Treatment of Diabetes: Learning Objectives

2020/01/08 20:40 1/35 Treatment of Diabetes
Treatment of Diabetes
Learning Objectives
By the end of the self study you should be able to:
1. Define the goals of therapy for type 1 and 2 diabetes in accordance with the American Diabetes
Association Clinical Practice Guidelines 2015.
2. List the categories of pharmacologic agents used in the management of patients with type 1 and 2
diabetes
3. Explain the following for each drug category:‡
mechanisms of action
❍
indications
❍
contraindications
❍
potential side effects

❍
major advantages /disadvantages

❍
4. List the first-line agent(s) for controlling hypertension and dyslipidemia associated with diabetes.
5. Describe the treatment of choice for ketoacidosis in a patient with Type 1 diabetes
6. Recognize the clinical features of Maturity Onset Diabetes mellitus of the Young (MODY) (discussed
in a MOD lecture on Diabetes).
‡
For this Learning Exercise, Focus on Drug Classes vs Individual Drugs
● the list of antidiabetic drugs is growing steadily, making it very challenging to

remember them all
● the main emphasis in this learning exercise will be on recognizing the
common traits of each drug category vs those of individual drugs
● e.g.:
❍ be able to compare and contrast the traits of “sulfonylureas” vs
“meglitinides” (as two types of insulin secretagogues) as compared to
getting bogged down with trying to remember the mostly subtle
differences between different drugs within each drug class
❍ during assessment exercises, you won't be asked to recognize glyburide,
glipizide & glimepiride as names for different sulfonylureas; that level of
detail can be dealt with later on in your clinical training.
❍ drug trade names are provided only for completeness, and they are not
included on exam questions (as is true for questions on the USMLE Step 1
exam); only characteristics of drug classes will be assessed
● because “prandial” and “basal” insulins are used differently, you will need to
recognize the various prandial & basal insulins
Drugs
● ORAL HYPOGLYCEMICS:
❍Sulfonylureas: glyburide, glipizide, glimepiride
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❍ Glinides: repaglinide, nateglinide

❍
Biguanide: metformin1)
❍ α-Glucosidase Inhibitors: acarbose, miglitol
❍ Thiazolidinediones or Glitazones: rosiglitazone, pioglitazone
❍ Dopamine agonist: bromocriptine
❍ SGLT-2 Inhibitors: canagliflozin, dapagliflozin, empagliflozin
❍ DPP-IV Inhibitors: sitagliptin, saxagliptin, linagliptin, alogliptin
● INJECTIBLE HYPOGLYCEMICS:
❍ GLP-1 Agonists: exenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, semaglutide
❍ Amylin Analog: pramlintide
● BILE ACID SEQUESTRANTS:
❍ colesevelam
● INSULINS:
❍PRANDIAL:
Rapid acting: lispro, aspart, glulisine, inhaled
■
Short-acting: regular crystalline zinc

■
❍BASAL:
Intermediate acting: NPH (or Isophane)
■
Long acting: glargine, detemir

■
Ultra-long acting: degludec

■
● INSULIN + GLP1 COMBINATIONS:

❍glargine + lixisenatide (Soliqua ®)
❍degludec + liraglutide (Xultophy ®)
● Diabetes Drug Trade Names
GOALS OF THERAPY
(according to ADA Clinical Practice guidelines 2017)
1. Aim to achieve normal or near normal glycemia with an A1C goal of <7 percent.
2. More stringent goals (ie, a normal A1C, <6.5 percent) without hypoglycemia can be considered in
individual patients.
3. Less stringent treatment goals (ie, <8 percent) may be appropriate for patients with a history of
severe hypoglycemia, patients with limited life expectancies, older adults, and individuals with
comorbid conditions.
4. Obtain an A1C at least:
twice yearly in patients who are meeting treatment goals and who have stable glycemic control
❍
quarterly in patients whose therapy has changed or who are not meeting glycemic goals
❍
5. Pre-prandial capillary plasma glucose: 80-130 mg/dl

6. 2 hrs post-prandial capillary plasma glucose: < 180 mg/dl
NON-PHARMACOLOGIC THERAPIES
1. Dietary modification
2. Exercise
3. Weight reduction
http://tmedweb.tulane.edu/pharmwiki/ Printed on 2020/01/08 20:40

ORAL HYPOGLYCEMICS
INSULIN SECRETAGOGUES:
Drug subclasses
● Sulfonylureas (2nd Gen):

❍ Glyburide
❍ Glipizide
❍ Glimepiride
● Glinides:
❍ Repaglinide
❍ Nateglinide
Indications:
● Type 2 DM
❍Monotherapy or in combination with other oral antidiabetes drugs.
❍Use in type 2 DM predicated upon:
adequate control not attained by medical nutrition therapy and physical activity alone
■
pharmacologic intervention is required based upon the presenting blood glucose levels and
■
diabetes symptomatology
there are sufficient numbers of viable β-cells.
■
Contraindications:
● Type 1 DM
❍Patients with type 1 DM have few, if any, pancreatic β-cells for these drugs to produce an effect
Mechanisms of action:
● The primary action of these drugs is to stimulate the release of endogenous insulin
● These drugs block ATP-regulated potassium channels in pancreatic β-cell membranes
❍K channel block depolarizes the cell resulting in Ca influx, which triggers insulin release

Figure 1. Secretagogue chemical structures. Sulfonylureas (SFUs) shown on the left panel have a
general structural formula consisting of a sulfonylurea group (highlighted in red), and two drug-
specific side chains (highlighted in blue). The structure of the SFU glyburide is shown as an example.
The right panel shows the structures of two glinides that are structurally different than SFUs. They
share the same SUR1 receptor binding site as SFUs, but have a weaker binding affinity, and
faster dissociation from the receptor associated with the KATP-dependent K channel.
Structures reproduced from Wikipedia.

