7 Best Alternatives to Metformin Reviewed

Metformin is not only one of the most prescribed drugs in the UK but also the most common medication used for the treatment of type 2 diabetes. Metformin is considered a first-line drug for the treatment of type-2 diabetes in adults (NICE, 2022). This recommendation explains the popularity of metformin. For some patients, metformin may not produce satisfactory results or side effects are troublesome. Patients may be prescribed alternatives to metformin instead or in addition to the current treatment.

What is metformin?

Metformin is classified as a biguanide type of drug. Metformin first-choice treatment in newly diagnosed type 2 diabetic patients, as recommended by a NICE guide, which advices prescribers on the management of diabetes (and all other conditions). Treatment with metformin usually follows unsuccessful changes in the lifestyle of an individual with failure to lower sugar levels in the body.

In the treatment of diabetes, metformin can be used on its own or in combination with other antidiabetic drugs. Drugs alternatives to metformin reviewed in this post are very often used alongside metformin or instead of metformin, very often when patients do not accept the side effects caused by metformin.

Metformin is also licensed to treat polycystic ovary syndrome.  

Metformin: mechanism of action

The main mechanism of action by which metformin improves glucose (sugar) in the body is a reduction in the production of glucose in the liver and a reduction of glucose absorption in the intestine (how much glucose gets inside the body). Metformin increases glucose uptake (utilisation) in muscles and improves insulin sensitivity, a hormone which regulates body sugar levels (Wiernsperger & Bailey, 1999).

Metformin does not cause insulin release, which means it cannot cause hypoglycaemia (low sugar level) unless used together with other antidiabetic drugs.  

Drugs alternative to metformin

Drugs alternative to metformin are reviewed according to NICE guidelines on the management of type 2 diabetes. This guide recommends prescribing information to doctors and other prescribers. This review focuses on first-line treatments of type 2 diabetes.

1. Modified-release metformin

Modified release metformin (MR) also called slow or prolonged release (PR) can be offered to patients who cannot tolerate standard release metformin, for example, due to side effects. MR metformin usually offers better gastrointestinal tolerability (Jabbour & Ziring, 2011). MR metformin may be prescribed on a trial basis, instead of immediate release metformin to patients who experience gastrointestinal side effects (NICE, 2020). Standard-release metformin is the first choice as it offers a low cost of treatment to patients. Patients who start treatment with standard-release metformin should have their dose increased over a few weeks to minimise the risk of gastrointestinal side effects (NIC, 2022).

The latest guide on the management of type 2 diabetes (NICE, 2022) recommends four classes of drugs alternative to metformin when treatment is not tolerated or contraindicated with metformin.  

• a dipeptidyl peptidase‑4 (DPP‑4) inhibitor (gliptins) or
• pioglitazone or
• a sulfonylurea
• an SGLT2 inhibitor (patients with chronic heart failure or established atherosclerotic cardiovascular disease or patients who have a high risk of developing the cardiovascular disease)

2. DPP-4 inhibitors (Gliptins) as metformin alternatives

The four most commonly used gliptins in the UK* (OpenPrescribing.net, 2022), in order, are:

• Sitagliptin (brand name: Januvia)
• Linagliptin (brand name: Trajenta)
• Alogliptin (brand name: Vipidia)
• Saxagliptin (brand name: Onglyza)

Gliptins: mechanism of action

Gliptins enhance the secretion of insulin in response to glucose presence. Gliptins reduce also the production of glucose by the liver. Gliptins have been shown to improve glycaemia (the 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 lists very common and common side effects for each gliptin:

Sitagliptin	Linagliptin	Alogliptin
Headache Hypoglycaemia*	No common side effect Hypoglycaemia**	Abdominal pain Gastroesophageal reflux disease Diarrhoea Skin itchiness Rash Headache Hypoglycaemia Increased risk of infection Skin reactions

 

 * when used in combination with other antidiabetic drugs, particularly with insulin and sulphonylurea, but not when used with metformin

** when used in combination with metformin and sulphonylurea

One of the uncommon side effects linked to the use of gliptins is a 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 who are treated for two years.

3. Sulfonylureas as an alternative to metformin

Sulfonylureas are commonly used together with metformin to control diabetes, however, they can also be prescribed on their own. By far the most commonly used sulfonylurea in the UK is gliclazide (OpenPrescribing.net, 2021).

Gliclazide vs metformin: what is the difference?

Sulfonylureas like gliclazide increase the release of insulin from pancreatic cells, therefore this class of antidiabetic drugs is only effective when pancreatic cells are still present (Sola et al., 2015). Sulfonylurea’s mechanism of action is therefore different from metformin. Diabetes is a condition which is characterised by the progressive loss of insulin-producing β-cells (Weir GC, Bonner-Weir, 2013).

Gliclazide vs metformin: common side effects

British National Formulary (BNF) lists the following possible common side effects:

• Abdominal pain
• Diarrhoea
• Hypoglycaemia (low sugar level)
• Nausea

Metformin and gliclazide have some side effects (gastrointestinal) in common.

