66. Insulin and oral hypoglycaemic agents. Glucagon

Insulin

Preparations

• Rapid-acting insulin
  • Insulin lispro (Humalog®)
  • Insulin aspart (NovoRapid®)
• Short-acting insulin
  • Soluble insulin (Actrapid®)
• Intermediate-acting insulin
  • NPH insulin (Insulatard®)
• Long-acting insulin
  • Insulin glargine
  • Insulin detemir
• Mixed insulin

The different insulin preparations have different pharmacokinetic properties. This is accomplished by modifying the insulin or by suspending insulin in certain solutions. The preparations are almost always given subcutaneously.

Most of the modified insulins (insulin analogues) differ from normal insulin by just a few amino acids. These small changes are enough to give the modified insulins different pharmacokinetic properties, and can make them act slower, longer, shorter or quicker. The only exception is NPH insulin, which is normal insulin in a suspension which causes the insulin to form crystals. Insulin is released slowly from the crystal.

Mixed insulin is a mix of short-acting insulin and intermediate-acting insulin.

The following table shows the pharmacokinetic properties of the different insulin preparations.

Insulin preparation	Onset of action	Peak of action	Duration of action
Rapid-acting insulin	5 – 30 min	30 min – 3 hours	3 – 5 hours
Short-acting insulin	30 min	2,5 – 5 hours	4 – 24 hours
Intermediate-acting insulin	1 – 2 hours	4 – 12 hours	14 – 24 hours
Long-acting insulin	1,5 – 4 hours	No peak	24 hours

Indications

• Type 2 diabetics who don’t achieve sufficient glycaemic control with oral antidiabetic drugs
• Type 2 diabetics who get pregnant
  • All oral antidiabetics are contraindicated during pregnancy
• Type 2 diabetes with end-stage renal failure
• Hyperglycaemic emergency (IV soluble insulin)
• Type 1 diabetes
• Hyperkalaemia
  • Given together with glucose, as insulin causes potassium to enter cells

Regimens

This is not part of the curriculum.

There are multiple regimens of insulin therapy, each of which have advantages and disadvantages.

Regimen	Time and form of injection	Advantages	Disadvantages
Conventional insulin therapy	Twice daily injection of mixed insulin	Simple, requires minimal patient education	High compliance required as patients must adhere to a rigid diet and exercise plan
Intensive insulin therapy	1-2 x daily basal intermediate-acting insulin + bolus short acting before meals	Optimal glycaemic control, more flexibility in diet and exercise	Complex and time-consuming, high risk of hypoglycaemia, high compliance required
Basal supported oral therapy	Long-acting insulin before bedtime + oral antidiabetics	Improved glycaemic control compared to oral antidiabetic monotherapy	Increased risk for hypoglycaemia compared to oral monotherapy

Adverse effects

• Hypoglycaemia
• Lipodystrophy
• Allergic reactions (rare)
• Antibody formation against modified insulin (rare)

Avoiding hypoglycaemia when taking insulin is very difficult. The dosage of insulin must be adjusted according to the carbohydrate intake, amount of physical activity and during stress reactions like surgery or illness. If the dose of insulin is too small the glycaemic control is not optimal. If it is too large hypoglycaemia occurs. Most type 2 diabetics have experienced hypoglycaemia and would rather avoid it. For this reason, they often administer too little insulin rather than too much.

Lipodystrophy occurs if the subcutaneous injection is always performed at the same site and can result in a lump or atrophy of the skin at the site. This can result in impaired insulin absorption from the site.

Oral antidiabetic drugs

Oral antidiabetic drugs, sometimes called hypoglycaemic drugs, are drugs which are used to treat hyperglycaemia associated with type 2 diabetes mellitus. Their use should be limited to those who can’t reach satisfactory glycaemic control with lifestyle changes only.

The first-choice drug is metformin. If metformin is contraindicated another drug should be used. If metformin is not sufficient in reaching satisfactory glycaemic control another antidiabetic drug should be added.

Contraindications

• Pregnancy (except maybe metformin)
• Surgery
• Severe infections
• Renal failure
  • A contraindication for most oral antidiabetics

Before and during pregnancy, severe infections and surgery all oral antidiabetic drugs should be replaced with insulin monotherapy. Metformin is the exception, as more and more evidence shows that it’s likely safe in pregnancy. However, it’s not recommended in pregnancy yet.

Metformin

Metformin is a biguanide.

Indications

Metformin is the first line drug for all patients with type 2 diabetes. If the blood glucose level is not adequately controlled with metformin another antidiabetic drug can be added.

