Role of GLP-1s in the management of persons with type 2 diabetes

The number of people in the UK with diagnosed diabetes has risen from 1.4 million in 1996 to 3.5 million today. Once the number of people with undiagnosed diabetes is factored in, this equates to over 4 million,2 with men accounting for 56% to women's 44%.
In the UK, type 2 diabetes accounts for approximately 90% of all diabetes cases.

An estimated £14billion is spent on treating diabetes and its complications annually, the latter being the much greater component.

Individualised treatment

In the management of adults with type 2 diabetes, UK Guideline 2015 recommends the adoption of an individualised approach that is tailored to the needs and circumstances of the patient, taking into account their personal preferences, comorbidities, risks from polypharmacy and their ability to benefit from long-term interventions because of reduced life expectancy.
Such an approach is of particular importance in the context of multimorbidity, and the person's needs and circumstances must be reassessed at each review.


For adults with type 2 diabetes being managed by lifestyle and diet, or by lifestyle and diet combined with a single drug ,Doctors should support the person to aim for an HbA1c level of 53 mmol/mol.
If HbA1c levels are not adequately controlled by a single drug and rise to 58mmol/mol or higher, the advice is to reinforce advice about diet, lifestyle and treatment adherence, to support the person to aim for the 53mmol/mol target and to intensify drug treatment.

Role for GLP-1s

Initial drug treatment for adults with type 2 diabetes is standard-release metformin.
If, however, triple therapy with metformin and two other oral drugs is not effective in optimising the lowering of HbA1c, or not tolerated or not indicated,
and for whom insulin therapy would have significant occupational implications,
and for whom weight loss would benefit other significant obesity-related comorbidities:

combination therapy metformin, a sulfonylurea and a glucagon-like peptide (GLP-1) mimetic is to be considered for those adults who have a BMI of 35kg.m2 or higher and specific medical problems associated with obesity, or who have a BMI lower than 35kg.m2.

NB- What are the GLP1 drugs? - watch this space!

Mohan,

Most of us can grasp the HbA1c level when expressed in %. It is a little more confusing when you express them in mmol. I am sure physicians dealing in diabetes will understand the result in mmol. I gather 53 expressed in mmol is 7% . I think it will help when both units are expressed together. Am I getting confused?

Badri.

P.S : There is a calculator for this - http://www.hba1cnet.com/hba1c-calculator/

Thank you Badri, useful web site to calculate.

mmol/mol, is the Internationally ( International consensus statement of European DA and the US Diabetic association) accepted measure , and it would be good for ALL to be educated in this . I do not know the Indian DA guidance on this .

Similar issues happened with Anticoagulation measures , and INR is the set measure all over the world now.

Mohan.

Hi friends.
About HbA1c, I have my own reservations. This test is widely used by doctors to know the control status of diabetic patients. This result gives an average blood sugar level in the particular individual during the last 3 months’ period. Compared to ordinary blood sugar estimation, this is quite a costly test. When a diabetic patient comes to us for a review what do we want to know? Whether his blood sugar level is satisfactory at the time of his visit. We would be able to adjust the dosage schedule depending upon the present level of blood sugar only. Not the average of three months. Three months is a long period. Suppose for any reason during this long spell of time, his blood sugar would have gone up for a short period. Either he missed the drugs or poor control in dieting due to some function at home for a week or so. This blood sugar rise would reflect in the 1Ac test. Wouldn’t it be? In that case when a patient sits before you with a high HbA1c value what is the option before you? If the value is more than 8 per cent, what is that you are going to do? This may be an indication of raised blood sugar for a short time as I mentioned above. Actually the present blood sugar may be within normal limit. By looking at this test value would you increase the dose of OHA or insulin? If so patient may go into a hypoglycaemic state. Instead, I prefer the patient to do blood sugar either by a glucometer at home or in a nearby lab at different times of the day, that is, fasting, before lunch and before dinner and record the results on a piece of paper and bring the same to us. These timings need not be all on the same day. That is not practical. Each test can be done on different days. When you see these results during consultation, you can have an idea about the blood sugar in different times of the day over some weeks and adjust the dose of medicines. If fasting blood sugar is high you can increase the dose at night and if the pre-lunch one is too low you can reduce the dose in the morning. Of course basic diet pattern should be standardised before these adjustments depending upon the person’s physical activity.
The only place where this test may be useful is to find out the incidence of diabetes in a section of people. Depending upon the average blood sugar we can rule out diabetes in each person. In your consulting room also it can be used on the first visit of the patient who was not a known diabetes. My point is that it is an unnecessary expense on the patient to do these tests every three months for the sake of management of diabetes.
In India, we express the value of HbA1c in terms of percentage only.

UA Mohammed

Mohammed,

Very interesting and valid argument. As you mentioned it is a very useful test for screening an individual for diabetes. I think it will also come in useful to check a patient who cannot be relied upon for a self test. They may be too old, not well educated etc to use a glucometer. I am not a diabetic but include the HbA1c as part of my yearly routine screening tests. Would you say that is unnecessary?

Hi Badri,
Even when you do it on a yearly routine, it gives you only an average of blood glucose over the three months period. if it is below normal, well and good. But if it is on the higher side, you need to test fasting and postprandial blood glucose to start a treatment schedule. Based upon the HbA1c value I wont start treatment, the reasons I have already mentioned above. Once we start treatment, I prefer to follow conventional method of blood glucose testing. For the patients who are old and unable to use glucometer, they need to go to a lab for HbA1c test to be done. In stead they can as well get ordinary blood glucose test done at much cheaper rate and if high or low they can go to their consultant then at once for the dosage adjustment. I will not ask any one to modify the dose of the therapy based on an average blood glucose level over the three months period. Then why should we do this at all in the middle of the treatment? I think I am clear. Just because we have a test with us the usefulness of which is only very limited why should we force this every three months on our patients?

