What’s next after Metformin?

Type 2 diabetes is a progressive condition, so over time, blood glucose levels rise and your HbA1c may not be in target anymore. This can be very frustrating and disappointing. Many things can happen in the body to cause this progression of type 2 diabetes. Insulin resistance increases, which means that:

• the insulin is not as effective at moving glucose out of the blood into the muscle
• the liver makes too much glucose and releases it into the blood stream.

Over time, the pancreas can no longer make as much insulin as it used to so glucose levels rise.

Persistent glucose levels above target range over many years can damage your blood vessels, including the large blood vessels. This increases your risk of having a heart attack or stroke.

Diabetes that is not well managed can also cause damage to the very small blood vessels resulting in microvascular complications such as damage to the eyes (retinopathy), kidneys (nephropathy) and nerves (neuropathy). To keep you well and help avoid diabetes complications, research has shown it is important to keep your blood glucose and cholesterol levels and blood pressure as close to normal as possible.

It is important that you see your doctor regularly to check how your diabetes is tracking. At this time your doctor will order the HbA1c and other investigations to check on your heart, liver and kidneys.

There are many medicines available these days to manage the different causes of increasing blood glucose levels. Some of the newer glucose lowering medicines have shown to be good for your heart and or kidneys as well as lowering glucose levels.

If your HbA1c is above target, your doctor or nurse practitioner will look at all your results and your personal situation before deciding the best treatment option for you. They will also consider any other medical conditions such as kidney disease and a family history of heart disease before prescribing a new glucose lowering medication.

Here are some of the most likely treatment options.

Metformin

If you need to lower your glucose levels, and are not already on diabetes tablets, metformin is usually the first one to be prescribed. It works by:

• reducing the amount of glucose released into the blood by the liver
• slowing down the absorption of glucose from the small intestine into the blood
• helps the muscle and fat cells to take up glucose from the blood stream.

Metformin comes in tablet form and should be taken with a meal or straight after. It may be prescribed to be taken with one or more meals. It is safe to take with other tablets including other glucose lowering medicines and/or blood pressure tablets.

Metformin is generally very safe. Side effects can include nausea, diarrhoea and a metallic taste in the mouth. If you start with a low dose and increase it slowly, this will minimise the side effects. Metformin also comes in extended-release form which may lessen the gut side effects. This type of tablet only needs to be taken once a day.

If you are having surgery or an Xray or scan requiring the injection of a dye, check with your doctor as you may need to stop taking metformin. If you have kidney disease, the dose of metformin may need to be reduced or stopped. Taking metformin for more than 5 years can lower your Vitamin B12 levels so your doctor may check this.

Sometimes metformin can be combined with another type of glucose lowering medicine. Some of the medicine names that contain metformin can be found here. https://www.healthdirect.gov.au/medicines/medicinal-product/aht,20727/metformin

Sodium Glucose co transporter 2 (SGLT-2) inhibitors (Gliflozins)

SGLT-2 inhibitors are likely to be the medicine your doctor will advise if you have:

• heart disease
• multiple cardiovascular risk factors (such as a strong family history, high blood pressure and/or high cholesterol)
• kidney disease.

These tablets may be taken in addition to metformin and can be taken at the same time.

Gliflozins reduce the amount of glucose reabsorbed by the kidney so that it goes out in the urine instead of staying in the blood. They work in different ways to lower blood glucose levels.

Examples of gliflozins include Dapagliflozin(Forxiga) and Empagliflozin (Jardiance).

These medicines may not be suitable for you if you are on a low carbohydrate diet or if you drink a lot of alcohol. They are not suitable for people with severe kidney problems. If you have moderate kidney problems or are over 75 years of age the dose may need to be adjusted by your doctor or nurse practitioner.

Side effects can include genital thrush, urinary tract infections (UTIs) and dehydration.

Diabetic ketoacidosis is a rare but serious side effect. The chance of developing this is higher if you are sick with gastro or a viral infection, are dehydrated or you are fasting for surgery or a procedure such as a colonoscopy.

If you are unwell and unable to eat or drink, if you are fasting for a procedure such as a colonoscopy, discuss with your diabetes team if you need to stop taking these medicines.

This medication does not cause hypoglycaemia and can be taken at any time with or without food. It is often taken with metformin.