Figure 2. Mechanism of action of sulfonylureas & glinides in pancreatic β-cells & regulation of insulin
release by plasma glucose. A & B) A rise in plasma glucose levels associated with a meal results in
increased glucose uptake, followed by intracellular metabolism resulting in an increase in intracellular
ATP. A rise in intracellular ATP inhibits ATP-sensitive K channels (Kir6.1 or Kir6.2). K channel inhibition
results in membrane depolarization, with a resulting activation of depolarization-activated Ca
channels. A rise in intracellular Ca promotes fusion of vesicles containing insulin with the cell
membrane, and subsequent release of insulin. C) Sulfonylureas and glinides bind to a site on the
sulfonylurea receptor (SUR1) channel subunit, which inhibits these channels. ATP binds to a different
nucleotide-binding domain (NBD) on the cytoplasmic side. Binding of either ATP or these drugs to
their sites of action produces a conformational change that inhibits K pore permeability. Glinides bind
with lower affinity than sulfonylureas, and as a result have a much shorter duration of action. To be
effective, glinides have to be given with each meal, while sulfonylureas can be given once a day.
Pharmacokinetics:
● Sulfonylureas have once a day dosing

● Glinides have a rapid onset & short duration of action; they have to be taken just prior to
each meal.

Figure 3. Differences in Time Course (Duration) of Action of sulfonylureas (glyburide) & glinides
(nateglinide). Both glyburide and nateglinide augmented the insulin response to meal consumption,
but with markedly different time course. The glinide increased insulin release associated with
consumption of a meal, but insulin levels returned to placebo/baseline levels in-between meals. In
contrast, the insulin response to the sulfonylurea was more delayed after the morning meal, and did
not return to placebo-treated control, or baseline levels in-between meals throughout the day. Thus
the likelihood for producing hypoglycemic events is greater for the once-daily sulfonylurea compared
to three-times daily use of a glinide. Adapted from Hollander et al (2001).
Secretagogue Disadvantages:
● Hypoglycemia
● Weight gain
● Frequent dosing
DRUGS ACTING ON LIVER, MUSCLE & ADIPOSE TISSUE
Drug subclasses:
● Biguanide:
❍ metformin (the only biguanide available)
● Thiazolidinediones (TZDs / glitazones):
❍ rosiglitazone
❍ pioglitazone

Indications:
● Individuals with a significant component of insulin resistance

● Type 2 DM
❍ Use in type 2 DM predicated upon:
■inadequate control with medical nutrition therapy and physical activity
■pharmacologic intervention is required based upon the presenting blood glucose levels and
diabetes symptomatology
■patient has adequate endogenous or exogenous insulin
Mechanisms of action:
● METFORMIN:
❍Decreases hepatic glucose production via activation of AMP-activated protein kinase
(AMPK)(Figure 4) (its primary mechanism of action).
❍Under metformin-free conditions AMPK is activated whenever hepatic energy stores are reduced
(e.g. as reflected by a fall in ATP & increase in AMP). Its activation results in stimulated glucose
uptake, fatty acid oxidation, and reduced gluconeogenesis.
❍Other mechanisms that may contribute to metformin's effects include:
inhibits the breakdown of fatty acids used to produce glucose
■
at very high doses it may increase the removal of glucose from muscle, the liver, and other
■
body tissues where glucose is stored
Figure 4. Metformin acts primarily to suppress glucose production in the liver. While metformin's
mechanism(s) of action remain controversial, current evidence indicates that metformin's most
important effect in treating diabetes is to lower the hepatic production of glucose (as summarized in
the top left box). Current evidence suggests that results from a combination of intracellular effects in
the liver. When metformin is taken orally, it is absorbed into hepatocytes from the portal vein through
plasma membrane transporters, including the organic cation transporter 1 (OCT1). Inside the cell

metformin inhibits mitochondrial respiratory-chain complex 1, resulting in reduced ATP levels and
increased AMP. Increased AMP levels activate Adenosine Monophosphate-Activated Protein Kinase
(AMPK), which contributes to lowering of glucose production by at least 2 pathways: i) increased AMPK
phosphorylates CBP & CRTC2 transcription factors, which inhibits genes involved in the production of
glucose (“gluconeogenic genes”); ii) increased AMPK also inhibits mitochondrial glycerol-3-phosphate
dehydrogenase (mGPD), leading to an increase in cytosolic NADH, which both stimulates the
conversion of pyruvate to lactate, and simultaneously decreases gluconeogenesis. An accumulation of
lactate to dangerous levels (lactic acidosis) can occur when metformin is taken by patients with
other conditions resulting metabolic acidosis (liver disease, heart failure, sepsis, alcohol abuse), or
kidney disease (as indicated by elevated creatinine levels) because metformin is eliminated by renal
excretion) (He & Wondisford, 2015; Kennedy & Masharani, 2015).
● ROSIGLITAZONE & PIOGLITAZONE:

