Antidiabetic drugs

Summary

Antidiabetic drugs (with the exception of insulin) are all pharmacological agents that have
been approved for hyperglycemic treatment in type 2 diabetes mellitus (DM). If lifestyle
modifications (weight loss, dietary modification, and exercise) do not sufficiently
reduce A1C levels (target level: ∼ 7%), pharmacological treatment with antidiabetic drugs
should be initiated. These drugs may be classified according to their mechanism of action as
insulinotropic or non-insulinotropic. They are available as monotherapy or combination
therapies, with the latter involving two (or, less commonly, three) antidiabetic drugs
and/or insulin. The exact treatment algorithms are reviewed in the treatment section
of diabetes mellitus. The drug of choice for all type 2 diabetic patients is metformin. This
drug has beneficial effects on glucose metabolism and promotes weight loss or at least weight
stabilization. In addition, numerous studies have demonstrated that metformin can
reduce mortality and the risk of complications. If metformin is contraindicated, not tolerated,
or does not sufficiently control blood glucose levels, another class of antidiabetic drug may
be administered. Most antidiabetic drugs are not recommended or should be used with
caution in patients with moderate or severe renal failure or other significant comorbidities.
Oral antidiabetic drugs are not recommended during pregnancy or breastfeeding.

Overview

Overview of antidiabetic drugs

Class Mechanism of Side effects Contraindications

action
Biguanide (metformin)
Enhances Lactic Chronic
the effect of insuli acidosis kidney disease
n
Weight loss Liver failure

Gastrointest Metformin
inal complaints aremust be
common (e.g. diarr paused before
hea, abdominal administration of
cramps) iodinated contrast
medium and major
Reduced vit surgery.
amin
B12absorption
 Class Mechanism of Side effects Contraindications
action
Sulfonylureas (e.g., glyburi
de, glimepiride) Increase in Risk Severe
sulin secretion of hypoglycemia cardiovascular
from pancreaticβ- comorbidity
cells Weight
gain Obesity

Hematologi Sulfonamide
cal allergy (particularly
changes: agranuloc long-acting substan
ytosis, hemolysis ces)

Meglitinides (nateglinide, r
epaglinide) Increase in Risk Severe renal
sulin secretion of hypoglycemia or liver failure
from pancreaticβ-
cells Weight
gain

DPP-4
inhibitors (saxagliptin, sita Inhibit GL Gastrointe Liver failure
gliptin) P-1 degradation stinal complaints
→ Moderate to
promotes glucose- Pancreatiti severe renal failure
dependent insulin s
secretion
Headache,
dizziness

Arthralgia

GLP-1 agonists (incretin

mimetic Direct Nausea Preexisting,
drugs: exenatide, liraglutid stimulation of symptomatic gastro
e, albiglutide) the GLP-1 recepto Increased intestinal motility
r risk disorders
of pancreatitisand
possibly pancreatic
cancer

SGLT-2
inhibitors(canagliflozin, da Increased Genital yea Chronic
pagliflozin, empagliflozin) glucosuria throug st infections and u kidney disease
h the inhibition rinary tract
 Class Mechanism of Side effects Contraindications
action

of SGLT-2 in the infections Recurrent

kidney urinary tract
Polyuria an infections
d dehydration

Diabetic
ketoacidosis

Alpha-glucosidase
inhibitors(acarbose) Reduce Gastrointest Any
intestinal glucose inal complaints preexisting
absorption (flatulence, diarrh intestinal conditions
ea, feeling of (e.g., inflammatory
satiety) bowel disease)

Severe renal
failure

Thiazolidinediones(pioglita
zone) Reduce ins Weight Congestive
ulin gain heart failure
resistance through
the stimulation of Edema Liver failure
PPARs (peroxiso
meproliferator- Cardiac
activated receptor failure
s)
Increased
Increase tr risk of
anscription of adi bone fractures (ost
pokines eoporosis)

Amylin
analogs (pramlintide) Reduce gl Risk Gastroparesi
ucagon release of hypoglycemia s

Reduce Nausea
gastric emptying

Increase
satiety
Common contraindications of antidiabetic
agents
 Type 1 diabetes mellitus: Patients require insulin therapy (see principles of insulin
therapy).

