Type 2 diabetes medications
Advice for patients

Type 2 Diabetes Medications Guide

Type 2 diabetes is a common condition affecting around 3.5 mln people in the UK (Diabetes UK, 2019). In this post, I will discuss the most common type 2 diabetes medications used in the UK, reflecting current guidelines in the management of this condition. In relation to each drug, I will focus mainly on:

  • Mechanism of action
  • Common side effects
  • Any essential and relevant information about the drug

The following type 2 diabetes medications will be discussed:

  • Metformin
  • Sulphonylurea
  • Gliptins (DPP-4 inhibitors)
  • SGLT2 inhibitors
  • GLP-1 mimetics (Incretin mimetics)
  • Pioglitazone
  • GLP-1 mimetics

In the final part of this post, I listed the most common type 2 diabetes drugs prescribed in the UK (prescribing information based on the year 2019).

What is type 2 diabetes?

Type 2 diabetes is a chronic condition characterised by high concentration (level) of glucose (sugar) in the blood caused by decreased production of insulin and reduced capacity to use the insulin effectively. Insulin is a hormone produced by the pancreas, which has a broad role, including the promotion of the uptake of glucose from the blood into the liver, muscle cells, and fat cells.

Type 2 diabetes is related to:

  • Obesity
  • Lack of physical activity
  • High blood pressure
  • High cholesterol levels

Type 1 vs Type 2 diabetes medications

Type 2 diabetes medications: treatment recommendations

Type 2 diabetes is managed in a step up manner, which means patients start the treatment with one drug (monotherapy), and if diabetes is not controlled, patients move towards combination therapy of two or more drugs.

Diabetic patients have HbA1c measured with a blood test to check average sugar levels for the last 2-3 months. Initially, this is done every 3-6 months, and once therapy is stable every 6 months (recommendation).

Type 2 diabetes: newly diagnosed patients

Unless contra-indicated a newly diagnosed patients are usually started on metformin (NICE, 2019).

The aim of the treatment is to keep an HbA1c level of 48 mmol/mol (6.5%) or below.

If metformin fails to control type 2 diabetes, the addition of another drug is considered (combination therapy). There are several different type 2 diabetes medications which can be added at this stage, including:

  • Sulphonylurea DPP-4 inhibitor (gliptins)
  • Pioglitazone
  • SGLT2 inhibitor

The aim of the treatment is to aim for an HbA1c level of 53 mmol/mol (7.0%) or below.

If a combination of two different antidiabetic drugs fails to deliver satisfactory results, triple therapy is considered. Three different drugs are taken at the same time, including:

  • Metformin and DPP-4 inhibitor and Sulphonylurea
  • Metformin and pioglitazone and Sulphonylurea
  • Metformin and pioglitazone and Sulphonylurea or SGLT2 inhibitor

Insulin based treatment can also be considered at the stage of type 2 diabetes management.

When triple therapy fails to control diabetes, a GLP-1 mimetic can be considered as a part of triple therapy with metformin and Sulphonylurea in obese patients with BMI over 35 kg/m2 or patients with BMI below 35 kg/m2 in whom insulin therapy is not recommended, for example, due to occupational reasons. 

Type 2 diabetes medications summary
Type 2 diabetes medications summary. Druggist.Online

Type 2 diabetes medications

1. Metformin

Metformin is considered a ‘gold standard’ treatment in the management of type 2 diabetes due to its effectiveness and relatively good safety profile (side effects).

Metformin: mechanism of action

Metformin:

  • reduces the production of glucose (sugar) in the liver
  • reduces the absorption of glucose (how much glucose gets into the body)
  • increase glucose use in different tissues in the body

Metformin does not cause insulin release and consequently does not cause hypoglycaemia (low sugar level). 

Additionally, metformin does not cause a weight gain, which is a possible side effect with other antidiabetic drugs.

Metformin is the most common type 2 diabetic medication used in the UK and one of the most commonly prescribed drugs in the UK

Metformin: common side effects

The most common side effects associated with metformin use include:

  • gastro-intestinal side effects, including:
    • nausea, vomiting diarrhoea
    • abdominal pain
    • loss of appetite

Gastro-intestinal side effects usually happen at the beginning of the treatment. A slow increase in metformin dose (number of tablets taken) is typically recommended to minimise GI side effects. Additionally, it is recommended to take metformin with or after food.  

Read product information leaflet to learn more about possible side effects.

Metformin comes in the form of tablets. Modified release metformin (slow release) is recommended when standard metformin is not tolerated by a patient.