❍Reduce insulin resistance in muscle and adipose tissue, reduce both fasting and postprandial
hyperglycemia.
❍Thiazolidinediones are ligands of the peroxisome proliferator-activated receptor-γ
(PPAR-γ) that is expressed in the nucleus of adipocytes, myocytes and hepatocytes.
❍PPAR regulates the expression of genes involved in lipid and glucose metabolism, insulin signal
transduction, and adipocyte differentiation. In diabetics, a major site of TZD action is adipose
tissue.
Figure 5. Glycemic mechanism of action of thiazolidinedione “insulin sensitizers” (using an adipocyte

for illustration purposes). These drugs are synthetic ligands for the transcription factor PPARγ, a
member of a superfamily of nuclear receptors including thyroid and steroid receptors. PPARγ is
expressed in multiple tissue types (e.g. skeletal muscle, fat & liver). PPARγ stimulation
upregulates the expression of genes involved in lipid & glucose metabolism, insulin signal
transduction, and adipocyte differentiation. As illustrated, one mechanism contributing to the
hypoglycemic effect of thiazolidinediones is an increased expression of the glucose transporter
GLUT4. The increased expression of GLUT4 (in addition to mediators of insulin signal transduction)
increases the ability of cells (e.g. adipocytes) to take up glucose when stimulated by insulin.
Pioglitazone, which also stimulates PPARα (e.g. a mechanism shared with fibrate hypolipidemics)

exerts more significant lipid-lowering effects compared to rosiglitazone (a pure PPARγ

agonist)(McCulloch, 2016b).
Pharmacokinetics & Dosing:
● Monotherapy
● Combination therapy with other oral anti-diabetic agents or insulin
● Type 1 DM: metformin may be used as adjunct to insulin (in obese T1 diabetics only), must not be
used as monotherapy
Side Effects:
● Metformin:
❍GI side effects: diarrhea, bloating; Vit B12 deficiency.
❍Lactic acidosis (rare but potentially life-threatening).
contraindicated in renal dysfunction (estimated glomerular filtration rate [eGFR] <30
■
mL/min)(Wexler 2019).2).
contraindicated in heart failure, sepsis & liver disease (other conditions that can
■
contribute to the development of metabolic acidosis.

● TZDs:
❍Weight gain, edema, heart failure, bone fractures. There has been “much discussion” but,
unclear evidence that rosiglitazone may be associated with an increased risk for MI.
α-GLUCOSIDASE INHIBITORS
Drugs:
● Acarbose
● Miglitol
Indications:
● Used in individuals with significant postprandial hyperglycemia. These drugs have minimal effect on
pre-prandial or fasting blood glucose levels.
● Type 2 DM
❍ Monotherapy or in combination with insulin or other oral anti-DM agents
❍ Use in type 2 DM predicated upon:
■adequate control not attained by medical nutrition therapy and physical activity alone.
■pharmacologic intervention is required based upon the presenting postprandial blood glucose
levels and diabetes symptomatology
■patient has adequate endogenous or exogenous insulin
Mechanism of action:
Mechanism: acarbose and miglitol are carbohydrate analogs that act within the intestine to inhibit α-

glucosidase, an enzyme necessary for the conversion of complex starches, oligosaccharides, and
disaccharides to the monosaccharides that can be transported out of the intestinal lumen and into the
bloodstream. As a result of slowed absorption postprandial hyperglycemia is reduced. They have no
effect on fasting blood sugar.
Side Effects:
● Flatulence, diarrhea and abdominal pain resulting from increased fermentation of unabsorbed
carbohydrate by bacteria in the colon.
BILE ACID SEQUESTRANTS
Drugs:
● Colesevelam
● lowers LDL cholesterol in patients with primary hypercholesterolemia. Colesevelam's mechanism of

action to improve glycemic control is uncertain. One possibility is that bile acid sequestrants act in
the gastrointestinal tract to reduce glucose absorption.
Side Effects:
● nausea
● dyspepsia
● constipation
● interference with absorption of other oral meds
● increase in triglycerides
DOPAMINE AGONISTS
Drugs:
● Bromocriptine
Background:
The idea of using bromocriptine for the treatment of type-2 diabetes came from the study of the
metabolism of migrating birds. Migrating birds (like humans) are sensitive to circadian rhythms that
result in a leaner body in the summer, and a heavier body in the winter. The study of migrating birds
revealed that the circadian rhythm during the winter & summer included the development of a
seasonal insulin resistance during the winter that is modulated by dopamine effects on the
hypothalamus (which controls the release of cortisol, growth hormone & prolactin).
In patients with type 2 diabetes, an abnormally high caloric intake disrupts the normal
circadian pattern, such that patients become “stuck” in a winter rhythm that contributes
to elevated plasma levels of glucose & free fatty acids. Stimulation of the hypothalamus
by dopamine (bromocriptine) once a day within a few hours upon waking helps to reset
the circadian clock which affects plasma levels of glucose and free fatty acids in both
fasting and postprandial states.
Decreased dopaminergic tone in the hypothalamus is involved in the pathogenesis of insulin

