Metformin is the most commonly prescribed medication for the treatment of diabetes in the UK. It is also one of the most prescribed drugs overall in the UK. As with other drugs, it is possible to experience side effects during the treament or medicine may not be suitable. Metformin can commonly cause gastrointestinal side effects and this very often leads to switching to another drug. Although there are many type-2 diabetic drugs, patients would be offered metformin alternatives according to the national guidance on the management of type 2 diabetes. Today I will summarise metformin alternative drugs, which may be prescribed to type 2 diabetic patients who cannot tolerate metformin.
Summary of the post:
- What is metformin?
- Drug classification
- Licensed use
- Mechanism of action
- Why is metformin so popular?
- Metformin alternatives
Terminology found in this post
- Beta-cells: cells present in the pancreas, which produce insulin.
- Insulin: a hormone that allows glucose (sugar) to be used for energy in the body.
- Hypoglycaemia: low sugar ‘level.’
- Monotherapy: use of a single drug to treat a disease
- NICE (The National Institute for Health and Care Excellence): a public body that provides national guidelines to the public and healthcare professionals to improve health.
- The official guide on type-2 diabetes management: document produced by NICE for healthcare professionals in the UK, which recommends treatment for type-2 diabetes.
What is metformin?
Metformin is generally perceived as a ‘gold standard for the treatment of diabetes. Metformin is the only type 2 diabetic drug which is classified as a biguanide. Newly diagnosed type 2 diabetic patients, particularly overweight, who failed to implement lifestyle changes to control sugar ‘level’ in the body, usually get prescribed metformin. However, the official guide on the management of type 2 diabetes in adults recommends using metformin as a first-line drug in the treatment of type 2 diabetes.
Metformin can be prescribed on its own or in conjunction with other type-2 diabetes drugs. Drugs reviewed in this post can be used as an alternative treatment to metformin or in conjunction with metformin if patients fail to control their condition.
Metformin can also be prescribed to treat polycystic ovary syndrome.
Metformin: mechanism of action
Metformin has several actions which cause control of glucose (sugars) in the body. It mainly reduces the production of glucose in the liver and stops glucose from being absorbed in the intestine. Metformin also increases glucose uptake, particularly in skeletal muscle. Lastly, metformin improves sensitivity to insulin (Wiernsperger & Bailey, 1999), which regulates body sugar levels. Metformin does not increase insulin release. Therefore there is no risk of hypoglycaemia with metformin unless used in combination with other anti-diabetic drugs.
1. Lifestyle changes
According to the twin cycle hypothesis, excess fat in the liver causes an excess supply of fat in the pancreas, which leads to impaired functioning of this organ. The pancreas produces insulin which is the key to sugar control in the body. Studies have confirmed that it is possible to achieve remission from type 2 diabetes by restricting calorie intake. Reduced intake of calories not only decreases the production of glucose but also contributes to weight loss.
The most crucial factor which determines the success of remission from diabetes is the duration of the condition. Patients who had type 2 diabetes for less than four years achieved a fast reduction in blood glucose. On the other hand, only 50% of patient with type 2 diabetes (8 years or longer) reached normal sugar levels with a calorie-restricted diet (Taylo, 2020).
2. Modified-release metformin alternative to standard metformin
Modified release metformin (also knows as slow or prolonged release) can be offered to patients who cannot tolerate standard release metformin. Modified-release metformin provide better gastrointestinal tolerability (Jabbour & Ziring, 2011). Modified-release metformin can be offered on a trial basis instead of standard release metformin to patients who experience gastrointestinal side effects (NICE, 2020).
Modified-release metformin is usually taken once or twice daily, whlist standard, immediate-release metformin can be taken up to three times a day.
Popular brands of modified-release metformin:
- Sukkarto SR
- Glucophage SR
- Yaltormin SR
A NICE guide on the management of type 2 diabetes (NICE, 2020) recommends mainly three alternatives (classes) of drugs:
- a dipeptidyl peptidase‑4 (DPP‑4) inhibitor (gliptins) or
- pioglitazone or
- a sulfonylurea
3. Sulfonylurea type 2 diabetic drugs
Sulfonylurea drugs are considered as metformin alternatives. Commonly sulfonylureas are used together with metformin to control diabetes. By far, the most widely used sulfonylurea in the UK is gliclazide (OpenPrescribing.net, 2021).
Gliclazide vs metformin: what is the difference?
Sulfonylureas like gliclazide increase insulin release from pancreatic beta cells. Therefore this class of anti-diabetic drugs is only effective pancreatic cells are still present (Sola et al., 2015). Diabetes is a condition which is characterised by progressive loss of insulin-producing β-cells (Weir GC, Bonner-Weir, 2013).
