Insulin types are classified b the duration of insulin action

• 1)  Rapid (ultra-short)
• 2)  Short 
• 3)  Intermediate 
• 4)  Long-acting 

• Lispro 
• Glulisine 
• Aspart 

• Amino acid subsitutions are made at the C-terminus 
• The name of the insulin reflects the amino acid substitutions 
• For example with insulin aspart there is a substitution of aspartate residue for the proline residue at position 28 of the beta-chain 

• Novolin R
• Humulin R 

The R stands for regular

• ONLY for completeness!!!
• Intermediate acting/NPD insulin was used prior to modified recombinant insulins 
• NPH insulin is no longer recommended 

• Novolin N
• Humulin N

The N stands for NPH

• Insulin detemir 
• Insulin glargine 

• Insulin detemir:  Insulin is myristoylaed 
• Insulin glargine:  Glycine substitution is made at the C-terminus of the alpha chain and two arginines are added to the C-terminus of the beta chain 

• Sulfonylureas 
• Meglitinides 

• Hypoglycemic agent
• Targets I-K-ATP channel in beta-cells

• Hypoglycemic agent 
• Targets I-K-ATP channel on beta-cells 

Sulfonylureas

Specific MOA

What happens when therapy is initiated vs later phase?

MOA: 

• Bind to specific site in the I-K-ATP channel complex called the sulfonylurea receptor (SUR) 
• These bind and block the potassium channel → cause depolarization of the beta-cell → cause release of insulin 

Initially after therapy vs later:

• Initially, increased insulin levels and decreased glycemic levels
• Later, insulin levels return to decreased levels but glycemic levels remain normalized.  This is reversible phenomenon. 

What is "secondary failure"

What drug class causes "secondary failure"

Secondary failure:  Overtime the agents stop working. This is seen with sulfonyureas.  This is consistent with progressive loss of beta-cell function.  

Glimepiride

Glipizide

Glyburide

Sulfonylurea 

Absorption

Elimination

Contraindications

Half-life

• Absorption:  Absorbed by the GI-tract and vast majority is bound to plasma proteins (90%) 
• Metabolism:  Liver metabolizes 
• Elimination: Kidneys clear metabolites 
• Contraindications:  Since they are metabolized by the lvier and eliminated by the kidneys, be careful in people with kidney or liver failure.  
• Half-life:  4 hours but effects last 12-24 hours 

Side-effects of sulfonylureas?

Drug interactions of sulfonylureas?

Side-effects:  

• Hypoglycemia
• Nausea, vomiting 
• Jaundice
• Blood dyscrasias (hemolytic anemia) 

Drug interactions:

• Since 90% are protein bound, other protein bound drugs affect their function such as salicylates → increase free drug 
• Ethanol enhances sulfonylurea action → hypoglycemia 

Repaglinide 

Nateglinide

Meglitinide drugs

MOA

Use

Metabolized 

Contraindication

• MOA:  Acts the same way as sulfonylureas by blocking I-K-ATP channels in beta-cells.  
• Use:  Control post-prandial glucose levels 
• Metabolized:  Liver
• Contraindications:  Use w/caution when people have hepatic dysfunction 

Megllitinides

Side-effects

Drug interactions

Side effects:  

• Hypoclyemica (less common with nateglinide)
• "secondary failure" 

Biguanides 

General MOA 

• Low cellular ATP → AMP-dependent protein kinase (AMPK) is acitvated → causes decreased gluconeogenosis (liver) and increased glycogen formation (skeletal muscle) 
• AMPK also increases insulin sensitivity 
• Both of these effects decrease circulating glucose 
• Biguanides activate AMPK

Biguanide drug example

Use

Metformin 

• This is the ONLY drug in this class
• This is considered the first-line of treatment for DM-2 
• Evidence also suggests the metformin slows glucose intolerance progression in DM-2 
• NOT useful in DM-1

Metformin 

Absorption

Distribution

Elimination

Contraindications

• Absorption:  Small intestine 
• Distribution:  NOT bound to plasma proteins 
• Elimination:  Excreted unchanged in the kidneys
• Contraindications: Renal function should be considered.  Clearance is not affected till creatine clearance drops below 50ml/minute.  So it is safe until then.  Also it should be withheld if patient is undergoing any treatment that may cause acute renal dysfucntion (imagin w/radio-opaque dye) .  Should be discontinued w/severe illness (cardiovascular decompensation).  Also organic cation transporters (OCT) 1 and 2 play role in metformin actions.  So mutations in OTC may predispose patients refractory to metformin therapy.  