resistance, resulting in increased glucose, triglyceride & fatty acid levels in both the fasting and
postprandial state in insulin-resistant patients. A daily morning dose of bromocriptine can reset the
circadian rhythm, and improves glycemic control, lowering A1C levels by 0.3 to 0.5 percent when
taken alone or in combination with a sulfonylurea (Weiland & Hilaire, 2013).
Side Effects:
● dizziness, vomiting, fatigue.
DPP-IV INHIBITORS (Gliptins)
Drugs:
● Sitagliptin
● Saxagliptin
● Linagliptin
● Alogliptin
Background:
The incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide) are
produced by endocrine cells of the intestine following ingestion of food (figure 1). GLP-1 and GIP
stimulate insulin secretion from the β-cells and reduce glucagon secretion. The incretins are
metabolized by dipeptidyl peptidase-4 (DPP-4). Hence, DPP-IV inhibitors enhance the effects produced
by incretins.
Can be used as monotherapy and/or as an add-on therapy to metformin, SU or thiazolidinediones.
Doses of the sitagliptin & saxagliptin have to be adjusted for renal dysfunction (Cr Cl <50) however,
linagliptin does not need any adjustment.
The effect produced by DPP-4 inhibitors is dependent on endogenous GLP-1 levels, and produce a
modest effect on GLP-1 activity compared to that which can be achieved by giving synthetic direct-
acting GLP-1 receptor agonists (that are DPP-4 resistant). Clinical trials indicate that DPP-4 inhibitors
produce no change in weight, in contrast to GLP-1 agonists, such as exenatide, which produce
moderate weight loss which has been attributed to the ~5x stronger “incretin mimetic” effect

produced by GLP-1 analogs compared to DPP-4 inhibitors (Charbonnel & Cariou, 2011)
Figure 6. DPP-4 is a serine protease that is expressed on the surface of endothelial cells, T-
lymphocytes & in a circulating form. An important role is to inactivate incretins (GLP-1 & GIP).
Inhibition of incretins by DPP-4 inhibitors prolongs the half-life of incretins (GLP-1 & GIP) and is
associated with increased insulin release & reduced glucagon release. DPP-4 inhibitors do not have
significant effects on GI motility or appetite that are observed with more efficacious (DPP-4 resistant)
GLP-1 agonists.
Side effects:
● occasional reports of urticaria/angioedema, cases of pancreatitis observed, long-term safety

unknown.
SGLT-2 INHIBITORS
Drugs:
● Canagliflozin
● Dapagliflozin
● Empagliflozin

Background:
SGLT-2 is a sodium-glucose low affinity & high-capacity co-transporter that is expressed in the
proximal renal tubule and mediates reabsorption of ~90% of filtered glucose into blood. SGLT-1 is a
second transporter expressed in a distal segment of the proximal tubule that acts in concert with
SGLT-2. Together these two transporters produce a relatively complete reabsorption of glucose from
the renal tubules, so that glucose is barely detectable in the urine of healthy adults. Mutations in the
SGLT-2 gene cause renal glycosuria and urinary glucose excretion. SLGT-2 inhibitors reduce glucose
reabsorption, resulting in increased urinary glucose excretion, and lower plasma glucose. SGLT-2
inhibitors efficiently lower plasma glucose levels independently of insulin action and secretion.
Efficacy depends on renal function. Canagliflozin can be prescribed to patients with normal or
moderate renal function (GFR above 45 ml/min). However, dapagliflozin is not recommended in
patients with even moderate to severe renal dysfunction (if the GFR is below 60 ml/min).
Figure 7. Glucose is filtered by the renal glomeruli and is reabsorbed in the proximal tubule.
Approximately 90% of glucose reabsorption is produced by a sodium-glucose transporter (SGLT-2). Its
inhibition results in increased glucose in the urine (glycosuria) and a lowering of plasma glucose level
in patients with type 2 diabetes.
Side effects:

● genito-urinary infections, hypotension, dehydration, potential for weight loss.
INJECTABLE NON-INSULIN HYPOGLYCEMICS
GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS
Drugs:
The differences between available GLP-1 receptor agonists are primarily pharmacokinetic, but short
vs long duration agents differ in terms of the predominant mechanisms by which they lower plasma
glucose. All of them act by stimulating GLP-1 receptors that are expressed in multiple tissue types.
Short Acting
● Exenatide
❍ Exenatide is a synthesized hormone that acts like GLP-1; it is a synthetic analog of exendin-4, a
naturally occurring reptilian peptide that has considerable homology to GLP-1, and is potent GLP-
1 agonist.
❍ twice daily s.c. injections (half life ≅ 2-3 hours).
● Liraglutide
❍ once daily s.c. injections
● Lixisenatide
❍ once daily s.c. injection
❍ has the potential for better adherence over exenatide (because of fewer injections per day, and
lower hypoglycemic risk).
Long Acting
● Albiglutide
❍ once weekly GLP-1 agonist
● Dulaglutide
❍ once weekly GLP-1 agonist
● Exenatide extended release
❍ once weekly (microsphere slow release formulation)
● Semaglutide
❍ 2 formulations:
■once weekly injections (Ozempic ®)
■daily oral tablets (Rybelsus ®) NEW
the 1st oral GLP-1 agonist (FDA approved 9/20/19)
●
Mechanisms of Action:
● Binding of GLP-1 agonists to their receptor activates different pathways in target tissues including
the cAMP-PKA pathway, and PKC/PI3K.
● Stimulation of GLP-1 receptors:

