INSULIN AND INSULIN ANALOGUES

Generic Name Brand Name Mechanism of action Adverse effects

Rapid-acting insulin (onset: 15-30 mins, Lowers blood glucose and promotes glucose homeostasis by: Hypoglycemia
duration: 3-6 hrs except for exubera: 6-8  Increased glucose uptake and utilization by peripheral tissues  More common in Type1
hrs)  Increased glycogenesis (glu to glycogen in liver and muscle) and decreased glycogenolysis (glycogen to glu) than Type2
 Decreased gluconeogenesis (formation of glu from noncarbs, like amino acids)  Sympathetic symptoms:
Insulin lispro Humalog®
 Decreased lipolysis and ketogenesis (breakdown of fats to ketone bodies) tachycardia,
Insulin aspart Novolog®, Novopen®  Increased formation of proteins from amino acids tremulousness, sweating
Insulin glulisine Apidra®  Increased formation of adipose tissue from TG and FA ◦ NOT experienced
by people with
Inhaled human Exubera® (DC due to ADMINISTRATION hypoglycemia
insulin low sales)  TYPE 1 DM: Initial Total daily dose (TDD) = 0.5-1.0 U/kg/day in 3-4 inj (because 1-2 inj can't achieve euglycemia) unawareness
Short-acting insulin (onset: 30-60 mins, ◦ THREE inj per day: (should temporarily
duration: 3-8 hrs) ▪ Prebreakfast – 2/3 of TDD raise glycemic goals
and reduce insulin
 25-35% lispro, aspart or reg
Regular insulin Humulin R®, Novolin dose)
R®  65-75% NPH or lente
 Neuroglycopenic
▪ Presupper – 10-20% of TDD given as lispro, aspart or reg
Intermediate-acting insulin (onset: 2-4 symptoms: confusion,
▪ Bedtime (10PM) – 10-25% pf TDD given as NPH or lente
hrs, duration: 8-18 hrs) agitation, LOC, and/or
◦ FOUR inj per day:
progression to coma
NPH (neutral Humulin N®, Novolin ▪ Premeal (three inj) – 40-50% of TDD divided b/n 3 meals given as lispro, aspart or reg
◦ Treated by adm of
protamine N®  proportional to CHO intake per meal CHO (glucose), LOC
hagedorn) – ▪ Bedtime – 50-60% of TDD given as NPH or glargine is treated with IV
isophane insulin  If NPH:bedtime, premeal must be reg glu or Glucagon inj
suspension ◦ Insulin Pump therapy (external pump – continuous SC insulin infusion) Weight gain
▪ Premeal and pre-snack boluses – 40-50% of TDD, dosage based on premeal BG and anticipated CHO  From increased truncal
Lente insulin DC
intake given as lispro or aspart fat
Long-acting insulin (onset: detemir ~ 2 ▪ Basal insulin – delivered continuously (initial rate: 0.5-1.25 U/hr) 50-60% of TDD given as lispro or aspart  Undesirable in Type2 but
hrs, glargine ~ 4-5 hrs, duration: detemir ~  TYPE 2 DM: Initial TDD = 0.15-0.4 U/kg/day (varies depending on extent of insulin resistance and Beta cell beneficial in underwt
14-24 hrs, glargine ~ 22-24 hrs) dysfunction) Type1 pts
◦ ONE inj per day: BEDTIME (0.25 U/kg/day) given as NPH or glargine, usually in comb'n w/ oral antidiabetics  Minimized by physiologic
Insulin detemir Levemir®
or may also be monotherapy replacement of insulin
