কিছু দিন আগে, ইনসুলিন নিয়ে Group-এ পোস্ট দিয়েছিলাম। বাস্তবে ইনসুলিনের থেকে মুখে খাবার ঔষধ দিয়েই

বেশি সংখ্যক রোগীকে চিকিৎসা দেয়া হয়। এবং অনেক ক্ষেত্রেই রোগীর প্রেসক্রিপশন হাতে নিলে ডায়াবেটিসের
ঔষধ নিয়ে অনেক অসঙ্গতি চোখে পড়ে যা হয়তো সামান্য সচেতনতার অভাবেই অনিচ্ছাবসত ভাবেই হয়ে যায়।
এই সমস্যার সমাধানে কিছু তথ্য নিয়ে পরবর্তী অংশে আলোচনা করছি। সাইন্টিফিক ডিসকাশনের অংশ হিসাবে
পরবর্তী অংশ ইংরেজিতে লিখছি।

In following discussion, I’m going to use the term “Oral Antidiabetic Drugs (OAD)” instead of “Oral
Hypoglycemic Drugs (OHD)”, because not all anti-diabetic drugs cause hypoglycemia and few drugs in
general settings don’t lower the blood sugar below normal range (eg: euglycemic). They are particularly
important for management of hypoglycemia prone DM patients.

All medical professionals know the basics about these OADs. I’m merely trying to highly some key points
that may help you to peek up which one is the right one for your patient and help you to avoid some
common mistakes.

Cost is an important issue, when it comes to disease that needs chronic care, like diabetes. Keeping
aside the classical pharmacological classifications, if we classify the OADs based on their cost profile for
patient care, we get a picture like this...

Cat-1: Low cost OADs: Metformin (1st choice in Type 2 DM). Glibenclamide (Lowest cost, but there is
higher chance of hypoglycemia which can be as long as 48 hours), Repaglinide (A short acting non-SU
secretagogue having less chance of hypoglycemia making it suitable for hypoglycemia prone patient, eg:
renal impairment), Glipizide (Cost effective, carries high risk of hypoglycemia), Glimepiride (Cost
effective, carries the standard risk of hypoglycemia, once daily dose profile).

*Pioglitazone: A good drug but use has been banned by drug administration authority due to possible
association with bladder carcinoma.

Daily administration of these drugs costs usually less than 10 taka/day from an acceptable
pharmaceutical brand. So, when you are seeing patient who are less fortunate, preferable drug or drug
combinations should ideally come from these group.

Cat-2: Moderate Cost OADs: Gliclazide Plain (Can be given twice daily) & Modified Release (once daily)
formulations (MR formulation carries least chance of Hypoglycemia among SU drugs), Acarbose (Use is
limited by GI side effects, suitable for patients who takes a large amount of carb containing meal),
Daily administration of these drugs costs usually >10 to 20 taka/day from an acceptable pharmaceutical
brand. Few local brands produce them in lower cost, but I’m considering brands that comes from
originator.

Cat-3: Considerably higher cost OADs: DPP-4i (Sitagliptin, Vildagliptin, Linagliptin). SGLT-2i (Canagliflozin,
Dapagliflozin, Empagliflozin).

If you are wondering why DPP4i are in high cost drug list when locally produced linagliptin is available
only 7/8 taka, this is because a quality product from this group in regular dose (For Sitagliptin
100mg/day, Vildagliptin 100mg/day, Linagliptin 5mg/day) from a originator brand (or at least a good
local pharmaceutical company) costs much more than 20 taka/day. On the other hand, DPP4i are weak
drugs. Use it alone and it almost always results in unsuccessful sugar control. Multiple OADs also
increases the cost burden.

I don’t have any complaints about local brand. I’m also comfortable in using drugs from top 10
renowned pharmaceutical companies considering cost effectiveness. But a vildagliptin from Novartis is
not going to work like a local vildagliptin, you can always expect roughly 20-30% reduced
pharmacological effectiveness and answer to impurity is often uncertain/unanswered. If a rich patient
can afford, use originator brand.

This category may help you to choose what drugs are suitable for your patient from cost point. But apart
from this there are some other factors. The key message regarding OADS to deliver to are:

1. If your patient is not in a catabolic state or in an emergency, always choose metformin. Start in 500
mg post meal in lunch then gradually you may increase up to 2500mg/day twice weekly if
needed/tolerated. Use newer eGFR based recommendation for renal contraindication assessment of
metformin. See my previous post regarding insulin.

2. If patient is in any state of emergency/catabolism, ALWAYS USE INSULIN. After stabilization (both
blood sugar and HbA1c) if total daily dose of insulin gets lowered below ~ 20unit/day, then maybe you
can consider switching to OADs. But always encourage the patient if he/she wants to stay in insulin
(providing insulin is necessary for sugar control). This will help in beta cell preservation with some added
benefit. But add metformin if continuing insulin after crisis is averted to prevent insulin induced weight
gain.
3. When using oral drugs, counsel the patient that result will be slow. Tell them don’t expect that sugar
will be normal within days. It will take weeks to month to decide if the regimen is failing or not.