 Pregnancy and breastfeeding (also see gestational diabetes): All antidiabetic agents
are contraindicated. Antidiabetic drugs should be substituted with human insulin as
early as possible (ideally prior to the pregnancy).

 Renal failure : Antidiabetic drugs that may be administered if GFR < 30

mL/min include DPP-4 inhibitors, incretin mimetic drugs, meglitinides,
and thiazolidinediones.

 Morbidity and surgery

 Pause antidiabetic treatment in the following cases:

 Major surgery performed under general anesthesia

 Acute conditions requiring hospitalization (infections, organ failure)

 Elective procedures associated with an increased risk

of hypoglycemia (periods of fasting, irregular food intake)

Sulfonylureas are associated with the highest risk of hypoglycemia. All other substances do
not carry a significant risk of hypoglycemia when used as a monotherapy. Combination
therapy, particularly with sulfonylurea, significantly increases the risk of hypoglycemia!

Antihyperglycemic therapy algorithm for type 2

diabetes
References: [1][2]

Effects

 Insulinotropic agents

 Mechanism: stimulate the secretion of insulin from pancreatic β-cells

 Glucose-independent: Insulin is secreted regardless of the blood

glucose level, even if blood glucose levels are low → risk of hypoglycemia

 Sulfonylurea, meglitinides
  Glucose-dependent: Insulin secretion is stimulated by elevated blood
glucose levels (postprandially). These antidiabetic agents depend on residual β-
cellfunction.

 GLP-1 agonists, DPP-4 inhibitors

 Non-insulinotropic agents

 Mechanism

 These agents do not depend on residual insulin production.

 Effective in patients with nonfunctional endocrine pancreatic β-cells

 Biguanides (metformin), SGLT-2 inhibitor, thiazolidinediones, alpha-

glucosidase inhibitors

Biguanides (metformin)

Active agent
 Metformin

Clinical profile
 Mechanism of action: enhances the effect of insulin

 Reduction in insulin resistance via modification of glucose metabolic

pathways

 Inhibits mitochondrial glycerophosphate dehydrogenase (mGPD)

 Decreases hepatic gluconeogenesis and intestinal glucose

absorption

 Increases peripheral insulin sensitivity

 Lowers postprandial and fasting blood glucose levels

 Reduces LDL, increases HDL

 Indications: drug of choice in all patients with type 2 diabetes

 Clinical characteristics
 Glycemic efficacy: lowers HbA1c by 1.2–2% over 3 months

 Weight loss or weight stabilization

 No risk of hypoglycemia

 Beneficial effect on dyslipidemia

 Studies show metformin reduces the risk of macroangiopathic complications

in diabetic patients.

 Cost-effective

 Important side effects

 Metformin-associated lactic acidosis

 Incidence: ∼ 8 cases/100,000 patient years

 Clinical features: frequently nonspecific

 Gastrointestinal prodromal symptoms: nausea,

vomiting, diarrhea, abdominal pain

 Severe symptoms: muscle cramps, hyperventilation, apathy,

disorientation, coma

 High-risk groups

 Elderly individuals

 Patients with cardiac or renal insufficiency

 Diagnostics

 Arterial blood gas (ABG): metabolic acidosis and anion gap

 ↑ Serum lactate

 Treatment: discontinue metformin and treat acidosis

 Gastrointestinal complaints are common: nausea, diarrhea, flatulence

 Vitamin B12 deficiency

 Metallic taste in the mouth (dysgeusia)

 Contraindications
  Renal failure (if creatinine clearance < 30 mL/min)

 Severe liver failure

 Intravenous iodinated contrast medium

 Pause metformin prior to surgery

 Chronic pancreatitis, starvation ketosis, ketoacidosis, sepsis

 Heart failure (NYHA III and IV), respiratory failure, shock, sepsis

 Alcoholism

 Important interactions: sulfonylureas

Metformin treatment must be paused prior to the administration of a contrast medium or

scheduled surgery to reduce the risk of lactic acidosis!