Glucagon-like peptide receptor agonists (GLP-1 RA)

GLP-1RA medications are an injection which mimics the effect of a natural hormone made in your gut called an incretin. They are not insulin.

Examples of GP-1 RA medicines available in Australia to treat type 2 diabetes are Semaglutide (Ozempic), Dulaglutide (Trulicity) and Tirzepatide (Mounjaro).

Incretins are gut hormones which are released whenever we eat carbohydrate foods. They send a message to the pancreas to produce more insulin. People with type 2 diabetes may not make as much of this hormone or the incretins they do make are not as effective, so the pancreas doesn’t release enough insulin. Taking a GLP-1RA will increase the amount of insulin released after a meal and slow the emptying of the stomach (leaving you feeling full for longer).

These medications also reduce the amount of glucose produced by the liver.

This leads to improved blood glucose levels and some weight loss. GLP-1 RA medicines can also lower blood pressure and have been shown to have benefits for the kidneys and heart.

Some of the side effects of GLP-1RAs include nausea, headache, dizziness, weight loss, vomiting, diarrhoea and or constipation.

Tell your doctor immediately if you experience a rash or persistent abdominal pain or if the vomiting, diarrhoea, heartburn and/or stomach pains do not improve.

This medication comes in a pre-filled pen device and is injected into the fat layer under the skin of the tummy or the thigh.

The injection should be given once a week on the same day of the week. A diabetes educator, nurse practitioner or your doctor can teach you how to do this. If you forget you can give it the next day.

To avoid side effects, the dose should be increased slowly as prescribed.

To obtain GLP-1 RAs through the PBS you must have tried metformin and SGLT2 inhibitors first.

It is safe to take metformin, sulphonylurea tablets, and insulin at the same time if your diabetes practitioner prescribes it for you.

GLP1-RAs do not cause hypoglycaemia if taken alone. However, in combination with insulin or glucose lowering medicine in the class of sulphonylureas this is possible. Therefore, check your blood glucose levels and see your doctor regularly because your insulin and/or sulphonylurea doses may need to be reduced.

Over the last couple of years there has been a shortage of GLP-1RAs which has been frustrating and difficult for people who have been prescribed this medicine. If they become difficult to obtain again ask your diabetes team for advice. Do not buy imitation versions of these medicines as they are not effective and may be harmful.

Ozempic: https://www.ozempic.com/how-to-take/ozempic-pen.html

Trulicity: https://trulicity.lilly.com/how-to-use

Mounjaro: https://mounjaro.lilly.com/how-to-use-mounjaro

Dipeptidyl peptidase 4 (DDP-4) inhibitors (Gliptins)

DPP-4 is an enzyme which destroys incretins.

DPP4 inhibitors (Gliptins) are tablets which block this enzyme, so that incretins can work. Incretins are the gut hormones which send a message to the pancreas to release insulin when we eat carbohydrates and the blood glucose level rises.

They also reduce the amount of glucose released into the blood stream by the liver.

Some examples of Gliptins are Alogliptin (Nesina), Linagliptin (Trajenta), Saxagliptin (Onglyza), Sitagliptin (Januvia) and Vildagliptin (Galvus).

These tablets can be taken with or without food at the same time each day. It is safe to take metformin, sulphonylurea tablets, and insulin at the same time if your diabetes practitioner prescribes it for you.

Taken on their own, Gliptins do not cause hypoglycaemia (low blood glucose). However, in combination with insulin or sulphonylureas this is possible. Check your blood glucose levels and see your doctor regularly because your insulin and/or sulphonylurea doses may need to be reduced.

Side effects can include headaches, nausea, runny nose and sore throat.

In very rare instances, DPP4 inhibitors can cause pancreatitis

Seek urgent medical help if you develop a rash, hives, swelling to your face, lips, mouth, tongue or throat or abdominal pain.

The dose of Sitagliptin may need to be lowered if you have kidney problems. Vildagliptin and Saxagliptin should not be used if you have moderate or severe kidney impairment. Do not take Vildagliptin if you have liver problems.

There are several diabetes medicines available for people living with type 2 diabetes if your blood glucose levels become more difficult to keep in target. The medicines we have discussed are the ones most used.

The decision for which medicine to use should be individualised depending on your medical conditions and history. Your regular doctor or nurse practitioner will be able to get you started on the right one when they say “Your HbA1c is not what we were hoping for…”

Written by Eileen Collins (Credentialled Diabetes Educator – RN)