1st phase due to release of preformed insulin & delayed 2 nd phase
Explanation

What are the functions of Insulin?

Insulin is an anabolic hormone.
Controls the rate of entry of glucose inside the cell
Increases glucose utilization rate in the cell.
Increases rate of glucose transport in the cell by more than 10 times.
It helps in storage of glucose as glycogen in the liver, muscle & adipose
tissue(glycogenesis).

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Furthermore, it helps in the storage of fats as triglycerides in the

adipose tissue(lipogenesis) & amino acids as proteins in the
muscle(protein synthesis).
Inhibits glycogenolysis, gluconeogenesis, lipolysis & proteolysis.

What is the role of Glucagon?

Unlike insulin, glucagon is a catabolic hormone released by
alpha cells of the pancreas.
Released during fasting stage.
Promotes glycogenolysis, gluconeogenesis & lipolysis.

What are major defects in diabetes?

Inability to properly utilize glucose(Insulin resistance)
Impaired insulin secretion encompassing both loss of rapid 1 st phase as
well as relative insulin deficiency.

Diabetes can cause acute medical

emergencies
Too much glucose (hyperglycemia)
Too little glucose (hypoglycemia)- Blood glucose levels below 60 mg/dl is
called hypoglycaemia. This happens mostly in Type 1 diabetic patients
while on insulin therapy. May also occur in Type 2 diabetes in patients
on combination therapy.

How is Diabetes diagnosed?

State as ADA criteria and add HbA1C values also

Impaired Glucose Tolerance(IGT)
2hr plasma glucose is between 7.8mmol/l (140mg/dl) and
11.0mmol/l (199mg/dl)

Impaired Fasting Glucose(IFG)

Fasting plasma glucose is 6.16.9mmol/l (100125mg/dl)

Diabetes-
Confirmed fasting plasma glucose is 7.0mmol/l (126mg/dl)
2hr plasma glucose is 11.0mmol/l (200mg/dl)

Classical Symptoms of Diabetes- Polyuria(excess urination),

Polyphagia(excess hunger) & Polydipsia(excess thirst)

What are the types of Diabetes?

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Type 1 Diabetes- Insulin Dependent Diabetes (IDDM)

-Beta Cells stop production of insulin in the pancreas leading to
absolute insulin deficiency.
Immune system has destroyed them.

Type 2 Diabetes- Non Insulin Dependent Diabetes (NIDDM)

90-95% 0f diabetes.
- Insulin resistance
Initially beta cells produces more insulin
Then beta cells unable to keep up with demand

Gestational Diabetes- Diabetes onset during pregnancy.

How does a Dr monitor glycemic control and what are the ADA values?

Measuring FPG & PPG & HbA1c.

HbA1c- Glycosylated Haemoglobin test-

This is done to know the glycemic control over past 3 months. The normal
values are <7%.
The life span of RBC is 6 to 8 weeks, hence any amount of glucose getting
attached to RBC is likely to remain throughout the life span of RBC. Thus
HbA1C measurement provides a reliable tool to identify diabetic patients
who do not follow the advise of the Dr & have erratic lifestyles.

What is insulin resistance?

Major defect in individuals with type 2 diabetes
Reduced biological response to insulin.
Strong predictor of type 2 diabetes
Closely associated with obesity
Occurs due multiple factors like defective insulin receptor, decreased
number of insulin receptors, abnormal insulin molecule etc.

What are the causes of insulin resistance?

Obesity
Genetics
Sedentary lifestyle
Smoking

What is -cell dysfunction?

Major defect in individuals with type 2 diabetes

Reduced ability of -cells to secrete enough insulin in response to
Hyperglycemia.

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Why does the -cell fail?

At physiological levels, both glucose and free fatty acids stimulate insulin
secretion.

-cell dysfunction may occur as a result of genetic factors.

