The Pharmocology of Oral Hypoglycaemic Agents

Question 1

Why does blood glucose rise?

Answer 1

Inability to produce insulin due to beta cell failure and/or

Insulin production adequate but insulin resistance prevents insulin working effectively

Question 2

Explain how diabetes is a progressive disorder.

Answer 2

Declining beta cell function independent of changes in insulin resistance

Deterioration of glycaemic control

Increased risk of cardiovascular disease

Beta cell function slowly deteriorates over time

Question 3

Explain the connection of insulin resistance to liver fat.

Answer 3

Insulin resistance increases with liver fat content

A low-calorie diet can help to reduce liver fat content

Question 4

How do we treat diabetes? (overview)

Answer 4

Type 1
Lifestyle plus insulin (many formulations)

Type 2
Lifestyle plus non-insulin therapies
- Biguanides, sulphonylureas, thiazolidinediones, DPP4
inhibitors, alpha-Glucosidase inhibitors, SGLT2s, GLP1
analogues
- Then insulin might be considered

(Both require patient education and ability to monitor results of therapy)

Question 5

What are some key challenges to treatment for patients with type 2 diabetes?

Answer 5

Weight gain and hypoglycaemia are risks of treatment

This can lead to poor adherence

Question 6

What is the relation between hypoglycaemic treatment and weight?

Answer 6

Most treatments result in weight gain over time

Question 7

What are the NICE targets in type 2 diabetes?

Answer 7

Target for all is HbA1c 6.5 to 7.5%

HbA1c 6.5%: Diet and first 2 treatment steps
HbA1c 7.5%: Beyond this or if at risk of severe hypoglycaemia

Question 8

Tell me about metformin.

Answer 8

Decreases insulin resistance and hepatic glucose production

Limited weight gain
Decreases CCVS events
Can be combined with all other diabetes medications
Side effects include GI symptoms
Lactic acidosis rare
Vitamin B12 deficiency uncommon
Stop if CKD

Question 9

Tell me about sulphonylureas.

Answer 9

Stimulate beta cell to ease insulin
Decreases microvascular risk
Side effects:
- Weight gain
- Hypoglycaemia

Cost low

Commonly used include:
- Gliclazide (Modified Release too) (hepatic metabolism
so can be used in renal impairment)
- Glimepiride

Question 10

Tell me about alpha glucosidase inhibitors.

Answer 10

Acarbose
Only 1 available in class

Inhibits breakdown of carbohydrates to glucose by blocking action of the enzyme alpha-glucosidase

Side effects are predictable:

• Flatulence
• Loose stools
• Diarrhoea

Modest reduction in HbA1c ~ 0.5%
Rarely used

Question 11

Tell me about glitazones.

Answer 11

Increase in insulin sensitivity in muscle & adipose tissue
Decrease in hepatic glucose output

They bind to and activate one or more peroxisome proliferator-activated receptors (PPARs)

Can be used in combination with other oral agents

Cardiovascular concerns with Rosiglitazone

Pioglitazone still available but concerns for weight gain, fluid retention and heart failure

Rarely used nowadays

Question 12

What are the two incretin based therapies?

Answer 12

DPP-4 inhibitors
protect native GLP-1 from inactivation by DPP-4

GLP-1 receptor agonists
Mimic native GLP-1

Question 13

What are the physiological effects of GLP-1?

Answer 13

Come from intestinal L cells

Pancreas:

• Increase Insulin secretion
• Decrease glucagon secretion
• Increase insulin biosynthesis

Brain
- Decrease food intake through increased satiety

Stomach
- Decrease in gastric emptying

Liver (indirect effect)
- Decreases glucose production

Muscle (indirect effect)
- Increase in glucose uptake

Question 14

Tell me aboutDPP-4 inhibitors.

Answer 14

Gliptins
Stops DPP-4 from breaking down incretin gut hormones
Then active release of incretin gut hormones results in an increase in insulin and decrease in glucagon

Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin

Side effects include GI symptoms
Low risk of hypoglycaemia
Weight neutral

Modest HbA1c reduction
Cost high

Consider adding second line to metformin or sulphonylureas with HbA1c > 6.5%

Question 15

What are some of the side effects of GLP-1 agonists?

Answer 15

Gastrointestinal symptoms, nausea, loose stools or diarrhoea
Gastro-oesophageal reflux
Low risk of hypoglycaemia
Occasional painful to inject
??Pancreatitis and pancreatic carcinoma??
Generally perceived to be safe and well tolerated

Question 16

Tell me about SGLT2 inhibitors.

Answer 16

Sodium-Glucose Co-Transporter 2 inhibitors

Block the SGLT2 in the proximal tubule that is responsible for reabsorption of glucose
This results in the patient excreting more glucose through their urine, and so results in less glucose on the body.

Dapagliflozin, Canagliflozin and Empagliflozin
Can be used for both type 2 and type 1 patients

Side effects:
Increased risk of lower urinary tract symptoms including genital and urinary infections especially in women
Polyuria

Hypoglycaemia risk low