DRUGS USED IN TREATMENT OF

DIABETES MELLITUS
A. Tuthill
Definition

 Diabetes mellitus is an absolute or relative deficiency

of insulin

 Pancreatic failure
 Insulin resistance

 Insulin deficiency results in reduced glucose uptake by

insulin-sensitive tissues, increased lipolysis and
proteolysis (weight loss, weakness)
 The Supersizing Phenomenon
Portion Control - It Does Matter!
29G
26G
700 77G
610
22G 68G
600
500 10G Fat 57G 450
Calories

400 26 Grams Carbs 320

300
210
200
100
0
1960 1978 1995 1999
Year
 DM Trends Among Adults
in the United States, 1991 and 2001
1991 2001

No Data <4% 4%-6% 7%-8% 9%-10% >10%

Adapted from Mokdad AH et al. JAMA. 2003;289:76-79.

Diabetes Mellitus

 Hyperglycaemia –uncontrolled hepatic glucose

output, reduced uptake of glucose by skeletal muscle,
and reduced glycogen synthesis

 Polyuria, polydipsia, weight loss

 Ketoacidosis (accelerated breakdown of fat to

acetoacetate and β-hydroxybutyrate)

 Vascular disease
Diabetes Mellitus

 Type 1 (auto-immune)
 Type 2 (insulin-resistant)

 Treatment according to predominant pathogenic factor

– significant hyperglycaemia with weight loss usually
requires insulin
 Good Glycaemic Control Reduces Incidence of
Complications

DCCT Kumamoto UKPDS

9  7% 9  7% 8  7%
HbA1c
Retinopathy 63% 69% 17-21%
Nephropathy 54% 70% 24-33%
Neuropathy 60% – –
Macrovascular disease 41%* – 16%*

* not statistically significant

Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med. 1993;329:977-986.
Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117.
UK Prospective Diabetes Study Group (UKPDS) 33: Lancet. 1998;352:837-853. 10
DIABETES TREATMENTS

 Diet
 Exercise
 Insulin 1922
 Sulphonylureas 1942
 Biguanides 1950s (metformin first used in France in 1979)
 Post-prandial Glucose Regulators
 Alpha-glucosidase Inhibitors

 Thiazolidinediones 1990s

 DPP IV Inhibitors 2000s

 GLP1 analogues 2000s

 SGLT2 Inhibitors 2010s

Insulin

 Recombinant DNA technology – human insulin

 Destroyed by gastric enzymes – given SC, IV or
intraperitoneal
 Excreted in urine
 Different types differ in timing of peak effect and
duration of action

 Longer duration of insulin action obtained by

precipitating insulin with protamine or zinc which
form relatively insoluble crystals from which insulin is
slowly absorbed
Insulin : Actions
 Carbohydrate Metabolism :
- ↑ glucose uptake into fat and muscle
- ↑ Glycerol synthesis in fat
- ↑ Glycogenesis
- ↓ Gluconeogenesis, ↓ Glycogenolysis

 Fat Metabolism :
- ↑ Lipogenesis, ↓ Lipolysis

 Protein Metabolism :
- ↓ Protein breakdown, ↑ protein synthesis
Non-diabetic Insulin and Glucose Profiles
Breakfast Lunch Supper
75
Insulin
Insulin 50
(µU/mL)
25

0 Basal insulin

9.0
Glucose
6.0
Glucose
(mmo/L) 3.0
Basal glucose
0
7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
a.m. p.m.
Time of Day

14
Available Insulins
 Short-acting analogues
- Humalog (Insulin Lispro)
- Novorapid (Insulin Aspart)
- Apidra (Insulin Glulisine)

 Long-acting Analogues
- Levemir (Insulin Detemir)
- Lantus (Insulin Glargine)

 Premixed Insulins
- Humalog Mix 25 / Novomix 30 / Insuman Comb
 Insulin Pens

The first insulin pen was developed by NovoNordisk in 1926 but not
launched until 1985. Since then, numerous pens, both disposable and
reusable, have been developed adding to accuracy in dosing and
convenience to insulin injection therapy.

Disposable Lilly Pen

Novo Reusable Pen with Aventis Reusable Pen with

Disposable NovoNordisk Pen
disposable cartridge disposable cartridge
 Normal Blood Glucose Levels

Blood Glucose (mmols)

10-

8- 6-

4- 2-

8am noon 6pm 2am 4am 8am

Time

17
 Blood Glucose (mmols)

10- Two injections/day

8- 6-

4- 2-

8am noon 6pm 2am 4am 8am

Time

18
 Blood Glucose (mmols)

10- Four injections/day

8- 6-

4- 2-

8am noon 6pm 2am 4am 8am

Time

19
Blood Glucose (mmols)

10- Continuous Infusion

8- 6-

4- 2-

8am noon 6pm 2am 4am 8am

Time

20
HYPOGLYCAEMIA

 In 2004-5 there were approx. 8,000 hospital

admissions related to hypoglycaemia
 However there can be up to 90,000 ambulance callouts
per year for this condition