2. Sulphonylurea

Sulphonylureas work by increasing the amount of insulin in the body (remember: insulin helps the body to use glucose) by two different mechanisms (Sola et al, 2015):

  • Increase insulin secretion (release)
  • Decrease clearance (removal) of insulin by the liver

Because of its mechanism of action, Sulphonylureas will only work if pancreatic β-cells are present. The role of β-cells is to release insulin. In diabetes, reduction of β-cells is observed on the diagnosis of type 2 diabetes, which usually progresses as the disease progress (Lencioni et al, 2008).

Sulphonylureas available in the UK for the management of type 2 diabetes include:

  • glibenclamide
  • gliclazide 
  • glimepiride
  • glipizide
  • tolbutamide

The most common (by far) sulphonylureas used in the UK is gliclazide.

Sulphonylureas can be used on their own or in combination with another type 2 diabetes medication.

Gliclazide: common side effects

The most common side effect associated with gliclazide use is hypoglycaemia (low sugar level). Patients need to beware of hypoglycaemia symptoms.

Other common side effects include:

  • diarrhoea,
  • nausea, and
  • abdominal pain

Gliclazide can contribute to weight gain, although it is not listed side effect of this medication.  

Read product information leaflet to learn more about possible side effects.

3. Gliptins (DPP-4 inhibitors)

In order of popularity, the most common gliptin drugs used are:

  • Sitagliptin (brand name: Januvia)
  • Linagliptin (brand name: Trajenta)
  • Alogliptin (brand name: Vipidia)
  • Saxagliptin, much less popular (brand name: Onglyza)

All of the above drugs belong to a class of medicines called dipeptidyl peptidase 4 (DPP-4) inhibitors. DDP-4 increases the level of two hormones GLP-1 and GIP, whose role is to increase insulin production and release by the pancreas and consequently improve the use of the glucose in the body. Additionally, GLP-1 decreases the secretion of glucagon (another hormone) and reduces the production of glucose in the liver and improves the amount of glucose that is present in the blood.

Gliptins can be used on their own (monotherapy) in the management of type 2 diabetes in patients whom metformin is not recommended (contraindicated or due to intolerance) or as dual or triple therapy with another type 2 diabetes drug.

Special warnings related to gliptins
  • There is a risk of acute pancreatitis developments when DPP-4 inhibitors are used (frequency not known). Patients need to be aware of symptoms of acute pancreatitis, such as severe pain in the stomach area. 
  • There is a risk of hypoglycaemia, mainly when gliptins are used with other drugs which are associated with hypoglycaemia such as sulphonylureas.
  • Severe anaphylactic reactions were observed in patients who used DPP-4 inhibitors
  • There is a risk of bullous pemphigoid (skin disease characterised by the formation of blisters) associated with the use of ‘gliptins’ (frequency not known).
DPP-4 inhibitors: common side effects

The possibility of common side effects differs between each brand of the DPP-4 inhibitor. The risk of hypoglycaemia is listed as a common side effect for all brands of ‘gliptins.’ Another common side effect associated with the use of the most common DPP-4 inhibitor, sitagliptin (Januvia), are headaches.  

Read product information leaflet to learn more about possible side effects.

4. SGLT2 inhibitors

SGLT-2 class of antidiabetic drugs is represented by 4 drugs licensed in the UK:  

  • Empagliflozin (brand name: Jardiance)
  • Dapagliflozin (brand name: Forxiga)
  • Canagliflozin (brand name: Invokana)
  • Ertugliflozin, the newest drug licensed in the UK (brand name: Steglatro)

SGLT-2 inhibitors have an unusual mechanism of action whereby increase excretion (removal) of glucose from the body in the urine by stopping reabsorption of sugars by kidneys

SGLT-2 inhibitors can be used on their own (when metformin is not recommended) or in combination with another type 2 diabetes medication.

SGLT2 inhibitors: important safety information

SGLT2 inhibitors: risk of diabetic ketoacidosis

MHRA issued a safety update for the whole class of SGLT2 inhibitors advising on the possible risk of diabetic ketoacidosis, which can be life-threatening, and fatal (cases reported). Patients treated with SGLT2 inhibitors need to be aware of symptoms of diabetic ketoacidosis and seek prompt medical advice should they experience any of the associated symptoms:

  • fast weight loss
  • vomiting or nausea
  • abdominal pain
  • fast and deep breathing
  • sleepiness
  • a sweet smell of the breath
  • a sweet or metallic taste in the mouth,
  • a different odour to urine or sweat

SGLT2 inhibitors: risk of serious infection

A second warning for this class of type 2 dietetic drugs include warning on possible risks of Fournier’s gangrene (a life-threatening infection). The patient should seek urgent medical attention if they experience the following symptoms:

  • Redness or swelling in the genital area
  • Fever and feeling sick (malaise)
  • Severe pain
SGLT2 inhibitors: other risks

Lower limb amputations

Long-term studies found increased cases of lower limb amputations (mainly toes) when canagliflozin was used; however, it is not known if this was related to the use of the drug.   