❍ slows down gastric emptying (mediated by reduced vagal nerve, subject to tachyphylaxis)
❍ stimulates insulin release
❍ inhibits glucagon secretion
❍ reduces appetite
❍ reduces liver fat
● Short acting GLP-1 receptor agonists exert their primary hypoglycemic effect by lowering
postprandial glucose due to their inhibitory effect on gastric emptying. This upper GI effect is
mediated by a reduction of parasympathetic stimulation, an effect that undergoes tachyphylaxis in
the presence of chronic GLP-1 stimulation (Wettergren et al, 1998; Nauck et al, 2011). Short acting
agents may be best suited for patients with type 2 diabetes that includes exaggerated postprandial
glucose excursions, and for co-administration with basal insulin therapy (Guo, 2016; Madsbad 2016).
● Long acting GLP-1 receptor agonists have relatively little effect on the rate of gastric emptying
due to the development of tachyphylaxis of parasympathetic-mediated effects. In contrast, long-
acting agents appear to have a larger effect on lowering fasting glucose due to their ability to
increase insulin release and inhibit glucagon release (Meier 2012). Long-acting GLP-1 agonists may
be of greatest benefit in patients who require specific control of fasting hyperglycemia (Guo 2016;
Madsbad 2016).
Figure 8. Potent GLP-1 agonists exert effects by multiple mechanisms including increased glucose-
dependent insulin secretion, delayed gastric emptying, reduced glucagon levels, and reduced food
intake by CNS effects to cause appetite suppression. Short acting agents exert their effect mostly by
slowing gastric emptying, which reduces post-prandial glucose levels. In contrast, long-acting agonists
have a stronger effect to reduce fasting glucose levels mediated by their effect on insulin and

glucagon release. Long-acting GLP-1 receptor agonists have little effect on gastric emptying due to
the development of tolerance to GLP-1 effects mediated by changes in parasympathetic tone
(Wettergren et al, 1998; Nauk et al, 2011; Madsbad 2016).
Side Effects:
● GI side effects: nausea, vomiting (mild to moderate; decreases with time)

● Acute pancreatitis
● possible risk for C-cell hyperplasia/medullary thyroid tumors (seen in animals)
● Long term safety unknown
AMYLIN ANALOG
Drugs:
● Pramlintide
Mechanism of Action:
● exerts its effect by slowing down food absorption & suppressing appetite. Amylin is a small peptide
hormone that is released into the bloodstream by the β-cells along with insulin.
● Amylin is deficient in individuals with diabetes (e.g. following the loss of β-cells).
● Amylin can suppress appetite via hypothalamic receptors (different receptors than for GLP-1),
Suppresses glucagon secretion and slows gastric emptying (see Figure 9).

Figure 9. Pramlintide injected before a meal slows gastric emptying by a vagal mechanism,
suppresses glucagon release, and acts centrally to decrease appetite. It does not alter insulin levels.
Pharmacokinetics:
● ideally should be injected before a meal.

● approved to be used along with the use of a prandial insulin, and typically requires a reduction of
prandial insulin dose (Dungan, 2019).
● should be injected at a separate location from insulin injections because it will precipitate at pH
>5.5.
ADVANTAGES & DISADVANTAGES OF TREATMENT OPTIONS

SULFONYLUREAS (SFUs) - insulin secretagogues
ADVANTAGES DISADVANTAGES
♦ Well tolerated ♦ Risk for hypoglycemia
♦ Inexpensive ♦ Weight gain
GLINIDES - insulin secretagogues
♦ Well tolerated ♦ Expensive
♦ Three times a day (before meals) dosing