Other indications:

• Polycystic ovary syndrome
• Non-alcoholic fatty liver disease

Mechanism of action

The exact targets of metformin are not well known, but their biochemical actions on the body are. These include:

• Reduced gluconeogenesis
• Increased glucose uptake and utilization in skeletal muscle (= decreased insulin resistance)
• Reduced carbohydrate absorption from the intestine
• Increased β-oxidation
• Reduced LDL and VLDL

Metformin inhibits mitochondrial oxidative phosphorylation, thereby increasing the intracellular level of AMP. This activates AMP-activated protein kinase (AMPK). AMPK then stimulates the release of GLP-1, which again stimulates insulin release. AMPK also decreases the transcription of gluconeogenetic enzymes.

Pharmacokinetics

Metformin has a short half-life (3h) and is excreted unchanged in the urine.

Advantages

• Causes weight loss or at least weight stabilization
• Carries no risk for hypoglycaemia
• Cheap

Disadvantages

• Contraindicated in renal failure, which is common in T2D

Side effects

• GI symptoms
• B12 deficiency
• Metallic taste in mouth

Metformin can cause metformin-associated lactic acidosis, a very rare but potentially fatal complication. It primarily occurs when the contraindications are disregarded.

Contraindications

• Renal failure (GFR < 30 mL/min)
• Severe liver failure
• Heart failure
• Alcoholism
• Surgery
• Iodinated contrast medium

Metformin is eliminated by the kidneys, which is why renal failure is a contraindication. The liver eliminates lactate, and so severe liver failure increases the risk for lactic acidosis. Heart failure and alcoholism also increase the risk.

Metformin must be stopped before surgery and before giving iodinated contrast, as these two factors increase the risk for lactic acidosis.

GLP-1 agonists/analogues

These drugs are also called incretin mimetics, as GLP-1 is a type of incretin. GLP stands for glucagon-like peptide.

Incretins

GLP-1 and GIP are incretins. Incretins are released from enteroendocrine cells in the GI tract in response to food intake. The incretins stimulate insulin release and inhibit glucagon release, causing a net reduction of blood glucose.

The incretins are inactivated by an enzyme called dipeptidyl peptidase-4 (DPP-4).

Compounds

• Liraglutide (Victoza®)
• Semaglutide (Ozempic®)

Indications

GLP-1 analogues have proven beneficial effects on cardiovascular disease and should (together with SGLT-2 inhibitors) be consideres as first-line choices after metformin in patients with both DM2 and cardiovascular disease. They also cause moderate weight loss, which is almost always beneficial for DM2 patients. They're also indicated for weight loss (without DM2 present).

Some GLP-1 analogues are also indicated for the treatment of obesity even in the absence of DM2.

Pharmacokinetics

The older GLP-1 agonists are injected subcutaneously once daily or weekly, but nowadays newer oral formulations exist as well.

Advantages

• Decreases appetite -> weight loss

Disadvantages

• Long-term safety not established
• Must be injected
• Expensive

Side effects

• GI symptoms

SGLT-2 inhibitors (gliflozins)

Compounds

• Empagliflozin (Jardiance®)
• Dapagliflozin (Forxiga®)

Indications

SGLT-2 inhibitors have proven beneficial effects on cardiovascular disease and should (together with GLP-1 analogues) be consideres as first-line choices after metformin in patients with both DM2 and cardiovascular disease. They also cause moderate weight loss, which is almost always beneficial for DM2 patients.

Without heart failure, it may be more relevant in treating young males, as they’re less prone to developing UTIs and genital infections.

SGLT-2 inhibitors have proven benefit in heart failure and is recently (2021) indicated for all cases of heart failure, with or without DM2.

Mechanism of action

These drugs inhibit SGLT-2, the transport protein responsible for the reabsorption of glucose in the proximal tubule of the kidney. When this transporter is inhibited filtered glucose cannot be reabsorbed, causing glucosuria. Up to 70 grams of glucose can be lost per day. The filtered glucose acts as an osmotic diuretic.

The mechanism by which SGLT2 inhibitors are beneficial in heart failure is still unknown.

Advantages

• Weight loss
• Decreased blood pressure
• Reduced cardiovascular mortality

Disadvantages

• Long-term safety not established

Side effects

• Urinary tract infections
• Genital infections
• Dehydrations
• Hypotension

SGLT2 use during acute illness or surgery can yield normoglycaemic ketoacidosis. Administration of these drugs must therefore be paused in these cases.

DPP-4 inhibitors (gliptins)

DPP-4 inhibitors are also called gliptins.