Chronic hyperglycemia, however, may negatively affect the -cell
through a process known as glucotoxicity (the ability of glucose to
stimulate the death of -cells).
Similarly, chronically elevated free fatty acids have a lipotoxic effect
upon the pancreas, inducing -cell dysfunction.
Lipotoxicity is the ability of free fatty acids to stimulate the death of
-cells.
Oversecretion of insulin to compensate for insulin resistance also
contributes to -cell dysfunction.
It is estimated that 50% of beta cell function is lost at diagnosis of
diabetes. This really calls for an aggressive therapeutic approach.

Ticking Clock Hypothesis

The clock for coronary heart disease starts ticking even before the
onset of clinical diabetes(Macrovascular complications)

What are the complications of Diabetes?

Microvascular Retinopathy, Nephropathy & Neuropathy.
Macrovascular MI, Stroke & PVD(Peripheral Vascular Disease)

State the conclusions of UKPDS & DCCT trials.

Landmark trials in diabetes:

UKPDS(United Kingdom Diabetes Prospective Study)- Large trial

conducted in Type 2 diabetes patients which confirmed that tight glycemic
control significantly reduces microvascular complications.

DCCT(Diabetes Control & Complications trial) Large trial conducted in

Type 1 diabetic patients which confirmed similar results as UKPDS.

How is Diabetes managed?

Regimen must be customized to the individual patient
Education
Diet
Exercise
Oral medications
Insulin
Any or all of the above

Re-assess periodically

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Effectiveness of prescribed therapy

Development of progression of complications

ADA-EASD GUIDELINES ON MANAGEMENT OF DIABETES

What are the sites and mechanism of action of oral antidiabetic agents?

Primary sites of action of oral antidiabetic agents

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Therapeutic Class MOA

Sulfonylureas/Meglitinides Insulin
secretion from beta cells

Biguanides- Metformin Hepatic Glucose

output, Insulin resistance

-glucosidase inhibitor-Acarbose Carbohydrate

breakdown/
absorption in the intestine

Thiazolidinediones-Pioglitazone, Insulin
resistance

DPP 4 Inhibitors increase insulin secretion

as per Glucose
concentration.

SGL2 Inhibitors increases serum glucose

excretion through kidney
and lowers blood glucose
concentration in blood

BRANDS
Essential things to remember & communicate

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AMARYL
Glimepiride 1, 2 & 3 mg tablets

How is Amaryl able to stimulate physiological insulin secretion?

Amaryl preserves the reactivity of human beta cells to glucose stimulated

insulin secretion. Thus Glimepiride has been demonstrated to induce a more
physiological insulin secretion which is not only drug dose dependent but also
glucose concentration dependent. Thus, Amaryl increases both 1 st & 2nd phase
insulin secretion. This effect on 1 st phase insulin secretion leads to significant
reduction in hepatic glucose output.

How Amaryl is exercise friendly?

During exercise muscles can take up glucose even without insulin. Amaryl has
a unique action at the beta cells wherein Amaryl does not secrete insulin
during exercise thus reducing the risk of exercise induced hypoglycemia. This
action of Amaryl is different from glibenclamide which stimulates insulin
release even during exercise.

How unique is the binding affinity of Amaryl with sulphonylurea

receptor?
Studies suggest that the beta cell sulfonylurea receptor consists of at least
two protein subunits of 140 kDa and 65kDa which bind sulfonylurea of
different structure with different affinities and kinetic parameters. Amaryl binds
to the 65kDa subunit of the sulfonylurea receptor. The association of Amaryl
to the sulfonylurea receptor is 3 times faster & dissociation is 9 times faster.

Is Amaryl safe & effective in in various profiles of diabetic patients.

In obese no dose adjustment is required and there is no weight gain.
In elderly there is effective glycemic control with enhanced
compliance, improved insulin resistance and fewer hypoglycemic
events.
In patients with renal insufficiency stable fasting blood glucose levels
have been observed.

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In patients with cardiovascular risk Amaryl maintains the cardio-

protective effect of ischemic pre-conditioning and therefore may
protect against myocardial infarction.

What is Adiponectin? What are the effects of Amaryl on Adiponectin?