GLINIDES - insulin secretagogues

♦ Risk for hypoglycemia (less than SFUs)
♦ Weight gain
♦ Not very potent
METFORMIN - decreased hepatic glucose production
♦ Reduction in CV events/mortality ♦ Contraindicated when eGFR<30
♦ Contraindicated in patients at risk for lactic acidosis
♦ No hypoglycemia
(CHF or undergoing surgery)
♦ GI side effects (nausea, diarrhea, cramping) -less with
♦ No weight gain
extended release
THIAZOLIDINEDIONES (Glitazones) - Insulin Sensitizers
♦ Well tolerated ♦ Contraindicated in CHF (may worsen edema)
♦ Raises HDL ♦ Contraindicated in liver disease
♦ No hypoglycemia ♦ Slow onset: maximum effect requires a month or more of treatment
♦ Increases LDL
♦ Weight gain
♦ Bone fractures
α-GLUCOSIDASE INHIBITORS - decreased metabolism of carbohydrates in the GI tract
♦ Safe - drug is not absorbed ♦ Probably won't reach glycemic goal
♦ Three times daily dosing (before meals)
♦ Significant GI side effects (flatulence, diarrhea)
DPP-IV INHIBITORS - prevents metabolism of endogenous incretins (GLP-1)
♦ Effective ♦ Dose adjustments with Cr Cl <50 (except linagliptin)
♦ Oral ♦ Weight neutral
♦ No hypoglycemia ♦ Increased risk for pancreatitis?
GLP-1 ANALOGS - ↑ glucose-dependent insulin release, ↓glucagon release, ↓ appetite, ↓
gastric emptying
♦ Effective ♦ Requires injection
♦ Weight loss ♦ Nausea
♦ Potential for improved β-cell mass ♦ Caution - pancreatitis
♦ C-Cell hyperplasia/ MTC in animals
Caution in gastroparesis (slow gastric emptying assod with
diabetes)
AMYLIN ANALOG - ↓ gastric emptying, ↓ appetite, ↓ postprandial rise of glucagon
♦ Requires injection (TID with meals), at separate site from
♦ Effective
insulin
♦ Approved to be given with insulin ♦ Nausea
♦ Weight neutral ♦ Caution in gastroparesis
♦ Risk for hypoglycemia
DOPAMINE AGONIST - modulates hypothalamic regulation of metabolism

DOPAMINE AGONIST - modulates hypothalamic regulation of metabolism

♦ No hypoglycemia ♦ modest A1C efficacy
♦ No weight gain ♦ dizziness/syncope
♦ Nausea/fatigue
SGLT-2 INHIBITORS - decreases renal reabsorption of glucose
♦ Effective ♦ Hypotension risk
♦ Can be given with insulin ♦ Increased LDL (dose related)
♦ Weight loss ♦ Increased risk of UTIs
♦ Low risk of hypoglycemia ♦ Not effective in severe renal failure
♦ Reduces systolic BP
INSULIN
♦ Effective ♦ Requires injection
♦ Well understood ♦ Hypoglycemic risk
♦ Weight gain
American Diabetes Assn 2020 Update
Based upon recent research findings, the American Diabetes Asson & Europiean Asson for the Study
of Diabetes recently updated their consensus treatment recommendations (Buse et al, 2019) for the
following subsets of patients with diabetes:
● High risk diabetic patients

❍GLP-1 agonists & SGLT2 inhibitors
to reduce CV & renal risk in “high risk” patients, without regard to patient HbA1c levels
■
(baseline or target)
● High risk for atherosclerotic CV disease

❍GLP-1 agonists
GLP-1 agonists produce the greatest benefit against CV events
■
● Systolic heart failure (HFrEF) & chronic kidney disease (CKD)

❍SGLT2 inhibitors
SGLT2 inhibitors have the greatest benefit to prevent progression of CKD, reduce
■
hospitalization for HF, and reduce CV events & CV death
● Patients with foot ulcers

❍SGLT2 inhibitors
a recommended treatment, after consideration of risk vs benefits
■
INSULINS

Figure 10. In Type 2 diabetes there is a progressive decline in β-cell function and insulin secretion.
As a result, most patients with type 2 DM will eventually need insulin. Adapted from Kendall
et al (2009).
A. Introduction
1. The number of patients with diabetes mellitus (DM) is growing, largely due to an epidemic of
obesity. Insulin use will also increase. HbAlc goal is <7%.
2. Physicians and their patients need to understand when to use insulin and how to apply the
principles of physiologic insulin replacement using existing and new insulins.
3. Meticulous glucose control decreases long-term microvascular complication rates.
B. Concepts
1. The islets of Langerhans (the endocrine pancreas) contain at least four different types of endocrine
cells, including A (α, alpha, glucagon-producing), B (β, beta, insulin-producing), D (delta,
somatostatin-producing), and F (PP, pancreatic polypeptide-producing). Of these, the β (insulin-
producing) cells are of the greatest abundance.
2. The most common pancreatic disease requiring pharmacologic therapy is diabetes mellitus, a
deficiency of insulin production or effect. Most patients with type 2 DM progressively lose β-cell
function. At diagnosis they have less than 50% of normal insulin secretion and less than 25% of
normal insulin secretion 6 years after diagnosis (Fig 10). This decline in β-cell function
explains the initial and secondary failure of oral agents in patients with type 2 DM. Type
1 DM starts off with no β-cell function due to massive cell lesions or necrosis.
3. Glucagon, a hormone that affects the liver, cardiovascular system and gastrointestinal tract, can

be used to treat severe hypoglycemia in diabetics.
C. Physiological Effects of Insulin and Types of Insulin Available as Therapy
Insulin is synthesized as a prohormone, proinsulin, an 86-amino-acid single-chain polypeptide.

