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7 Best Metformin Alternatives For Type 2 Diabetes

7 Best Metformin Alternatives For Type 2 Diabetes

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 treatment, 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.

  ACTOPLUS MET 
GLOCOPHAGE
GLYCOMET
ACTOS
DUETACT
PRANDIN

Today I will summarise Metformin alternative drugs, which may be prescribed to type 2 diabetic patients who cannot tolerate Metformin.
Terminology Found In This Post

What Is Metformin?

Metformin is generally perceived as a ‘gold standard for the treatment of diabetes. Metformin is the only type 2 diabetic drug that 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 or buy 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 hypoglycemia with Metformin unless used in combination with other anti-diabetic drugs.

Metformin Alternatives

1. Lifestyle Changes

Lifestyle Changes

Studies have confirmed that it is possible to achieve remission from type 2 diabetes by restricting calorie intake.

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.

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 patients 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 known as slow or prolonged release) can be offered to patients who cannot tolerate standard release Metformin. Modified-release Metformin provides 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, whilst 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 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 that is characterized 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
  • Diarrhea
  • Hypoglycemia (low sugar level)
  • Nausea

Some common side effects (gastrointestinal) for Gliclazide are therefore very similar to Metformin. As previously discussed, hypoglycemia 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:

  • Glibenclamide: Glibenclamide is a prescription-only drug. It is commonly known as Glyburide in the USA. Diabeta is the most common name for this medicine.
  • Glimepiride: Glimepiride is less preferred than Metformin as it can lead to weight gain. It is not possible to buy Glimepiride over the counter. The most common Glimepiride brand is Amaryl.
  • Glipizide: Glipizide is often confused with Glibenclamide. The two drugs are different. Glipizide’s most common brand is Glucotrol. It was, however, withdrawn in October 2021 in the UK.
  • Tolbutamide: This is a fast-acting Sulfonylureas. The common brand name of Tolbutamide is Orinase. 

4. Gliptins

Gliptins

As per the statistics of openprescribing.net in the period between March 2020 to February 2021, the most commonly used Gliptins drug is Sitagliptin. 

A lot of people buy Januvia, which is Sitagliptin’s most common brand.

The following three drugs were sold after that in the same order.

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

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 been shown to improve glycemia (presence of sugars in the body) with a low risk of hypoglycemia (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
Hypoglycemia*
No common side effect
Hypoglycemia**
Abdominal pain
Gastrooesophageal reflux disease
Diarrhea
Skin itchiness
Rash
Headache
Hypoglycemia
Increased risk of infection
Skin reactions

 

* 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 characterized 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

DUETACT

Pioglitazone tablets: 15mg, 30mg and 45mg.
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 warnings related to pioglitazone (eMC, 2020):

  • Causing fluid retention, which may exacerbate or precipitate heart failure
  • Caution use with insulin elderly, because of increased risk of serious heart failure
  • Rare incidents of liver dysfunction
  • Weight gain
  • Eye disorders(worsening diabetic macular edema with decreased visual acuity – ability to recognize shapes)

It is clear from the above why pioglitazone is not considered the first-line treatment of type 2 diabetes. When looking at prescribing statistics 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

PRANDIN

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:

  • Hypoglycemia
  • Abdominal pain
  • Diarrhea
  • 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 are 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 agonist. 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):

  • Hypoglycemia (when used in combination with other anti-diabetic drugs)
  • Nausea, diarrhea, vomiting, abdominal pain
  • Decreased appetite
  • Dyspepsia (indigestion)
  • Flatulence (gas production)
  • Constipation
  • Fatigue

GLP-1 agonists have been 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.

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 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

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

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