4. Try not to add a second drug until first drug metformin is reached in maximum tolerable
dose/therapeutic dose in stable patient. For example: After starting metformin in 500mg/day dose,
don’t go for 2nd drug like DPP4i / SUs. But after gradually increasing dose of metformin to maybe
2gm/day over 3 months (based on blood sugar) adding a 2nd drug is the right step in diabetes remained
unchecked. It should be kept it mind that if blood sugar is high (eg: more than 16.7mmol/L or HbA1c
>10%), insulin is a better choice. In older American Diabetes Association guidelines, there is a narrow
range of HbA1c 9% to below 10% duel drug combination is advised as initial therapy. But those who are
in stable condition within regular follow up, adding multiple drugs when previous drugs are underdosed
is not a good practice. Again, I’m putting the importance of point 3 that slow adjustment is necessary for
OADs. It may not seem “good enough” for your practice in first look, but if you counsel properly patient
will realize the importance of it.

5. Learn about and recognize oral hypoglycemic drug failure early. This “OAD failure” term is particularly
used for Sulphonylureas (SUs) as they directly stimulate beta cells. Over the period of natural history of
diabetes when beta cells are burned out, patient’s pancreas don’t respond enough to SU type drugs
stimulation and insulin become necessary. As an example, A patient with metformin 850mg twice daily
with Glimiperide 4mg OD have persistent high blood sugar (eg: a period of 3months). Now Glimiperide
has acceptable pharmacological dose of 8mg/day. But keep that in mind, if 50 % dose of one SU fails to
control blood sugar, beta cell reserve is so poor that adding more dose or changing to different SUs is
not going to be beneficial and insulin is required. This is called OAD failure and should be prevented by
implementation early insulin therapy in patient is agreeable. This is why, if a patient agrees to continue
insulin from beginning, let them be with metformin’s coverage for insulin resistance.

6. Never use more than “3” OADs simultaneously. Add one after another at least providing enough time
for added drug to become responsive (eg: 3 months) in stable patient. If 3 drug combinations fail, don’t
add 4th drug. Carefully and gently counsel the patient about insulin initiation. If necessary, start with
once/twice daily insulin regimen. Always remove SUs from regimen when switching to insulin otherwise
patient will have high risk of hypoglycemia. Try to keep only metformin with insulin, as other drugs are
not very effective in such scenario and may only increase cost burden.

7. OADs (eg: SU) induced Hypoglycemia is not uncommon and more dangerous than insulin induced
hypoglycemia as it may last up to 48 hours (compared to general insulin induced hypoglycemia usually
not last more than 24 hours). If a patient become hospitalized by OAD induced hypoglycemia,
continuous carb/glucose supply by either enteral or parenteral route is recommended to prevent again
falling into hypoglycemia (eg: may need slow glucose infusion up to 24-36 hours).
8. Patient with other comorbidities: In renal failure: eGFR based metformin recommendation is used for
dose and patient selection. Short acting SUs may be appropriate (eg: gliclazide MR) as they carry lower
risk of hypoglycemia. DPP4i can be used with appropriate dose reduction (eg: Vildagliptin 50mg/day,
Sitaglipitin 50mg/day etc) or without dose reduction in case of linagliptin. In hepatic impairment, try to
avoid using DPP4i. In patient with heart disease and heart failure SGLT2i are recommended for
cardiovascular benefit but note that they need careful monitoring to prevent UTIs and electrolyte
imbalances. SGLT2i are costly drugs and only their cardiovascular benefits are not sufficient enough
justify their use unless blood sugar is not achieved. Patient prone to hypoglycemia (eg: unawareness),
drugs like metformin, DPP4i, SGLT2i and Non-SU secretagogues are safest.

9. Diabetes in pre-pregnancy (eg: 3 months before), pregnancy and breast feeding: Switch to insulin in
all these states. Many guideline/textbooks suggest few oral drugs (eg: metformin) are safe in pregnancy.
But truth is, these drugs passes through placenta to baby and also being excreted by breast milk in
considerable amount. Though short-term safety data suggests few drugs safety, long term safety data is
still unavailable (Eg: what happened to baby when he/she reaches adulthood). So, until recognized long
term follow-up trials has recommended something conclusive regarding OADs use in pregnancy, please
be safe than sorry.

10. Oral drugs in Surgery: During surgery, it’s is planned to keep blood sugar roughly below 10 mmol/L.
Surgery is a stressful condition. The bigger surgery is planned higher is the chance of glucose level
fluctuation. Insulin will be appropriate if we are expecting rapid control or minimizing fluctuation. Minor
day time surgery may be done with no/minimum modification of OADs.

Any discussion regarding OADs comes out big and this post is already big enough. Further detailed
discussion is not possible here and will only result in loss of concentration and time. May be in later
date, small topic discussion will be more helpful rather than elongating this post.

Till then if you have any input regarding this discussion, please drop it in comment section.

Dr. Lala Shourav Das

Endocrinologist

Comilla Medical College, 17th Batch.