Cleavage of proinsulin and cross-linking result in the two-chain 51-peptide insulin molecule and a 31-
amino-acid residual C-peptide. Neither proinsulin nor C-peptide appears to have any physiologic
actions.
Insulin has important effects on almost every tissue of the body. The insulin receptor, a
transmembrane tyrosine kinase, phosphorylates itself and a variety of intracellular proteins when
activated by the hormone. The major target organs for insulin action include the following:
● Liver: Insulin increases the storage of glucose as glycogen in the liver. This involves the insertion of
additional GLUT 2 glucose transport molecules in cell membranes, increased synthesis of the
enzymes, pyruvate kinase, phosphofructokinase, and glucokinase, and the suppression of several
other enzymes. Insulin also decreases protein catabolism.
● Muscle: Insulin stimulates glycogen synthesis and protein synthesis. Glucose transport into muscle
cells is facilitated by insertion of additional GLUT 4 transport molecules into cell membranes.
● Adipose tissue: Insulin facilitates triglyceride storage by activating plasma lipoprotein lipase, by
increasing glucose transport into cells via GLUT 4 transporters, and by reducing intracellular
lipolysis.
D. Hazards of insulin use:
1. Hypoglycemia: from excessive insulin effect.
1. Immunologic toxic effects from the development of antibodies: Human insulins are less antigenic
than insulin from animal sources.
1. Lipodystrophy, a change in fatty tissue at the site of injection, although common in the past, is not
seen often because of more purified, less antigenic forms of insulin.
E. Currently Available Insulin Products
Rapid acting insulins:
● Insulin lispro (Humalog ®) is recombinant human insulin that contains a transposition of two
amino acids, lysine and proline. This transposition alters the physical properties of the peptide so
that insulin lispro dissolves more rapidly at its site of administration and enters the circulation
approximately twice as fast as regular crystalline insulin. It is suitable for use immediately before
meals. Unlike other insulin preparations, increasing the dose only increases the intensity, not the
duration of effect.
● Insulin aspart (Novolog ®) contains an aspartic acid instead of proline at position 28. Neither self-
aggregate in solution as regular insulin does and they are rapidly absorbed.
● Insulin glulisine (Apridra®) contains an asparagine substituted for lysine at B3 and glutamic acid
for lysine at B29. Its absorption, action, and immunologic characteristics are similar to the other

injected rapid-acting insulins.
Short acting insulin:
● Crystalline zinc (regular) insulin, a rapid onset preparation, is used intravenously in

emergencies, or administered subcutaneously in ordinary maintenance regimens, alone or mixed
with intermediate- or long-acting preparations. Before the development of the ultra-rapid-acting
insulins, it was the primary rapid onset agent for use in tight control regimens but required
administration an hour or more before each meal.
Intermediate acting insulin:
● NPH insulin (Neutral Protamine Hagedorn, or isophane insulin suspension). Given by subcutaneous
injection. It is not suitable for intravenous use because of its particulate (cloudy) nature. NPH
contains a complex of insulin with protamine. After subcutaneous injection, tissue proteases slowly
degrade protamine, releasing insulin so that it can be absorbed. NPH is commonly used as twice-
daily basal insulin. Neutral protamine lispro (insulin lispro protamine; NPL) and protamine crystalline
(crystal) aspart, available in the US only, are premixed insulins that are functionally identical to NPH.
(Note: Lente insulin, another intermediate insulin was recently withdrawn from the market in the
US).
Long & Ultra-long acting insulins:
● Insulin glargine (Lantus ®), a modified human insulin that forms a microprecipitate in the
subcutaneous tissue, is released slowly with a peakless delivery of about 20-24 hours in most
patients, and is ultra-long-acting.
● Insulin detemir (Levamir ®), another long-acting insulin analog. The terminal threonine is dropped
from the B30 position and myristic acid (a C-14 fatty acid chain) is attached to the terminal B29
lysine). These modifications prolong the availability of the injected analog by increasing both self-
aggregation in subcutaneous tissue and reversible albumin binding.
● Insulin Degludec (Tresiba ®) is a modified form of human insulin where the last amino acid on the
B-chain has been deleted and replaced with a glutamyl link from LysB29 to a fatty acid. This
structural change allows it to form stable multiheximers at the injection site, from which soluble
monomers slowly separate and are absorbed into the circulation. This ultra-long acting insulin has a
duration of action of >40 hours, which reduces variability in plasma concentrations with once daily
dosing.
Commercial insulin preparations differ in a number of ways, such as differences in the recombinant
DNA production techniques, amino acid sequence, concentration, solubility, and the time of onset and
duration of their biologic action.
F. Insulin delivery systems:
The standard mode of insulin therapy is subcutaneous injection with conventional disposable
needles and syringes, portable pens or insulin pumps.
● Portable pen-sized injectors facilitate subcutaneous injection. Some contain replaceable cartridges

whereas others are disposable.