Increased cases of urinary tract infections

Increased cases of urinary tract infections were observed when patients were treated with SGLT2 inhibitors.

Volume depletion

Treatment with SGLT2 inhibitors may lead to a decrease in blood pressure; therefore, caution should be taken when SGLT2 inhibitors are used in some patients; for example, patients with cardiovascular disease.

SGLT2 inhibitors: common side effects

Empagliflozin is the most common SGLT2 inhibitor used. Common side effects listed include:

  • Hypoglycaemia (when used with Sulphonylurea or insulin)
  • Thirst
  • Itching of the skin
  • Rash
  • Increased urination
  • Urinary tract infections
  • Inflammation of the vulva and vagina
  • Vaginal yeast infection
  • Inflammation of the glans penis (balanitis)

Although he above side effects are listed as common side effects for an empagliflozin drug, many of them are shared across all SGLT2 inhibitors, for example, the risk of hypoglycaemia, urinary tract infections, candida (yeast) infections, and thirst.  

Read product information leaflet to learn more about possible side effects.

 5. Pioglitazone

Pioglitazone is licensed as monotherapy treatment I patient whom metformin is not recommended or intolerant or as part of dual or triple therapy in the management of type 2 diabetes.

Pioglitazone: mechanism of action

Pioglitazone improves insulin sensitivity (makes better use of the insulin produced), which increases glucose uptake (use) in the body and decreases the production of this sugar in the liver (Smith, 2001).

Pioglitazone: special warnings

Heart failure

Pioglitazone can cause fluid retention, which may precipitate or exacerbate (make worse) heart failure. Patients should report any sudden and quick changes in weight gain, swelling of legs, arms, or problems with breathing.

Bladder cancer

More frequent cases of bladder cancer were reported by patients on pioglitazone. Not all studies confirmed a statistically significant increased risk of bladder cancer. Patients need to seek urgent medical attention if they experience any symptoms of bladder cancer:

  • Blood in the pee
  • Problems with urination including the urgency to pee

Liver problem

Some liver problems have been observed in patients taking pioglitazone highlighted by increased liver enzymes. Patients need to be aware of symptoms of the liver problems, such as skin or eyes (white parts) going yellow.  

Pioglitazone: common side effects

Common side effects associated with pioglitazone use include:

  • Upper respiratory tract infections
  • Weight gain
  • Numbness
  • Visual disturbances (maybe temporary) related to changes in blood glucose
  • Increased risk of bone fractures (higher rates of bone fractures were seen in women takin pioglitazone)

Read product information leaflet to learn more about possible side effects.

6. GLP-1 mimetics (Incretin mimetics)

Glucagon-like peptide-1 receptor agonists (GLP-1 mimetics) are licensed as a monotherapy treatment for patients whom metformin is not tolerated or contra-indicate. However, the guideline on the management of type 2 diabetes reserves this class of drugs as combination treatment when other combination treatments have failed.

There is a number of GLP-1 mimetics licensed on the market. The main difference from a patient perspective is a different frequency of administration for each drug ranging from twice daily to once weekly administration.

GLP-1 mimetics come in the form of pre-filled injection pens.

The following GLP-1 mimetics are licensed in type 2 diabetes management:

  • Exenatide (brand name: Bydureon) – used once weekly
  • Exenatide (brand name: Byetta) – used twice daily
  • Liraglutide (brand name: Victoza) – used once daily
  • Lixisenatide (brand name: Lyxumia) – used once daily
  • Dulaglutide (brand name: Trulicity) – used once weekly
  • Semaglutide (brand name: Ozempic) – used once weekly

GLP-1 mimetics increase insulin release by acting as a naturally occurring incretin hormone (GLP-1) in the body. Other effects of this class of drugs include:

  • The appetite regulation
  • Lowering of glucagon secretions. Glucagon increases the production of glucose in the liver. 
  • Delay in gastric emptying (food stays in the stomach for longer). One of the benefits of GLP-1 mimetic is weight loss, as confirmed by results from clinical trials. One GLP-1 mimetic is licensed as a weight loss product in the UK under the brand name of Saxenda. Read more.
GLP-1 mimetics: special warnings

An episode of acute pancreatitis has been observed in patients using GLP-1 mimetics. Patients need to be aware of symptoms of acute pancreatitis, such as severe pain in the stomach area.

Increased risk of hypoglycaemia exists when GLP-1 mimetics are used with other drugs, which can cause hypoglycaemia.

GLP-1 mimetics are associated with many gastro-intestinal side effects, including nausea, vomiting, and diarrhoea.

GLP-1 mimetics: common side effects

Common side effects associated with GLP-1 treatment may include:

  • Headaches
  • Dizziness
  • Nausea
  • Vomiting
  • Dyspepsia
  • Constipation
  • Flatulence
  • Abdominal discomfort
  • Fatigue
  • Loss of appetite

Read product information leaflet to learn more about possible side effects.