Adiponectin is a cytokine that modulates a number of metabolic processes,
including glucose regulation and fatty acid catabolism. Adiponectin is
exclusively secreted from adipose tissue into the bloodstream and is very
abundant in plasma relative to many hormones. Levels of the hormone are
inversely correlated with body mass index (BMI)and insulin resistance.
As per Tsunekawa study, Amaryl improves the Adiponectin levels by 54%
thus increase peripheral glucose metabolism by 46% as shown by increase in
metabolic clearance rate of glucose and thus decreases insulin resistance by
41% as shown by the improvement in the HOMA-IR score which validates the
extra pancreatic activity of Amaryl.
How is Amaryl beneficial effect in type 2 diabetes patients with dilated
cardiomyopathy?
In a diabetic with dilated cardiomyopathy, there is shift from fatty acids to
glucose as energy substrate. But, insulin resistance at the level of the
myocardium limits glucose uptake. The failing hearts dependence on glucose
leads to the myocardium being starved of ATP. Amaryl, independent of insulin,
improves expression of GLUT1 & GLUT4 in the cardiomyocyte. This, results
in an increased uptake of glucose by the cardiomyocyte by as much as 80%.
This improved uptake of glucose supports the failing heart by generating more
ATP.

What is Ischemic Preconditioning? What is the effect of Amaryl on

Ischemic preconditioning
Ischemic Preconditioning is the condition in which exposure of
Cardiomyocytes to episodes of ischemia induces cellular adaptations that
make these cells resistant to damage during subsequent episodes of
Ischemia. At the cellular level the onset of ischemia causes the opening of the
cardiovascular ATP-sensitive potassium (KATP) channels, a mechanism that

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plays a role in protecting the myocardium; this process is called ischemic

preconditioning.
The Klepzig study has shown that Amaryl does not adversely impact ischemic
preconditioning unlike other sulphonylureas.

What is the effect of Amaryl on inflammatory markers?

As shown in Koshiba study, Amaryl significantly improves plasma Adiponectin
levels & decreases TNF-, interleukin-6 and high sensitive-CRP levels unlike
glibenclamide.

Name 3 add on indication for Amaryl as per current marketing strategy ?

add on amaryl in patients those who are uncontrolled on 1) Metformin
Monotherapy 2) Diet & Exercise 3) Metformin + DPP 4 Inhibitor..

What is the difference between Amaryl & its generics ?

Amaryl Vs Generics
The use of generic copies of drugs is one method of reducing healthcare
costs. However, manufacturing methods and standards may differ among
pharmaceutical companies, which, consequently, can lead to differences in
the quality and performance of the generic copies.

Glimepiride 1mg and 2mg are low dose pharmaceutical products; the
challenge is to produce tablets without any weight variation and to ensure
uniform distribution of drug in the granules for each tablet. If not manufactured
properly it may cause variability in doses leading to variability in insulin
secretion which may result in increased hypoglycemia or poor glycemic
control.

Amaryl is manufactured under Single Pot Processing Technology (SPPT)

which ensures - Uniform distribution of the drug, Uniform weight of tablets and
Right amount of drug to patients.

As per the study published in Journal of Medical Association, Thailand and

presented at IDF, levels of degradation product of glimepiride Sulfonamide
impurity were 12.5 times higher at day 21 for one generic VS Amaryl. 65% of
generics failed to meet dissolution profile of Amaryl and 74% of Generics do
not match the quality of Amaryl.

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Another data proving superiority of Amaryl over other branded generics from
Institution of chemical technology, Mumbai, which is an autonomous
institution. This report proves that Amaryl is superior on important parameters
like- Dissolution limit and disintegration time compared to other brands. Tablet
hardness also got decreased with other brands over one year time, but
Amaryl maintained it. Tablet friability was as per the GMP with Amaryl but not
with other brands.

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Stability up-gradation gives confidence about the products quality and Amaryl
is the only glimepiride with three years shelf life.

Amaryl M 1 & Amaryl M 2 ( glimepiride 1 mg & 2 mg + metformin 500 mg

extended release)
Amaryl M 1 Forte Amaryl M 2 Forte (Glimepiride 1 mg and 2 mg +
metformin 1000 mg extended release).