Other sulfonylureas (less commonly prescribed) licensed in the UK for the treatment of type 2 diabetes include:

• Glibenclamide
• Glimepiride
• Glipizide
• Tolbutamide

4. Alternatives to metformin: pioglitazone

Although considered as an alternative to metformin, overall pioglitazone is not commonly used on its own in the treatment of diabetes. Pioglitazone can also be used in combination with other anti-diabetic drugs like metformin or sulfonylurea.

Pioglitazone is considered a second-line treatment for type 2 diabetes, usually when metformin is not tolerated or cannot be used (NICE, 2022). Pioglitazone is the only thiazolidinedione licensed in the UK for the treatment of diabetes.

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)
• fractured bone (clinical trial in which 8100 patients took pioglitazone observed higher rates of bone fractures in women who took pioglitazone (2.6%), but not men).

Pioglitazone was subject to a 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 approval 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 warnings related to pioglitazone (eMC, 2020):

• pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure.
• pioglitazone should be used with caution together with insulin in the elderly, because of the increased risk of heart failure. 
• Rare incidents of liver dysfunction.
• Weight gain
• Eye disorders (worsening diabetic macular oedema with decreased visual acuity – ability to recognise shapes) 

5. SGLT2 inhibitors ‘flozin’

SGLT2 inhibitors prescribed in the UK include canagliflozin, dapagliflozin, empagliflozin and ertugliflozin with the latter being much less commonly used in the treatment of type 2 diabetes.

SGLT2 inhibitors reduce glucose absorption in the body.

SGLT2 inhibitors are recommended by NICE guidelines in addition to metformin in people with:

• chronic heart failure or established atherosclerotic cardiovascular disease
• high risk of developing cardiovascular disease

If patients from any of the two above groups cannot tolerate metformin, an SGL2 inhibitor would be a preferred first-line choice due to proven cardiovascular benefits.

Side effects for SGL2 inhibitors may include:

• Vulvovaginitis (inflammation of the vagina)
• Balanoposthitis (inflammation of the penis)
• urinary tract infection (UTI)
• Constipation
• Nausea

Common side effects vary slightly between each SGLT2 inhibitor.

SGL2 inhibitors were subject to some safety alerts:

• Increased risk of diabetic ketoacidosis (DKA), which is considered a rare side effect, but potentially fatal.
• Need to monitor blood ketone levels in patients during treatment interruption for surgical procedures or acute serious medical illness
• Risk of Fournier’s gangrene (necrotising fasciitis of the genitalia or perineum), a potentially life-threatening infection
• possible increased risk of lower limb amputation (mainly toes) with canagliflozin

6. GLP-1 agonists as metformin alternative

Although the NICE guide does not suggest GLP-1 antagonists as metformin alternatives, each drug from this class is licensed as monotherapy (treatment with one drug) for type-2 diabetes when metformin is not tolerated or contra-indicated, alone or in combination with other antidiabetic drugs.

Glucagon-like peptide-1 receptor (GLP-1) agonists are a newer class of anti-diabetic drugs. All GLP-1 agonists come in the form of injectable pens, except 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 are different between each GLP-1 agonist. Some side effects, for example, gastrointestinal side effects are similar within the class of GLP-1 agonists. Dulaglutide 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)
• Constipation
• Fatigue

GLP-1 agonists have been shown to promote weight loss and 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.

7. Lifestyle changes

According to the twin cycle hypothesis excess fat in the liver cause 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 important factor which determines the success of remission from diabetes is the duration of the condition. Patients with type 2 diabetes of fewer than 4 years achieved a fast reduction in blood glucose On the other hand, only 50% of patients with type 2 diabetes (8 years or longer) achieved normal sugar levels with a calorie-restricted diet (Taylo, 2020).

Conclusion: What is the best alternative to metformin?

Patients who cannot tolerate or take metformin have a good choice of alternative drugs. The most common approach to the initial treatment of type 2 diabetes would be to try a modified-release form of metformin if gastrointestinal side effects of metformin are troublesome. As we learned from this post many alternatives to metformin may cause similar, gastrointestinal side effects. Introducing a healthy lifestyle (exercise and diet control) can have a significant impact on glycaemic control.

References:

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 10/10/2022

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 10/10/2022

eMC (2020). SmPC: Pioglitazone 15mg tablets. Available at: https://www.medicines.org.uk/emc/product/7407/smpc Accessed on 10/10/2022

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 10/10/2022

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 10/10/2022

NICE (2022). Type 2 diabetes in adults: management. Available at: https://www.nice.org.uk/guidance/ng28/chapter/Recommendations#first-line-drug-treatment Accessed on 09/10/2022

Openprescribing.net (2022). prescribing information in England (period time: Mar ’20—Feb ’21). Available at: https://openprescribing.net/bnf/ Accessed on 10/10/2022

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 09/10/2022

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 09/10/2022

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 11/10/2022

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 11/10/2022