Insuline glargine Lantus® ◦ TWO inj per day: both given as premix insulin (70/30, 75/25, 50/50 depending on anticipated CHO intake) Lipohypertrophy – (anabolic
▪ Prebreakfast – 2/3 of TDD (CHO intake of bfast and lunch) action) raised fat mass at
Ultrelente insulin DC
▪ Presupper – 1/3 of TDD injection site causing varied
(extended insulin
◦ THREE or FOUR inj per day – similar to Type 1 insulin absorption, rotate inj
zinc suspension)
*Initial doses and regimen are adjusted as needed (based on SMBG, HgbA1C) sites
Premixed insulins *Insulin needs are INCREASED in infection, exacerbations of medical problems, wt gain, puberty, inactivity, Lipoatrophy – caused by insulin
hyperthyroidism, Cushing's dse antibodies with destruction of
Neutral protamine Humalog Mix 75/25®
*Insulin needs are DECREASED in renal failure, adrenal insufficiency, nutrient malabsorption, hypopituitarism, wt loss, fat at inj site
lispro/lispro Humalog Mix 50/50®
increased exercise
Aspart protamine Novolog Mix 70/30® *SUBQ routes – abdomen, arm, buttocks, thigh *IV insulin (insulin drip) – reg
suspension/aspart Record variations in absorption: if variation is great, AVOID RANDOM ROTATION insulin for acute hypoglycemia,
Avoid heat and exercise at site of inj during adm to prevent erratic absorption (preexercise inj: abdomen is preferred) ketoacidosis, HHNK syndrome,
NPH/regular Humulin 70/30®
*Insulin pump therapy – short-acting or rapid-acting insulin infusion (basal insulin) with premeal bolus for pts or during surgical
Humulin 50/50®
withwidely fluctuating blood glucose levels, TIGHTER GLYCEMIC CONTROL procedures/delivery
Novolin 70/30®
 OTHER INJECTABLES
Generic Name Brand Name Mechanism of Action Adverse effects
Exenatide Byetta®, Bydureon® Exendin-4 is a 39-amino acid peptide isolated from the saliva of the Gila monster (Heloderma GI in nature – Nausea (stomach fullness),
suspectum) and shares approximately 50% amino acid sequence with human glucagon-like protein 1 vomiting, anorexia, diarrhea
(GLP-1). Exenatide is the synthetic analog to exendin-4, Albiglutide, Dulaglutide, Liraglutide – incretin
Albiglutide Tanzeum® Weight loss
mimetic, Pramlintide is a synthetic analog of amylin (amylinomimetic), a neurohormone co-secreted
Dulaglutide Trulicity® from the β cells with insulin. (used for pts w/ insulin therapy)
Irritation and erythema on
 Bind to GLP-1 receptors in many parts of the body including the brain and pancreas.
injection sites
 Enhance glucose dependent insulin secretion while suppressing inappropriately high
Liraglutide Victoza®, Saxenda®
postprandial glucagon secretion in the presence of elevated glucose concentrations, resulting in
Pramlintide Symlin® a reduction in hepatic glucose production.
 Reduce food intake, which can result in weight loss, and slows gastric emptying so that the rate
of glucose appearance into the plasma better matches the glucose disposition.