Amaryl M-Objective
To establish Amaryl M as option that offers predictable results and
predictable safety early in life of patients by establishing following Key
Concepts:
Predictable bioequivalence
Predictable Control through persistence
Predictable Cardio safety

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Glycemic memory describes the deferred effects of prior glycemic

status on diabetic complications later in life, independent of more recent
glycemic control.
Most of the microvascular complications of diabetes are related to the degree
and the length of exposure to hyperglycemia.
New data from the follow-up studies of the Diabetes Control and
Complications Trial- the Epidemiology of Diabetes Intervention and
Complications Study (DCCT- EDIC) and the United Kingdom Prospective
Diabetes Study (UKPDS) emphasize the role of glycemic control early in the
course of the disorder and its value in prevention of later complications.
Early, intensive treatment of new onset diabetes mellitus aimed at tight
glucose control reduces the risk of microvascular complications and probably
macro-vascular disease as well.
Metabolic memory and legacy effect are terms that have been used to
describe the fact that glucose control early in the natural history of diabetes
profoundly influences the prognosis later on in life.

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PERSIST Trial
Objective
1. To assess the proportion of patients remaining on Amaryl M therapy
after a period of 6 months in everyday practice
2. Descriptive statistics for reasons of continuation, daily dosages of
Amaryl M, and adverse events were also assessed
Design
1. Observational, multicenter, prospective product registry comprising
patients in India, Indonesia, and Taiwan
2. 1309 T2D uncontrolled on mono or bi-therapy of oral anti-diabetic
treatment, with A1C >7%.
3. Patients were on Amaryl M for a period of 6 months with 3 evaluation
visits at baseline, 3 months and 6 months

Results- PERSISTance

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o A total of 1205 patients (92.1%) remained on Amaryl M at 3

months
o At 6 months, 1142 (87.2%) patients were still on Amaryl M
o Significant reduction in A1C and fasting blood glucose (FBG)
levels were recorded at both 3 and 6 months compared with
baseline (P < 0.0001).
Conclusion
The use of fixed-dose combination therapy such as Amaryl M may provide
physicians in Asia with a safe and effective option for T2D patients who are
uncontrolled on other therapies and require treatment with high persistence
rates

Bioequivalence-Concept
In FDC (fixed dose combinations) though patient compliance is superior, it is
always a challenge to ensure equivalent efficacy as free dose combination of
the same drugs. For this, each of the constituent drug need to have same
pharmacokinetic profile, i.e Cmax, Tmax & Area under the curve, as that of
the comparator (Original) brand. This ensures availability of same amount of
drug as free dose combination, giving desired efficacy & is called to be
Bioequivalent to the free dose combination of these drugs.

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Amaryl MV 1mg/2mg.

(Glimepiride 1 mg & 2 mg + Metformin 500 mg sustained release +

Voglibose 0.2)

What is the Care Giver communication which we give for Amaryl MV

Launch ?

60% of the family members are worried about the person with diabetes & only
23% of patients follow the diet restrictions. This non compliant behavior of
diabetic patients leads to hyperglycemia with high PPG peaks as Indian food
is high in glycemic index. It is also said that 59% of family members are willing
to be more involved in diabetes care, which may help to optimize outcome in
people with diabetes. To have optimum therapeutic benefits for patients of
T2DM uncontrolled on SU+ Met with PPG >260 & uncontrolled diet,
empower all care givers by giving Amaryl MV , which control Spikes Smartly..

In which patient profile Amaryl MV should be avoided ?

T2DM patients uncontrolled on SU+met with PPG > 260 & uncontrolled diet
along with co-morbid conditions like renal disorders e.g. Chronic kidney
disease , Kidney Injuries, nephropathy and gastric disorders like GI
intolerance , Flatulence, irritation, acidity, diarrhea, constipation .

What is the dose of Amaryl MV ?

Amaryl MV dose has to be taken twice daily 20-30 minutes before major meal.

Explain Amaryl MV positioning with respect to broader target group of

Drs ?

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All Physicians with more preference to voglibose.

What does ECG stands for in all promotional activities/Input for Amaryl
MV ?
Empower Care Giver.

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