Metformin 

Side effects 

Drug interactions

• Side-effects:  Affects certain GI-functions.  So biggest SE are associated with the GI (nausea, diarrhea, abdominal cramping). Can also lead to reduction in B12 levels.
• Drug interactions:  Cationic drugs excreted in the kidney (furosemide) 

Rosiglitazone 

Pioglitazone

• PPAR-gamma is a member of the nuclear receptor family.  
• Ligand binds (linoleic and arachadonic acid) → PPAR-gamma heterodimerizes with retinoic-x-receptor (RXR) → this binds t DNA target gene promoter → regulates genes involved in glucose + lipid metabolism
• PPAR-gamma is expressed in adipose tissue, all three muscle types, endothelial cels, and pancreatic beta-cells.  
• PPAR-gamma promotes adipocyte differentiation and lipid uptake 
• PPAR-gamma receptors are insulin sensitizers and enhance insulin-mediated glucose uptake 
• TZDs are NOT effective in DM-1 

TZDs 

Distrubtion/metabolism

Drug effect

• Metabolism:  CYP enzymes metabolize both drugs (CYP-2C8). CYP-2C8 should be considered int he context of rifampin therapy
• Drug effect:  Full effect of drugs not seen for months 

TZDs

Side effects

Side-effects:

• Weight gain:  Most frequent effect.  B/c of edema and increased adipose tissue.  Use of insulin with this, makes it worse. 
• Edema:  Generalized edema occurs.  Concern for people at risk of heart failure.  Macular edema has also been noted.  
• Increased adiposity:  Peripheral fat increases rather than central 
• Liver failure:  Has been reported. 
• Increased bone fractures and reduction in hematocrit:  Reported in women.  Might be because might cause differentation of cells to become adipocyes and decreases erythroid precursors.  

• Rifampin:  This increases CYP2C8 actvity and increases metabolism of TZD drugs
• Gemfibrozil:  Decreases TZD metabolism and reduction of TZD dose should be considered 

• Was once restricted, now it isn't
• Has been shown to have long lasting positive effects
• Has also been reported to limit transition of glucose intolerance to DM-2 and may help pre-diabetic patients 

Pioglitazone

Additional information

• Also binds to PPAR-alpha (in addition to gamma)
• This is NOT seen in rosiglitazone 
• Allows for decreased TG and increased HDL

• GLP-1 is secreted in response to food ingestion 
• GLP-1 increases insulin secretion + decreases glucagon secretion + decreases intestinal motility 
• Has a very short half half (1-2 minutes)  
• There are drugs that are GLP-1 agonists and GLP-1 protease inhibitors

GLP-1 agnoist drugs 

Exenatide 

Liraglutide

Exenatide

Half-life

Excretion

Contraindications

GLP-1 agonist

• Synthetic verious of GLP-1. It is refractory to degradation unlike the natural molecule GLP-1.  It can stay in the circulation for 2-3 hours 
• Excretion: Glomerular filtration 
• Contraindications:  Should not be given to patients with renal failure because it is cleared by the kidneys

GLP-1 agonist

• Addition of a fatty acid side-chain that allows for prolonged interaction with plasma proteins that extends its half-life.  
• Cleared by the same metabolic pathways for large plasma proteins 

• Both exenatide and liraglutide are appoved for adjunct therapy with sulfonylureas and metformin 

GLP-1 agnoists

SE

Drug interactions

• SE:  Associated with GI-side effects (nausea and vomiting). Remember that GLP-1 decreases motility and so that might be why these cause nausea and vomiting.  
• Drug interactions: Because these reduce GI-motility, they may be an issue when placed in combination with drugs that require rapid absorption (anti-biotics) 

Sitaglipin 

Saxagliptin

GLP-1 degradation

Mechanism of action of GLP-1 protease inhibitors 

• GLP-1 is degraded by DPP-4 serine protease 
• DPP-4 is present on the surface of endothelial cells and in the circulation. 
• There are two inhibitors of DPP-4 called sitaglipin and saxagliptin → these are thus going to cause an increase in insulin and decrease glucagon 

