Drugs to reduce hyperglycaemia

Treatment methods for diabetes include: 1- Dietary 2- Lifestyle modification. 3- Medications: A- Oral antidiabetic drugs B- Injected therapies.

Drugs to reduce hyperglycaemia

Oral hypoglycemic drugs
1- Biguanides 2- Sulphonylureas 3- Alpha-glucosidase inhibitors 4-Thiazolidinediones (TZD) 5- Incretin-based therapies: A- DPP-4 inhibitors B- GLP-1 receptor agonists 6- SGLT2 inhibitors

Biguanides

Mechanism of action

Clinical use

metformin is cleared by the kidneys, it can accumulate in renal impairment, so the dose should be halved when estimated glomerular filtration rate (eGFR) is 30–45 mL/min/1.73 m2, and it should not be used below an eGFR of 30 mL/min/1.73 m2.

It should be omitted temporarily during any acute illness where acute kidney injury is possible, as this greatly increases the risk of lactic acidosis; insulin treatment may be required while metformin is withheld. Its use is also contraindicated in patients with significantly impaired hepatic function and in those who drink alcohol in excess, in whom the risk of lactic acidosis is significantly increased.


Sulphonylureas
Sulphonylureas are ‘insulin secretagogues’, i.e. they promote pancreatic β­cell insulin secretion. Similar to metformin, the long­term benefits of sulphonylureas in lowering microvascular complications of diabetes were established

Mechanism of action

Sulphonylureas act by closing the pancreatic β­cell ATP ­sensitive potassium (KATP) channel, decreasing K+ efflux, which ultimately triggers insulin secretion.

Clinical use

Alpha-glucosidase inhibitors
The α-­glucosidase inhibitors delay carbohydrate absorption in the gut by inhibiting disaccharidases.Acarbose and miglitol are available and are taken with each meal. Both lower post­-prandial blood glucose and modestly improve overall glycaemic control.

Thiazolidinediones

These drugs (also called TZDs, ‘glitazones’ or PPARγ agonists) bind and activate peroxisome proliferator­ activated receptor­γ

TZDs enhance the actions of endogenous insulin, both directly (in the adipose cells) and indirectly (by altering release of ‘adipokines’, such as adiponectin, which alter insulin sensitivity in the liver). Plasma insulin concentrations are not increased and hypoglycaemia does not occur.

Clinical use

TZDs have been prescribed widely since the late 1990s but a number of adverse effects have become apparent and their use has declined. One popular TZD, rosiglitazone, was reported to increase the risk of myocardial infarction and was withdrawn in 2010.


The other TZD in common use, pioglitazone, does not appear to increase the risk of myocardial infarction but may exacerbate cardiac failure by causing fluid retention, and recent data show that it increases the risk of bone fracture and possibly bladder cancer.

Incretin-based therapies: DPP-4 inhibitors and GLP-1 receptor agonists

The incretin effect is the augmentation of insulin secretion seen when a glucose stimulus is given orally rather than intravenously, and reflects the release of incretin peptides from the gut.The ‘gliptins’, or DPP­4 inhibitors, prevent breakdown and therefore enhance concentrations of endogenous GLP­1 and GIP.

Mechanism of action of GLP1

1- Increased satiety in the brain and decrease appetite. 2- Decrease gastric emptying and impaired carbohydrate absorption. 3- Decrease hepatic gluconeogenesis.

Unlike sulphonylureas, both incretin ­based therapies promote insulin secretion only when there is a glucose ‘trigger’ for it. Thus, when the blood glucose is normal, the insulin secretion is not augmented and so these agents do not cause hypoglycaemia.

SGLT2 inhibitors

Sodium and glucose transporter 2 inhibitors: 1- Dapagliflozin. 2- Canagliflozin. 3- Empagliflozin.

Glucose is filtered freely in the renal glomeruli and reabsorbed in the proximal tubules. SGLT2 is involved in reabsorption of glucose.

Inhibition results in approximately 25% of the filtered glucose not being reabsorbed, with consequent glycosuria. Although this helps to lower blood glucose and results in calorie loss and subsequent weight loss, the glycosuria does also lead to genital fungal infections.


Empagliflozin therapy resulted in a 35% reduction in cardiovascular mortality and a similar reduction in admissions to hospital with heart failure. Euglycaemic diabetic ketoacidosis (i.e. DKA not associated with marked hyperglycaemia) has been recognised as a rare complication of this class of drugs.