Most common type 2 diabetes medication in the UK

The table below shows the top 17 most common type 2 diabetes medication used in the UK and associated NET cost for each drug. The data below include only information for drugs prescribed in generic form. In other words, this information does not include drugs being prescribed as branded products, for example, metformin exists in different brands, although usually prescribed generically, it can be also be prescribed as a brand, for example, Glucophage. 

Drug nameDrug classItems prescribed in 2019Net cost to NHS (£)
1MetforminBiguanides22,372,71784,568,78
2GlizlacideSulphonylurea6,810,95717,813,500
3SitagliptinDPP-4 inhibitor2,473,55082,868,560
4LinagliptinDPP-4 inhibitor2,136,59762,033,017
5AlogliptinDPP-4 inhibitor1,339,67536,235,611
6EmpagliflozinSGLT2 inhibitor1,310,05750,385,451
7DapagliflozinSGLT2 inhibitor1,122,45944,113,485
8PioglitazoneThiazolidinedione751,7021,652,996
9GlimeprideSulphonylurea607,9431,608,306
10DulaglutideGLP-1 mimetic538,45240,425,544
11LiraglutideGLP-1 mimetic520,80753,128,718
12CanagliflozinSGLT2 inhibitor482,70119,579,656
13SaxagliptinDPP-4 inhibitor218,4916,777,607
14ExenatideGLP-1 mimetic122,29910,138,495
15SemaglutideGLP-1 mimetic78,4177,264,578
16LixisenatideGLP-1 mimetic45,9222,884,541
17GlipizideSulphonylurea31,345212,227

Druggist.Online, Prescribing information for the year 2019.

Data source: OpenPrescribing.net, EBM DataLab, University of Oxford, 2017

Type 2 diabetes management: a healthy diet and exercise

One of the most important factors of type 2 diabetes prevention and ‘treatment’ is weight loss management through dietary changes (low-calorie diets or carbohydrate restrictions) and exercise. In some cases, type 2 diabetes can be reversed, although there is limited information available which supports long term maintenance of weight loss in relation to the management of sugars in the body (Hallberg et al, 2019).

Conclusion

In the UK, several drugs are licensed for the management of type 2 diabetes. Metformin, a ‘gold standard’ treatment, has the best safety profile; however, patients who fail to make appropriate lifestyle changes will normally require combination therapy with two or more type 2 diabetes medications. As we learned from this post taking antidiabetic drugs is associated with many common side effects.

FAQ

What is the most common diabetes medication?

In the UK the most common diabetes medication is metformin.

What is the best drug for diabetes?

Metformin is a common drug used in treatment of diabetes. It is one of the best anti-diabetic drugs due to its effectiveness and relatively good safety profile (side effects).

What drug can replace metformin?

There a number of drugs which are licensed for the treatment of diabetes instead of metformin. Some include Sulphonylurea, Gliptins (DPP-4 inhibitors), SGLT2 inhibitors, GLP-1 mimetics (Incretin mimetics), Pioglitazone and GLP-1 mimetics.

References:

Diabetes UK (2019). Diabetes Prevalence 2019. Available at: https://www.diabetes.org.uk/professionals/position-statements-reports/statistics/diabetes-prevalence-2019 Accessed on 07/02/2020

Hallberg SJ, Gershuni VM, Hazbun TL, Athinarayanan SJ. (2019) Reversing Type 2 Diabetes: A Narrative Review of the Evidence. Nutrients. 2019;11(4):766. Published 2019 Apr 1. doi:10.3390/nu11040766 Available at: https://dx.doi.org/10.3390%2Fnu11040766 Accessed on 06/03/2020

Lencioni C, Lupi R, Del Prato S. Beta-cell failure in type 2 diabetes mellitus. Curr Diab Rep. 2008;8(3):179–184. doi:10.1007/s11892-008-0031-0 Available at: https://doi.org/10.1007/s11892-008-0031-0 Accessed on 01/03/2020

NICE (2019). Type 2 diabetes in adults: management. Available at: https://www.nice.org.uk/guidance/NG28 Accessed on 06/03/2020

OpenPrescribing.net, EBM DataLab, University of Oxford, 2017 Available at: https://openprescribing.net/ Accessed on 06/03/2020

Smith U. Pioglitazone: mechanism of action. Int J Clin Pract Suppl. 2001;(121):13–18. Available at: https://pubmed.ncbi.nlm.nih.gov/11594239-pioglitazone-mechanism-of-action/ Accessed on 06/03/2020

Sola D, Rossi L, Schianca GP, et al. 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 01/03/2020

I am a community pharmacist working in UK. I blog about drugs, health and pharmacy.

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