Because of its favorable risk-benefit ratio, metformin is the drug of choice for monotherapy
and combination therapy in all stages of type 2 DM!
References: [1][3][4]

Thiazolidinediones (glitazones, insulin sensitizers)

Active agents
 Pioglitazone

 Rosiglitazone

Clinical profile
 Mechanism of action: activation of the transcription
factor PPARγ (peroxisome proliferator-activated receptor of gamma
type) → ↑ transcription of genesinvolved in glucose and lipid metabolism → ↑
levels of adipokines such as adiponectin → ↑ storage of triglycerides and
subsequent reduction of products of lipid metabolism (e.g., free fatty acids) that
enhance insulin resistance → glucose utilization is increased and hepatic glucose
production reduced

 Indications: may be considered as a monotherapy in patients with severe renal failure

and/or contraindications for insulin therapy

 Clinical characteristics
  Glycemic efficacy: lowers HbA1c by 1% in 3 months

 Favorable effect on lipid metabolism: ↓ triglyceride, ↓ LDL, ↑ HDL

 No risk of hypoglycemia

 Important side effects

 Fluid retention and edema

 Weight gain

 Increased risk of heart failure

 Increased risk of bone fractures (osteoporosis!)

 Contraindications

 Congestive heart failure (NYHA III or IV)

 Liver failure

 Pioglitazone: history of bladder cancer or active bladder

cancer; macrohematuria of unknown origin

References: [5][6]

Sulfonylureas

Active agents
 Glyburide: the standard substance of this class with a relatively long half-life

 Glipizide: a short-acting agent

Clinical profile
 Mechanism of action

 Sulfonylureas block ATP-sensitive potassium channels of the pancreatic β-

cells → depolarization of the cell membrane → calcium influx → insulinsecretion

 Extrapancreatic effect: decreases hepatic gluconeogenesis and increases

peripheral insulin sensitivity
  Indications: particularly suitable for patients who are not overweight, do not consume
alcohol, and adhere to a consistent dietary routine

 Clinical characteristics

 Glycemic efficacy: lowers HbA1c by 1.2% over 3 months

 Long-term experience

 Low-cost

 Important side effects

 Life-threatening hypoglycemia

 Increased risk in patients with renal failure

 Weight gain

 Hematological changes: granulocytopenia, hemolytic anemia

 Allergic skin reactions

 Alcohol intolerance

 Compared to metformin, sulfonylureas are associated with more

cardiovascular (macrovascular) complications.

 Contraindications

 Severe cardiovascular comorbidity

 Obesity

 Sulfonamide allergy (particularly long-acting substances)

 Severe liver failure

 Severe kidney failure

Beta-blockers may mask the warning signs of hypoglycemia (e.g., tachycardia) and decrease
serum glucose levels even further (→ see hypoglycemia). Since sulfonylureas also increase
the risk of hypoglycemia, the combination of these two substances should be avoided!
References: [7]

Meglitinides (sulfonylurea analogue)

Active agents
 Repaglinide: the leading agent in the class of meglitinides, which is well tolerated by
patients with chronic kidney disease

 Nateglinide

Clinical profile
 Mechanism of action

 Enhances insulin secretion (similar mechanism of action to that of

the sulfonylureas)

 Meglitinides should be taken shortly before meals.