Overall, gliclazide has a distinct mechanism of action from metformin.
Gliclazide vs metformin: common side effects
British National Formulary (BNF) lists the following possible common side effects:
- Abdominal pain
- Hypoglycaemia (low sugar level)
Some common side effects (gastrointestinal) for gliclazide are therefore very similar to metformin. As previously discussed , hypoglycaemia is not a side effect of metformin treatment.
There are other Sulfonylureas licensed in the UK to treat type-2 diabetes, but less commonly prescribed. These include:
Three most commonly used gliptins in the UK* (OpenPrescribing.net), in order, are:
- Sitagliptin (brand name: Januvia)
- Linagliptin (brand name: Trajenta)
- Alogliptin (brand name: Vipidia)
- Saxagliptin (brand name: Onglyza)
*rank based on prescribing information in England (period time: Mar ’20—Feb ’21)
Gliptins: mechanism of action
In simple terms, gliptins (scientific name: DPP-4 inhibitor) enhance insulin secretion in response to glucose presence. Gliptins also reduce the production of glucose by the liver. Gliptins have shown to improve glycaemia (presence of sugars in the body) with a low risk of hypoglycaemia (Ahrén et al., 2011).
Gliptins: side effects
Gliptins are generally well tolerated. Side effects differ between each gliptin. The table below list very common and common side effect for each gliptin:
|No common side effect|
Gastrooesophageal reflux disease
Increased risk of infection
* when used in combination with other anti-diabetic drugs, particularly with insulin and sulphonylurea, but not when used with metformin
** when used in combination with metformin and sulphonylurea
The low frequency of side effects explains the popularity of both sitagliptin and linagliptin, both prescribed in almost similar volumes.
One of the uncommon side effects associated with which patients need to be aware of (its symptoms) is the risk of acute pancreatitis (inflammation of the pancreas), which is mainly characterised by persistent, severe abdominal pain. The estimated risk of acute pancreatitis with gliptins is one to two cases for every 1000 patients treated for two years.
5. Metformin alternatives: Pioglitazone
Pioglitazone is the only thiazolidinedione licensed currently in the UK for the treatment of diabetes. Although considered as a metformin alternative, pioglitazone is not commonly used on its own to treat diabetes. Pioglitazone, however, can be used on its own or in combination with other anti-diabetic drugs like metformin or sulfonylurea.
Pioglitazone is considered the second or third-line treatment of type 2 diabetes, usually when metformin is not tolerated or cannot be used (eMC, 2020).
Pioglitazone: side effects
Common side effects associated with pioglitazone use (ibid):
- upper respiratory tract infection
- hypo-aesthesia (loss of sensation of part of the body)
- visual disturbance (usually at the beginning of the treatment)
- fracture bone (clinical trial in which 8100 patients took pioglitazone observed higher rates in bone fractures by women who took pioglitazone (2.6%), but not men).
Additionally, pioglitazone was subject to drug safety update: Pioglitazone: risk of bladder cancer. According to this update and based on scientific evidence, pioglitazone is associated with a small increased risk of bladder cancer. There was no evidence to suggest that the same is observed in humans during the approval process for pioglitazone’s license.
As the above document suggests, the evidence for increased risk of cancer came firstly from animal studies. European review on pioglitazone suggests that the benefit of the treatment outweighs the risk, which is ‘likely to be small.
There are other special warning related to pioglitazone (eMC, 2020):
- Causing fluid retention, which may exacerbate or precipitate heart failure.
- Caution use with insulin in elderly, because of increased risk of serious heart failure.
- Rare incidents of liver dysfunction.
- Weight gain.
- Eye disorders (worsening diabetic macular oedema with decreased visual acuity – ability to recognise shapes)
It is clear from the above why pioglitazone is not considered first-line treatment of type 2 diabetes. When looking at prescribing statistic for pioglitazone, it is clear that this drug is becoming a less popular choice in the management of type-2 diabetes.
6. Repaglinide: the forgotten metformin alternative
Interestingly, the NICE guide on type-2 diabetes management mentions repaglinide as a metformin alternative.
As with other options, repaglinide is recommended when metformin is not tolerated. The NICE guide suggests, repaglinide is equally effective as metformin and cost-effective.
Repaglinide common side effects:
- Abdominal pain
Repaglinide is rarely used in the UK.
7. Metformin alternatives: GLP-1 agonists
Although the ‘official guide does not suggest drug(s) listed below as metformin alternatives. Each drug however is licensed as monotherapy for type-2 diabetes when metformin is not tolerated or contraindicated, alone or in combination with other anti-diabetic drugs.
Glucagon-like peptide-1 receptor (GLP-1) agonists a newer class of anti-diabetic drugs. All GLP-1 agonists come in the form of injectable pens, except for semaglutide, which is also available in the form of tablets.
