Why a combination of multiple drugs are needed to treat diabetes in young

Though we may be keeping our blood sugar levels in check with medication, what really worries us is the constant battle to keep our HbA1c levels (blood glucose levels over a three month period) below the suggested seven per cent mark. A new study the US-based National Institute of Health holds out hope. Analysing the effectiveness of four different classes of diabetes medicines in over 5,000 people for years, researchers found that they were almost at par when used with the first-line drug Metformin. But the long-acting insulin glargine and another medicine liraglutide were the best at keeping HbA1c levels within limits. Significantly, despite using the drugs, nearly a fourth of the diabetics weren’t able to keep their blood glucose levels below the seven per cent mark. Does that mean that using medicines from different classes instead of a higher dose of a single medicine is better for controlling blood glucose levels?
Although the aim of the study was to figure out which drugs work the best for Type-2 diabetes patients, it shows that three-fourths of the diabetics weren’t able to maintain the target blood glucose levels. Why?
The findings are not surprising. Our INDIAB study findings released earlier this year showed that only 36.3 per cent of known diabetics in India were able to control their blood glucose levels. That’s because diabetes is a very complex disease – it is caused eight physiological defects called the ominous octet. Type 2 diabetes is caused decreased insulin secretion the pancreas, decreased effect of the gut hormone incretin that regulates the amount of insulin secreted after a meal, increased glucose reabsorption the kidneys, decreased glucose uptake muscles, increased glucose production the liver, increased glucagon secretion the islet cells on the pancreas, insulin resance in cells, and neurotransmitter dysfunction.
We usually ask patients to control their blood glucose, blood pressure and cholesterol levels. In contrast to diabetes, lipid control is the easiest – give the patients statins and the cholesterol levels will come down. Controlling blood pressure is also less complicated, with 48.8 per cent people in our study having it under check.
So, what is the message of the study for physicians writing prescriptions for diabetics?
The different classes of diabetes medicines target different mechanisms. For example, the most commonly used first line diabetes medicine Metformin reduces the glucose production the liver while a GLP-1 agon like Liraglutide works on the gut. This doesn’t mean that everyone needs eight different types of medicines. A combination of two drugs can address three or four defects. If we are able to correct six defects – with medicines and lifestyle changes – the patient will be able to keep the blood glucose levels under control.
So, what we are coming to is combination therapy instead of using one drug in large quantities. If we use optimal doses of two or three drugs, we will be able to get virtually everyone under control. However, we hesitate to give too many drugs. The patients also do not want too many drugs, so ultimately they remain uncontrolled. This study is a good example of how the combination of Metformin and another drug was not able to get everyone under control. Had they used two more drugs with Metformin, probably they would have been able to get it under control.
As a result of this study, there could be new guidelines stating that if the HbA1c level is above a certain mark, use two drugs instead of one to get it under control.
I had published this concept of using more drugs in optimal dosage – now we understand better – nearly 50 years ago with just the two medicines available then. In a trial, we gave full doses of the two medicines to two groups and half doses of both the medicines to the third group – the third group actually did better. That time we did not know about the ominous octet, but we concluded that the two different drugs with a different mechanism of action will not have an additive but a synergic effect.
Then, who would need just the first-line drug and who would be given say a second and a third drug for controlling the glucose levels?
Not everyone will need multiple drugs — it all depends on the stage of the disease, duration of diabetes and the age of the patient.
Older people can get it under control with say one drug; their disease is much milder. The very fact that they got the disease in their old age means they have only a mild genetic defect, so it can be controlled more easily. In older age groups, it is usually MARD — mild age related diabetes – and can be controlled with just Metformin.
Also, you need 20 to 30 years to develop complications of diabetes (heart disease, nerve damage, vision loss). So if a person gets diabetes at say 60 or 65 years of age, it is unlikely that they will develop the complications in their lifetime.
Other than that, we don’t aim for HbA1c of seven per cent in older people at all because they get hypoglycaemia (low blood glucose levels, a dangerous side effect). A 7.5 or 8 per cent is sufficient in older age groups, so even in that case we will not push too many drugs.
When people get diabetes at a younger age, it acquires a more severe form. Also, they have to live for a long time with the condition, so we have to get the HbA1c below seven per cent. That’s why we have to be more aggressive. So, they are the ones who will end up getting two or three drugs. Even that will not be enough after say four, five, or ten years of treatment; then they will need insulin shots to control their blood sugar levels. Younger people are always more difficult to treat.
Why Dr V Mohan?
Dr Mohan is a renowned diabetolog and the chairman of Dr Mohan’s Diabetes Specialities Centre. He is also the president of the Madras Diabetes Research Foundation, which is an ICMR advanced centre for studying the genomics of Type-2 diabetes. He has over 1,500 publications. He has also received the highest honour for doctors in India, Dr BC Roy Award, and the fourth-highest civilian award Padma Shri.