INSULIN SECRETAGOGUES
Generic Name Brand Name Mechanism of Action Adverse effects
Sulfonylureas (Duration, Generation) Enhancement of insulin secretion by: Hypoglycemia
 binding to sulfonylurea receptor (SUR) on pancreatic β  det. By pretreatment FPG
Glimepiride (Short, 2nd) Amaryl®
cells  RISK FACTORS - skipped meals, vigorous exercise, weight loss
Tolbutamide (Short, 1st) Orinase®  Binding closes an ATP–dependent K+ channel → decreased  Glyburide – severe prolonged hypoglycemia in elderly
Acetohexamide (Intermediate, Dymelor® potassium efflux → depolarization of the membrane.  less in meglitinides than SUs
1st)  Voltage-dependent Ca+2 channels open → inward flux of Hyponatremia (serum sodium <129 mEq/L)
Ca+2  with tolbutamide, but it is most common with chlorpropamide
Glipizide (Intermediate, 2nd) Glucotrol®, Minodiab®  Increased IC Ca+2 cause → translocation of secretory  increase in antidiuretic hormone secretion
Glyburide (Intermediate, 2nd) DiaBeta®, Glynase® granules to surface → exocytosis  RISK FACTORS - >60 y/o, female gender, and thiazide diuretics
 Elevated secretion of insulin from the pancreas travels viaWeight gain – store excess calories
Tolazamide (Intermediate, 1st) Tolinase®
the portal vein and subsequently suppresses hepatic Other less common ADRs
Chlorpropamide (Very long, Diabenese® glucose production.  GI – nausea, gastric discomfort, vomiting, constipation
1st) *Type 2 DM (also true for glitazones) meglitinides  Hematological – agranulocytosis, pancytopenia, hemolytic
 Used as monotherapy or in combination with other oral anemia
antidiabetics
 tachycardia, headache, skin rash
 Must have sufficient numbers of functioning B cells
 Cholestatic jaundice – for SUs
*Not indicated for Type 1 DM (also true for glitazones) meglitinides
Disulfiram-type reactions – with tolbutamide and chlorpropamide when
Meglitinides (Very short-acting insulin secretagogues) Repaglinide - benzoic acid derivative alcohol is consumed.
Nateglinide - phenylalanine amino acid derivative *Not recommended for children, pregnant and lactating women or as
Nateglinide Starlix®
 Binding site is adjacent to the binding site of monotherapy in pts w/o functioning pancreatic B cells
sulfonylureas, stimulate insulin secretion similarly to *Contraindicated in pts with sulfa drug allergies
sulfonylureas. *Increases risk for CV morbidity and mortality
 Both require the presence of glucose to stimulate insulin *Should not be used in stressful conditions (eg. Infection, surgery, injury)
secretion. As glucose levels diminish to normal, stimulated due to increased secretions of counterregulatory hormones – use insulin
Repaglinide Prandin® insulin secretion diminishes. in these cases
*Taken with meals Primary failure – failure within first 4 weeks, insufficient numbers of
functioning B cells
Secondary failure – works at first but still fails, represents progression
of DM w/ diminishing number of functioning B cells
 INSULIN SENSITIZERS
Generic Name Brand Name Mechanism of Action
Biguanide Metformin enhances insulin sensitivity of both hepatic and
peripheral (muscle) tissues
Metformin Glucophage®,
 increased uptake of glucose into insulin sensitive tissues.
Fortamet®, Glumetza®,
 Decreased GI glucose absorption
Riomet®
 The exact mechanisms of how metformin accomplishes
insulin sensitization are still being investigated, although
adenosine 5-monophosphate–activated protein kinase
activity, tyrosine kinase activity enhancement, and glucose
transporter-4 all play a part.
*Not to be used as monotherapy and should always be given with
insulin for Type 1 DM
*Type 2 DM
 Monotherapy or combination with other oral antidiabetics
 Pt must have adequate endogenous and exogenous
insulin
Thiazolidinedione (TZDs) or glitazones  Bind to the peroxisome proliferator-activated receptor- γ
(PPAR- γ ) on fat cells and vascular cells
Pioglitazone Actos®
 Enhance insulin sensitivity at muscle, liver, and fat tissues
indirectly
 Cause preadipocytes to differentiate into mature fat cells
in subcutaneous fat stores. Small fat cells are more
sensitive to insulin and more able to store FFAs.