GLP-1 agonists mechanism of action
GLP-1 agonists have multiple effects on the body (Collins & Costello, 2021):
- stimulate insulin secretion
- reduce the production of glucagon, which production of glucose in the liver
- decrease beta-cell death in the pancreas and promote an increase in their numbers
GLP-1 agonists: common side effects
Common side effects differ between each GLP-1 agonists. Some side effects, for example, gastrointestinal side effects, are similar within the class of GLP-1 agonists. Dulaglutide (the most common GLP-1 agonists) is associated with the following common side effects (eMC, 2021):
- Hypoglycaemia (when used in combination with other anti-diabetic drugs)
- Nausea, diarrhoea, vomiting, abdominal pain
- Decreased appetite
- Dyspepsia (indigestion)
- Flatulence (gas production)
GLP-1 agonists have shown to promote weight loss, lower blood pressure and total cholesterol (ibid).
GLP-1 agonists prescribed in the UK (in order of popularity*):
- Dulaglutide (brand name: Trulicity)
- Liraglutide (brand name: Victoza)
- Semaglutide (brand name: Ozempic)
- Exenatide (brand name: Byetta)
- Lixisenatide (bran name: Lyxumia)
* based on items prescribed in England between Mar ’20—Feb ’21. Data source: OpenPrescribing.net
Dulaglutide, liraglutide and semaglutide are considerably more prescribed than the remaining two drugs.
Conclusion: What is the best metformin alternative drug?
Patients who cannot tolerate or take metformin have a great choice of metformin alternative drugs. The most reasonable approach to initial treatment would be to try a modified-release form of metformin if gastrointestinal side effects are troublesome.
As we learned from this post, many metformin alternatives may cause similar gastrointestinal side effects as metformin. Introducing a healthy lifestyle (exercise and diet control) can have a significant impact on glycaemic management. The selection of the best treatment is based on each patient’s individual circumstances.
Ahrén B, Schweizer A, Dejager S, Villhauer EB, Dunning BE, Foley JE (2011). Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans. Diabetes Obes Metab. 2011 Sep;13(9):775-83. doi: 10.1111/j.1463-1326.2011.01414.x. PMID: 21507182. Available at: https://doi.org/10.1111/j.1463-1326.2011.01414.x Accessed on 04/05/2021
Collins L, Costello RA (2021). Glucagon-like Peptide-1 Receptor Agonists. [Updated 2020 Jun 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551568/ Accessed on 05/05/2021
eMC (2020). SmPC: Pioglitazone 15mg tablets. Available at: https://www.medicines.org.uk/emc/product/7407/smpc Accessed on 05/05/2021
eMC (2021). SmPC: TRULICITY 0.75 mg solution for injection in pre-filled pen. Available at: https://www.medicines.org.uk/emc/product/7482/smpc#UNDESIRABLE_EFFECTS Accessed on 05/05/2021
Jabbour S, Ziring B (2011). Advantages of extended-release metformin in patients with type 2 diabetes mellitus. Postgrad Med. 2011 Jan;123(1):15-23. doi: 10.3810/pgm.2011.01.2241. PMID: 21293080. Available at: https://doi.org/10.3810/pgm.2011.01.2241 Accessed on 01/05/2021
NICE (2020). Type 2 diabetes in adults: management. Available at: https://www.nice.org.uk/guidance/ng28/chapter/Key-priorities-for-implementation Accessed on 01.05/2021
Sola D, Rossi L, Schianca GP, et al (2015). Sulfonylureas and their use in clinical practice. Arch Med Sci. 2015;11(4):840-848. doi:10.5114/aoms.2015.53304 Available at: https://dx.doi.org/10.5114%2Faoms.2015.53304 Accessed on 02/05/2021
Taylor, R (2020), Newcastle University, Newcastle, UK. Type 2 diabetes and remission: practical management guided by pathophysiology (Review). J Intern Med 2020. Available at: https://doi.org/10.1111/joim.13214 Accessed on 01/05/2021
Weir GC, Bonner-Weir S (2013). Islet β cell mass in diabetes and how it relates to function, birth, and death. Ann N Y Acad Sci. 2013 Apr;1281(1):92-105. doi: 10.1111/nyas.12031. Epub 2013 Jan 30. PMID: 23363033; PMCID: PMC3618572. Available at: https://doi.org/10.1111/nyas.12031 Accessed on 01/05/2021
Wiernsperger NF, Bailey CJ (1999). The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs. 1999;58 Suppl 1:31-9; discussion 75-82. doi: 10.2165/00003495-199958001-00009. PMID: 10576523. Available at: https://doi.org/10.2165/00003495-199958001-00009 Accessed on 01/05/2021