 Indications: particularly suitable for patients with postprandial peaks in blood

glucose levels

 Clinical characteristics

 Glycemic efficacy: lowers HbA1c by 0.75% over 3 months

 More expensive than sulfonylureas

 Important side effects

 Life-threatening hypoglycemia (less risky than sulfonylureas)

 Increased risk in patients with renal failure

 Weight gain

 Hepatotoxicity (rare)

 Contraindications

 Severe liver failure

 Severe renal failure

 Interactions: sulfonylureas

Incretin mimetics (GLP-1 receptor agonists)

Active agents
 Exenatide

 Liraglutide: rapid-release formula that is administered daily

 Albiglutide: extended-release formula that is administered once weekly

 Dulaglutide

Clinical profile
 Mechanism of action

 Incretin effect: food intake → activation of enteroendocrine cells in

the gastrointestinal tract → release of GLP-1 → GLP-1 degradation via the
enzyme DPP-4 → end of the GLP-1 effect

 Incretin mimetic drugs bind to the GLP-1 receptors and are resistant to
degradation by DPP-4 enzyme → increase insulin secretion,
decrease glucagonsecretion, slow gastric emptying (↑ feeling of satiety, ↓ weight)

 Clinical characteristics

 Glycemic efficacy: lowers HbA1c by 0.5–1.5% over 3 months

 Subcutaneous injection

 Weight loss

 No risk of hypoglycemia

 Side effects

 Gastrointestinal complaints (particularly impaired gastric emptying!)

 Increased risk of pancreatitis and potentially pancreatic cancer :

 Contraindications

 Preexisting symptomatic gastrointestinal motility disorders

 Chronic pancreatitis or a family history of pancreatic tumors

References: [8][9][10][11][12][13]
Dipeptidyl peptidase-4 inhibitors (gliptins)

Active agents
 Sitagliptin

 Saxagliptin

Clinical profile
 Mechanism of action: Gliptins indirectly increase the endogenous incretin effect by
inhibiting the dipeptidyl peptidase-4 enzyme that breaks down glucagon-like
peptide 1 → increased insulin secretion, decreased glucagon secretion, delayed
gastric emptying

 Indications: See the antihyperglycemic therapy algorithm for type 2 diabetes.

 Clinical characteristics

 Glycemic efficacy: lowers HbA1c by 0.5–0.75% over 3 months

 No risk of hypoglycemia unless insulin and/or insulinotropic drugs are used

simultaneously

 Important side effects

 Gastrointestinal complaints: diarrhea, constipation (milder than in GLP-

1 agonist exposure)

 Nasopharyngitis and upper respiratory tract infection

 Arthralgia

 Headaches, dizziness

 Urinary infections (mild)

 Increased risk of pancreatitis

 Acute renal failure

 Contraindications

 Hypersensitivity
  Liver failure

References: [1][8][9][14][15]

SGLT-2 inhibitors (gliflozins)

Active agents
 Dapagliflozin

 Empagliflozin

 Canagliflozin

Clinical profile
 Mechanism of action: reversible inhibition of the sodium-dependent glucose co-
transporter (SGLT-2) in the proximal tubule of the kidney → reduced glucose
reabsorption in the kidney → glycosuria and polyuria

 Indications: a treatment option used especially in young patients with treatment-

compliant type 2 DM without significant renal failure

 Clinical characteristics

 Glycemic efficacy: lowers HbA1c by 0.6% over 3 months

 Promotes weight loss

 Reduces blood pressure

 Important side effects

 Urinary tract infections, genital infections (vulvovaginitis, balanitis)

 Dehydration as a result of polyuria

 Severe diabetic ketoacidosis

 Contraindications

 Chronic kidney disease

 Recurrent urinary tract infections (e.g., in patients with anatomical or

functional anomalies of the urinary tract)
Alpha-glucosidase inhibitors

Active agents
 Acarbose

 Miglitol

Clinical profile
 Mechanism of action

 Inhibits alpha-glucosidase → decreased intestinal glucose absorption → The

drug is particularly effective in controlling postprandial blood glucose levels.

 The undigested carbohydrates reach the colon, where they are degraded by
intestinal bacteria, resulting in the production of intestinal gas.

 Clinical characteristics

 Glycemic efficacy: lowers HbA1c by 0.8% over 3 months

 No risk of hypoglycemia

 Important side effects: gastrointestinal complaints (flatulence, abdominal

discomfort, diarrhea)

 Contraindications

 Inflammatory bowel disease

 Conditions associated with malabsorption

 Severe renal failure