Mohan, please give your opinion also on this aspect.

UA Mohammed

Mohammed,

I agree, you will not start treating a patient with anti-diabetic medication based on the HbA1c level. You will need a fasting and postprandial blood sugar level before starting treatment. However I still think the test will be useful to screen for diabetes in a non diabetic who is on the borderline of being a diabetic or who has a family history of diabetes. I would also like to hear what Mohan has to say about this.

On a different point I did not realise that to check for HbA1c is more expensive than fasting blood sugar

Badri
This test is very costly. Fasting blood sugar in my lab costs Rs 20 only; I have not revised this rate for the last 10 years. Whereas, HbA1c costs Rs 350 in labs in Tellicherry. I don't have this test in my lab since I don't do it for my patients. As I mentioned above it may be useful for one whom you see for the first time. In any case I am going to do a fasting and postprandial blood sugar and I will decide the treatment based on these reports. My opinion is this test is not worth for its cost. What I find in this part is this test is being done routinely on every diabetic patient once in every three months. Is this necessary? Apart from Mohan, I expect some response from our friends in other parts of India.

UA Mohammed

Hi friends
I am at pains to present another note of dissent on this topic. The DPP-4 (dipeptidyl peptidase IV) mentioned here in Mohan’s article, arrived in the market only recently and within a short time this drug has caught hold of the market by storm. Such is the aggressive marketing strategy now. When introduced it was claimed that unlike the already existing OHAs this molecule alone is sufficient to tackle the type 2 diabetes. The old OHAs exhaust the pancreatic beta cells in due course. No question of hypoglycaemia. Later slowly they advocated adding metformin to this group if necessary. Still later they said that if found not sufficient, sulphonylurea drugs (they have forgotten about pancreatic damage these suphonylureas cause) and insulin can be added to the regime. From the point of the middle class section of the society, it is prohibitively costly. And if you combine other drugs as noted above it is going to be further costlier. But more than the cost aspect one point I want to make about this drug is that I am concerned about the side effect profile of this group of drugs. Among the old antidiabetic drugs we have none which is known to cause organ specific damage. Mind you, it is not so in the case of the new gliptin group of drugs. The sulphonylurea drugs and insulin are with us for so many decades now. We only have very minor side effects, most important being hypoglycaemia. If doctors are a little more cautious and educate the patients properly this is not a big problem. But it is not so in the case of gliptin group of drugs.
After a person eats his food and blood sugar rises, hormones called incretin are released from intestinal cells. Incretin stimulates pancreatic beta cells to release insulin to metabolize sugar and signals the liver to stop making excess sugar. In people without diabetes, DPP-4 breaks down incretin to keep blood sugar and insulin levels balanced.
When DPP-4 inhibitors given, the action of the DPP-4 is blocked. So incretin continues to stimulate pancreas to release insulin. Incretins help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed.
Januvia (sitagliptin), a DPP-4 inhibitor, which comes under gliptin group is manufactured by Merck & Co. In clinical trials Januvia proved to be effective in controlling blood sugar levels. However, there are also reports of serious side effects, including acute pancreatitis, pancreatic cancer and thyroid cancer, which caused Januvia users to file lawsuits against Merck. In legal proceedings, plaintiffs accused Merck of negligence and concealing the risks of significant side effects.
For several years the FDA has been getting reports that drugs in both families of incretin drugs were causing pancreatitis, a painful inflammation of the pancreas that can destroy large portions of it and lead to full-fledged Type 1 diabetes or even death
DPP-4 was discovered through its association with the immune system, and some researchers thought that inhibiting it might impair the immune system Because it turns out that DPP-4 is also a tumor suppressor. And when you inhibit it, cells that have become cancerous get a 'get out of jail free' card.
One of the most horrific parts of this is the fact that cancer can take decades to form — unless the drug dramatically speeds up the process by inhibiting your body's ability to suppress tumor growth. Merck's lethal drug Vioxx was only withdrawn from the market after its lethality became too obvious to ignore. Ditto for the dangerous diabetes drug Avandia. Those drugs caused heart attacks and stroke. Cancer, on the other hand is not something that will tend to make people keel over after a relatively short period of time.
They could make MASSIVE amounts of money from these clearly dangerous drugs while cancer slowly and quietly grows in patients taking them, while biased shills maintain that the science is still "unclear." I for one would urge you to reconsider taking any kind of DPP-4 inhibitor. Why risk cancer for an ailment you can effectively address without ANY drug at all?

Just think about the logic (or rather, the lack thereof) of taking a drug that continuously inhibits one of your body's natural cancer suppressing mechanisms! According to Januvia's drug information, the drug inhibits the DPP-4 enzyme for 24 hours, and you take it daily, effectively permanently blocking the activity of a tumor suppressor gene. Yet none of the safety studies on Januvia addressed its impact on tumor growth! Is this wise?
Friends, look at these reports. And still we doctors are coerced to give these medicines which are under cloud to our patients. Efficacy wise these drugs are on a par with other existing anti-diabetic drugs only. Their only claim was less of hypoglycaemia and no weight gain. It is as if we have no other alternate options in the management of diabetes. I have a large number of diabetic patients. But I have not given this drug to any of my patients so far. Till I get a good report clearing all the suspicions about this class of drugs I will not prescribe this drug to any of my patients. I may sound a little anachronistic, not keeping pace with the current trends. That is my way.

UA Mohammed