 Result is a flux of FFAs from plasma, visceral fat, and liver
into subcutaneous fat, a less insulin-resistant storage tissue
– decline in insulin resistance
 Also affect adipokines, (e.g., angiotensinogen, tissue
necrosis factor- α , interleukin-6, plasminogen activator
inhibitor-1), which can positively affect insulin sensitivity,
endothelial function, and inflammation.
◦ adiponectin is reduced with obesity and/or diabetes
Rosiglitazone Avandia® but is increased with TZD therapy, which improves
endothelial function, insulin sensitivity, and has a
potent anti-inflammatory effect.
*Not to be used as monotherapy and should always be given with
insulin for Type 1 DM
*Type 2 DM
 Monotherapy or combination with other oral antidiabetics
 Pt must have adequate endogenous and exogenous
insulin
Adverse Effects
GI side effects - abdominal discomfort, stomach upset, diarrhea, Anorexia
and stomach fullness (reasons for loss of weight)
CI in situations with high risk for Lactic acidosis (flu-like symptoms):
 Renal dysfunction (Scr > 1.4 mg/dl)
 Hypoperfusion (hypoxic states)
 Radiographic procedures using iodinated contrast media w/c may
cause transient renal dysfunction
 Chronic or binge alcohol ingestion
 Liver dse
*Troglitazone - first TZD approved
 DC due to idiosyncratic hepatotoxicity (increased ALT levels)
 Prior to therapy of all glitazones: check ALT levels
◦ ALT levels >2.5 times the upper limit of normal should not start
either medication
◦ DC medication if ALT is >3 times the upper limit of normal the
medication should be discontinued.
 CI in hepatic dse
Retention of fluid
 due to peripheral vasodilation and/or improved insulin sensitization
with a resultant increase in renal sodium and water retention
 Edema – increased when a TZD is used in combination with insulin
◦ CI in pts with CHF
◦ Worsen macular edema in the eye.
Weight gain - fluid retention and fat accumulation
 TZDs reduce leptin levels, which stimulate appetite and food intake
 Weight gain positively predicts a larger HbA lc reduction but must be
balanced with the well documented effects of long-term weight gain.
Increased fracture rate in the upper and lower limbs in postmenopausal
women, but not men. osteopenia
 effect of TZD in bone marrow - reduction in osteoblast activity and an
increase in bone marrow fat.
Resuming of ovulation – in premenopausal anovulatory women, risk for
pregnancy
Headache
Fatigue
 ALPHA-GLUCOSIDASE INHIBITORS
Generic Name Brand Name Mechanism of Action Adverse Effects
Acarbose Precose® Competitively inhibit enzymes (maltase, isomaltase, GI side effects - flatulence, bloating, abdominal discomfort, and diarrhea
sucrase, and glucoamylase) in the luminal side of small  caused by distal intestinal degradation of undigested carbohydrate by the
intestine, delaying the breakdown and absorption of microflora, which results in gas (carbon dioxide and methane) production
sucrose and complex carbohydrates.  Should be initiated at a low dose and titrated slowly to reduce GI
 They do not cause any malabsorption of these intolerance.
nutrients.  CI in IBD, colonic ulcerations, obstructive bowel disorders, chronic
 Net effect: Reduced postprandial blood glucose intestinal disorders of digestion and absorption
rise  Beano, an α -glucosidase enzyme, can help to decrease GI side effects but
*For pts with significant postprandial hyperglycemia can decrease efficacy slightly.
Miglitol Glyset® *Type 2 DM Hypoglycemia within several hours of ingesing drug
 monotherapy or in combi with insulin or insulin  Oral glucose is advised because the drug will inhibit the breakdown of more
secretagogues complex sugar molecules.
 Pt must have adequate endogenous or  Milk, with lactose sugar, can be used as an alternative when no glucose is
exogenous insulin available, as acarbose only slightly (10%) inhibits lactase.
*Type 1 DM Elevated serum aminotransferase levels have been reported
 adjunct to insulin therapy, useful in individuals with the highest doses of acarbose
with delayed absorption of SC insulin  dose and weight related and is the premise for the weight-based maximum
 Not to be used as monotherapy doses.
 CI in liver cirrhosis