Compounds

• Saxagliptin
• Linagliptin

Mechanism of action

Gliptins inhibit DPP-4, the role of which is to inactivate endogenous incretins.

Pharmacokinetics

Gliptins are orally absorbed and therefore taken PO. Unlike GLP-1 agonists they don’t decrease appetite.

Disadvantages

• Long-term safety not established
• Expensive

Side effects

• GI symptoms
• Heart failure

Like for GLP-1 agonists there is no long-term experience with DPP-4 inhibitors, so we don’t really know how effective they are long-term. Studies have shown that they significantly increase the risk for heart failure. They’re also expensive.

Sulfonylureas

Compounds

• Glimepiride
• Glipizide

There are many sulfonylureas. Some are long-acting, and some are short-acting. The long-acting ones have increased risk for hypoglycaemia and so are less used. Both glimepiride and glipizide are short-acting ones.

These drugs are rarely used anymore due having high risk for hypoglycaemia, causing weight gain, and the introduction of newer and better oral antidiabetics.

Mechanism of action

Sulfonylureas bind to a sulfonylurea receptor on ATP-gated K+ channels on pancreatic β-cells. This causes the channels to close, which causes depolarization of the β-cells. This causes insulin release.

Advantages:

• Acts quickly

Disadvantages:

• High risk for hypoglycaemia
• Risk for interactions via plasma protein binding
• Weight gain

Pharmacokinetics

Sulfonylureas have strong plasma protein binding, predisposing them to interactions with other drugs. Most sulfonylureas are eliminated by the kidney.

Interactions

Beta blockers mask the symptoms of hypoglycaemia and should therefore not be taken together with sulfonylureas (or in any patient with high risk for hypoglycaemia).

Side effects

• Hypoglycaemia
• Weight gain (increased appetite)
• Disulfiram-like effect

The hypoglycaemia can be severe and prolonged.

Meglitinides

Meglitinides have similar mechanism of action as sulfonylureas but are structurally different.

Compounds

• Repaglinide
• Nateglinide

Mechanism of action

Same as for sulfonylureas, although meglitinides bind to a slightly different binding site than the sulfonylureas.

Side effects

Same as for sulfonylureas but cause less weight gain and have lower risk for developing hypoglycaemia.

Thiazolidinediones (glitazones)

Compounds

• Pioglitazone
• Rosiglitazone

Indications

Often combined with metformin. Can be used as monotherapy in patients with severe renal failure. They’re rarely used anymore due to their potentially severe adverse effects. Rosiglitazone is no longer on the market.

Mechanism of action

Thiazolidinediones activate the transcription factor PPAR-γ. This transcription factor increases the transcription of genes involved in the glucose and lipid metabolism, most importantly:

• Lipoprotein lipase
• Fatty acid transporter protein
• GLUT4
• Adipocyte fatty acid binding protein

The result is increased lipogenesis and enhanced cellular uptake of fatty acids and glucose.

Side effects

• Fluid retention
• Increased risk of heart failure
• Weight gain
• Increased risk of osteoporosis
• Increased risk of AMI (rosi) and bladder cancer (pio)

Alpha-glucosidase inhibitors

Compounds

• Acarbose
• Miglitol

These drugs are rarely used due to their low efficacy and their compliance-reducing gastrointestinal side effects.

Mechanism of action

Alpha-glucosidase is an enzyme of the brush border of the small intestine. The enzyme cleaves disaccharides like sucrose, increasing their absorption.

By inhibiting this enzyme these drugs reduce carbohydrate absorption. The undigested carbohydrates reach the colon, where intestinal bacteria degrade them into gases.

Advantages

• No risk for hypoglycaemia

Disadvantages

• Must be taken three times daily

Side effects

• GI symptoms
  • Flatulence
  • Abdominal pain
  • Diarrhoea

Glucagon

Indications

• Severe hypoglycaemia (in those with diabetes)
• Beta blocker overdose-related cardiogenic shock

Glucagon is given IM in cases of severe hypoglycaemia if administering oral or IV glucose is impossible.

Mechanism of action

Glucagon rapidly stimulates gluconeogenesis and glycogenolysis in the liver, quickly raising the blood glucose. However, it's mostly used in those with diabetes mellitus, as in non-diabetes related hypoglycaemia the liver is often depleted of glucose anyway, which wouldn't allow glucagon to release any glucose.

Activation of the glucagon receptor activates adenylate cyclase which increases intracellular levels of cAMP. By increasing cAMP in the myocardial cells, glucagon will elicit positive heart effects, thereby reversing the beta-blocking effect on the heart.