GLP-1 protease inhibitor

Use

Excretion 

Contraindications

• Use:  The inhibitors may be used also or in combination with other drugs such as:  insulin, sulfonylurea, metformin, and thiazolidinedione agents
• Excretion:  Kidneys excrete sitagliptin and saxagliptin 
• Contraindications:  Doses should be adjusted in patients with compromised renal function 

GLP-1 Inhibitors

Side-effects

Drug interactions

Side-effects:

• Comparable to placebo 

Drug interactions:

• Neight of the inhibitors alters cytochrome oxidase function in the liver but there is a hepatic component (CYP3A4) to saxagliptin metabolism. Thus the dose should be reduced when administed with drugs that inhibit this system.  (anti-viral agents for HIV, anti-fungal drugs, anti-biotics) 

• Alpha-glucocosidase is in the intestine, it degrades disacchardies and carbohydrates → attenuation of this causes decreased glucose absorption in the gut however glucose will still be absorbed but it is just attenuated

Acarbose + miglitol

Absorption

Elimination

Contraindications

Alpha-glucosidase inhibitor 

• Absorption: Acarbose is minimally absorbed. 50-100% of miglitol is absorbed in the intestine. 
• Elimination:  Kidneys excrete miglitol 
• Contraindications:  Since miglitol is excreted by the kidneys, renal function should be considered. When renal creatinine clearance < 30 ml/mins, doses of miglitol should be decreased.  Miglitol should not be given to individuals with stage 4 renal failure.  

Alpha-glucosidase inhibitors

SE 

Drug interactions 

Side-effects:

• Main side-effect is from inadequate digestion of disaccharides and complex carbohydrates.  So you see lactose intolerance, flatulence, bloating, and diarrhea.  
• Are NOT ASSOCIATED WITH HYPOGLYCEMIA when given alone.  Can be seen if given with insuilin or insulin secretagogues 
• Glucose should be given to treat the hypoglycemia if it does occur

Drug interactions:

• Reduce absorption of digoxin (acarbose) propranolol (miglitol) 

• Amylin, also known as islet amyloid peptide, is co-secreted with insulin from beta-cells.  The amylin receptor is found in the brain. When amylin binds to its receptor, glucagon is reduced + gastric motility is slowed + increased satiety 

Pramlinide

What is it 

Use

Absorption

Synthetic version of amylin 

• Use:  Used in both type-1 and type-2 DM as an adjunt to insulin taken pre-prandially 
• Absorption/distribution/elimination:  Pramlinide should not be given in the same solution as insulin because the pH is going to vary.  Doses for DM-1 is 50% of DM-2.  Cleared through the kidneys but can still give to patients as long as creatinine clearance > 20 ml/min 

Pramlinide

Side effects

Drug interactions

Side-effects:

• Hypoglycemia (not uncommon).  Does not occur because of pramlinide but because of the interaction with insulin.  
• Nausea 
• Weight loss 

Drug interactions:

• Decrease pre-prandial dose of insulin by 30-50% because hypoglycemia is a major concern 
• Do not give to patients with disordered gastric motility and may alter absorption of drugs by the GI-tract

Colesevelam

MOA

Use

Absorption

Side-effects 

Drug interactions

• MOA:  Bile acid binding resin and decreases glucose levels 
• Use:  Treatment of DM-2
• Absorption: Poor because stays in the GI tract
• Side-effects: Stays in the GI-tract and causes SE there. Nausea, abdominal pain, and dyspepsisa. Also causes an increase in TG 
• Drug interactions:  B/c of the lack of absorption, the interactions are restricted to the GI-tract and cause decreased absorption. This affects drugs like glyburide and thyroxine.  Take other drugs 4 hours before this. 

• SGLT2 is found in the S1 segment of the proximal renal tubule.  
• Reabsorbs 90% of the glucose.  The other 10% is reabsorbed by SGLT1 in the S2 and S3 segments.  
• Inhibition of this is going to cause elimination of glucose via the urine

Canagliflozin 

Dapagliflozin

Canagliflozin 

Use

Absorption 

Half-life

Metabolism 

Side-effects

• Use:  Monotherapy and in combination with other hypoglycemic agents for the treatment of DM-2
• Absorption:  Rapid and dose dependent 
• Half-life:  Dose dependent 
• Metabolsim:  Glucuronidation to inactive metabolite 
• Side-effects:  Reduction in BP and weight loss.  Vulvovaginal mycoses, urinary tract infections.  Polydipsia, thirst, constipation, nausea.