DIPEPTIDYL PEPTIDASE-IV INHIBITORS (DPP-IV Inh)

Generic Name Brand Name Mechanism of Action Adverse Effects
Sitagliptin Januvia® In type 2 DM, GLP-1 levels are deficient. DPP-IV inh: Mild hypoglycemia appears to be the only significant adverse effect,
 Prolong the half-life of an endogenously produced glucagon- and the rate is similar to metformin.
Alogliptin Nesina® like peptide-1 (GLP-1) by blocking nearly 100% of the DPP-IV May potentially affect other regulatory systems
enzyme activity for at least 12 hours  DPP-IV enzymes metabolize a wide variety of peptides (peptide
Linagliptin Tradjenta® YY [PYY], neuropeptide Y, growth hormone releasing hormone,
 Partially reduce the inappropriately elevated glucagon
postprandially and stimulate glucose-dependent insulin and vasoactive intestinal polypeptide, and others) potentially.
Saxagliptin Onglyza®
secretion Adverse immunologic reactions (theoretically)
 Near normal, nondiabetic GLP-1 levels are achieved.  DPP-IV (also known as CD26) plays an important role for T-cell
Vildagliptin Investigational
 do not alter gastric emptying. activation.

SELECTIVE SODIUM-GLUCOSE TRANSPORTER-2 (SGLT-2) INHIBITORS

Generic Name Brand Name Mechanism of Action Adverse Effects
Canagliflozin Invokana® SGLT2 is expressed in the proximal renal tubules and is responsible for UTI
the majority of the reabsorption of filtered glucose from the tubular Fungal infections (more common in female genitalia than in males)
Dapagliflozin Farxiga® lumen Diuresis and thirst
 SGLT2 inh reduce glucose reabsorption and lower the renal Pruritus
Empagliflozin Jardiance® threshold for glucose, thereby increasing urinary glucose Nausea, Constipation
excretion Renal impairment
 MICROVASCULAR COMPLICATIONS
COMBINATION PRODUCTS
 Glyburide/Metformin – Glucovance® 1. RETINOPATHY
 Glipizide/Metformin – Metaglip® -Basement membrane thickening
 Rosiglitazone/Metformin – Avandamet® -Retinal blood flow change
 Rosiglitazone/Glimepiride – Avandaryl® -Microaneurysm
 Pioglitazone/Metformin – ACTOplus Met® -Retinal Hemorrhages
 Pioglitazone/Glimepiride – Duetact® -Retinal Ischemia
 Sitagliptin/Metformin – Janumet® -Retinal neovascularization --> Retinal detachment
 Repaglinide/Metformin – PrandiMet®
-Vitreous hemorrhage --> mild to severe visual loss
-Iris neovascularization --> neovascular glaucoma --> severe visual loss
 Alogliptin/Metformin – Kazano®
 Linagliptin/Meftormin – Jentadueto®
 Saxagliptin/Metformin – Kombiglyze® 2. NEPHROPATHY
 Canagliflozin/Metformin – Invokamet® -Hyperperfusion
 Dapagliflozin/Metformin – Xigduo XR® -Renal Vasodilation --> increased GFR --> increased protein excretion
 Empagliflozin/Linagliptin - Glyxambi® -Inc. intraglomerular cap pressure --> increased protein excretion
-Protein glycation
MACROVASCULAR COMPLICATIONS
1. PVD *micro/macroalbuminuria
- blood is viscous due to glucose *glomerular damage
- slower flow of blood -- low oxygen distribution *KIDNEY FAILURE
- low wound healing -- slow movement of blood which is supposed to nourish
the wound, nourishes bacteria instead
3. NEUROPATHY
*Cilostazol -Thickening of nutrient vessels that surround nerves
*Local debridemen -Demyelinization --> slower conduction
*Fitted footwear
*Somatic - affects sensory motor function
2. Atherosclerotic CHD and Diabetic cardiomyopathy -eg. pain
- prone to CHF -- prolonged HTN and chronic hyperglycemia *Autonomic - PANS or SANS, vasomotor
- DM increases CHD risk -eg. syncope

3. Cerbral vascular complications *Gabapentin

- insulin has neuroprotective effect *Sodium valproate
- low insulin, low protection
- cognitive defects -- dementia, Alzheimers