 ALL UNCONSCIOUS PATIENTS SHOULD BE

ASSUMED TO BE HYPOGLYCAEMIC UNTIL
PROVEN OTHERWISE
Change in Body Weight

7.5 cross-sectional, mean values

Intensive
5.0
kg

2.5
Conventional

0.0

-2.5
0 3 6 9 12 15
Years from randomisation
Insulin : Side-Effects

 Hypokalaemia

 Mitogenesis

 Antibody formation

 Lipohypertrophy
Sulphonylureas
 Second generation agents now in use (Gliclazide)
 Stimulate insulin secretion from β-cell by blocking KATP
channel activation resulting in depolarisation and Ca++
entry into cells. The rise in intracellular Ca++ leads to
increased fusion of insulin granules with the cell membrane

 Well absorbed orally

 Excreted in urine
 Cross placenta

 Side-effects: Weight gain, hypoglycaemia

 May results in earlier β-cell failure / increased mortality post
MI
Post-Prandial Glucose Regulators

 Act on same part of β-cell as Sulphonylureas but

shorter-duration
 Administered at mealtime
 Repaglinide
 Less risk of hypoglycaemia particularly as renal
function declines
Biguanides

 Metformin
 Reduce hepatic gluconeogenesis, increase glucose
uptake and utilisation in skeletal muscle
 Small effect on GLP-1 axis

 GI side-effects
 Lactic acidosis

 Polycystic ovary syndrome

α- Glucosidase Inhibitors

 Acarbose
 Delays carbohydrate absorption by inhibiting
hydrolysis of oligosaccharides, trisaccharides, and
disaccharides to glucose and other monosaccharides in
the intestine

 GI side-effects

 Post-prandial hypoglycaemia (pre-diabetes)

Thiazolidinediones (Glitazones)

 Bind to a nuclear receptor peroxisome proliferator-

activated receptor γ (adipose tissue, muscle, liver) and
promote transcription of genes involved in insulin
signalling pathways
 Differentiation of adipocytes, increases lipogenesis,
enhances uptake of fatty acids and glucose
 Promotes Na+ reabsorption

 Side-effects: fluid retention, bladder cancer, post-

menopausal bone thinning, liver toxicity, weight gain
 Pioglitazone
 Non-alcoholic fatty liver disease/ insulin resistance
Insulin Resistance

Skin Tags

Acanthosis
Nigricans

30
GLP-1 Analogues / Agonists

 GLP-1 stimulates insulin secretion, inhibits glucagon,

in setting of hyperglycaemia
 Slows gastric emptying
 Improves satiety

 Weight loss in addition to glucose lowering

 SC injection
 Liraglutide (od), Exenatide (bd), Exenatide LAR (once
weekly)
 The Incretin Effect in Healthy Subjects

Oral Glucose
Intravenous (IV) Glucose
*

200 2.0 *
*
Plasma Glucose (mg/dL)

C-peptide (nmol/L)
1.5
*Incretin Effect
*
100 1.0
*

0.5

0 0 60 120 180 0.0 0 60 120 180

Time (min) Time (min)

N = 6; Mean ± SE; *P0.05

Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.
 GLP-1 Effects in Humans

GLP-1 secreted upon

the ingestion of food
Promotes satiety and
reduces appetite

Alpha cells:
↓ Postprandial
glucagon secretion

Liver:
↓ Glucagon reduces
Beta cells: hepatic glucose output
Enhances glucose-dependent
insulin secretion Stomach:
Slows gastric
emptying

Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from
Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
34
DPPIV Inhibitors (Gliptins)

 Competitive inhibitors of dipeptidylpeptidase 4 which

usually degrades incretin hormones (GLP-1, GIP)

 Weight neutral
 Dose reduced in renal impairment (sitagliptin/
vildagliptin)/ use of an agent excreted in bile
(linagliptin)

 GI side-effects, skin rashes

 MAJOR TARGETED SITES OF DRUG CLASSES

GLP1 analogues
Pancreas Beta-cell dysfunction DPP IV Inhibitors

Sulfonylureas
Meglitinides Muscle & fat
Liver
Insulin
Hepatic glucose
overproduction Insulin
↓Glucose level resistance

GLP1 analogues
Biguanides Gut Thiazolidinediones
DPP IV Inhibitors
Insulin Biguanides
Thiazolidinediones
Reduced α-glucosidase
glucose inhibitors
absorption
Diabetes Care 2012;35:1364–1379
Diabetologia 2012;55:1577–1596
SGLT2 Inhibitors

 Inhibit glucose reabsorption in proximal renal tubules

 Glucosuria, weight loss, lowering of blood glucose

 Genito-urinary tract infections, dehydration

 Dapaglifozin, canagliflozin
Summary
 Choice

 Weight gain
 Hypoglycaemia

 Oral / sc

 Efficacy (HbA1c)
 Safety

 Co-morbidities