● Continuous subcutaneous insulin infusion devices are convenient and can deliver a constant 24-hour
basal rate via programmable insulin pumps. Manual adjustments in the rate of delivery can be
made to accommodate changes in insulin requirements (before meals or exercise)
G. Pharmacokinetics of Insulin Preparations
Commercial insulin preparations differ in a number of ways, such as differences in the recombinant
DNA production techniques, amino acid sequence, concentration, solubility, and the time of onset and
duration of their biologic action.
RAPID ACTING
Generic Name Onset of Action Peak Effect Duration of Action
Lispro, Aspart, Glulisine 5-15 minutes 45-75 minutes 2-4 hours
SHORT ACTING
Regular ~30 minutes 2-4 hours 5-8 hours
INTERMEDIATE ACTING
NPH ~2 hours 4-12 hours 18-28 hours
NPL ~2 hours 6 hours 15 hours
LONG ACTING
Detemir ~2 hours 3-9 hours 6-24 hours*
Glargine ~2 hours No peak 20 - >24 hours
Degludec ~2 hours No peak >40 hours
* Duration is dose-dependent (longer & less variable duration at higher doses); ♠ Adapted from
McCulloch, 2016

Figure 11. Subtypes and approximate durations of action of different insulin formulations. The
duration of action of regular & NPH insulin increases at higher doses (adapted from Nolte, 2009).
H. Major issues of insulin delivery and types of insulin regimens
1. Important issues include insulin pharmacokinetics, compatibility, technological issues, and costs.
2. Insulin absorption variability is the biggest confounder of efforts to mimic physiologic insulin
secretion.
3. The onset and duration of action of types of insulin vary greatly when different insulins are mixed,
by injection site, and among patients.
4. Regimens that do not mimic normal β-cell secretion are commonly referred to as “non-physiologic”
insulin replacement” (Fig. 12).
5. In general, physiologic regimens replace basal and prandial insulin (often referred to as “bolus”)
separately.
Figure 12. A) Once-daily long-acting insulin glargine (typically given at bedtime) achieves a steady-
state within ~2 hours, does not display a distinct peak, and has a 20-24 hour duration of action in
most patients. B) Intermediate-acting NPH is the oldest basal insulin that is still in common use. There
is a ~ 2-hour delay in the onset of its effect because insulin is injected as a complex of insulin &
protamine, and insulin is not free to become absorbed until protamine is digested by proteolytic
enzymes present in body tissues. Arrows indicate the time of insulin injection. Figure adapted from
DeWitt & Hirsch (2003).

Figure 13. Examples of physiologic insulin delivery. A) Once-daily glargine serves as a basal insulin
that is typically given at bedtime and has a ~24-hour duration of action. A rapidly acting insulin
(typically either lispro or aspart) are used as prandial insulins that the patient administers at meal
time. This formulation allows patients to skip meals or change meal times at will. B) Intermediate-
acting NPH, given twice daily, can be used as a basal insulin and can be combined with a rapid-acting
“prandial” insulin. This regimen (shown as a 50:50 dosage ratio) is more difficult to adjust because
NPH has both a 2 hour delay, limited duration of action, and a time course that gives it “prandial-like”
properties that can result in different levels of insulin “stacking” when another prandial insulin is
given concomitantly (see Figure 14). Figure adapted from DeWitt & Hirsch (2003).

Figure 14. Insulin stacking. The combination of intermediate-acting NPH and short-acting regular
insulin were used to mimic the physiologic time course of insulin secretion by the normal pancreas.
Each insulin functions a both a basal & prandial insulin. The timing of meals and consistency of use
are important to avoid excessive overlap of effect (insulin stacking), which increases the risk for
hypoglycemia. Many patients using this insulin algorithm will consume both a late-morning & bedtime
snack to reduce the likelihood of hypoglycemia. Moving the dinner time NPH injection to bedtime can
also decrease insulin stacking, and lower the risk of nocturnal hypoglycemia. Figure adapted from
DeWitt & Hirsch (2003).
Figure 15. Insulin infusion protocol for patients using a computerized, battery operated insulin pump.
The pump contains a reservoir of a rapid-acting or short-acting insulin that can be delivered by
continuous infusion via a subcutaneous catheter to mimic basal insulin, and by additional bolus
injections of variable volume depending on the estimated carbohydrate content (glucose load) to be
consumed with each meal or snack. Adapted from Kroon et al. (2009).
Insulin Regimens for type 1 DM
Overall, patients using insulin analogues (lispro, aspart, glargine) in physiologic regimens (e.g.
Fig.13A), including patients with hypoglycemia unawareness, have fewer hypoglycemic episodes than
patients using traditional insulins (regular and NPH) (Fig 14).
It may be that the main impact of physiologic insulin regimens and insulin glargine, in particular, is
that the separation of prandial and basal components improves our understanding of insulin use,
simplifies dosing adjustments, and allows patients more flexibility in meal timing.
CLINICAL CASES

CASE 1
Mr. Sweet, a 50-year-old musician, presents at the clinic with the complaint that for the
past several months he has been experiencing excessive thirst. He also states that he has
had to urinate more frequently, which at times interferes with his music performances. He
also states that his vision has been getting progressively blurred. While he denies any
significant past medical history, he has observed that during the past several weeks he
has been experiencing shortness of breath, which is worse on lying down and at times
wakes him up during the night, and he has to sit up in order to relieve his symptoms of
shortness of breath. He also complains of swelling of his ankles.
Question 1: What are some possible causes for increased thirst & urination?
● Answers (differential diagnosis):

❍Increased thirst:
Hyperglycemia (diabetes)
■
Alcohol
■
Amphetamines, cocaine (stimulants)

■
❍Increased urination:
Hyperglycemia (diabetes)
■
Alcohol
■
Caffeine
■
BPH, infection
■
Pathophysiology of polyuria and polydipsia in type 2 diabetes:

Essentially, the kidney serves as a filter that rids the body of waste. Since the
cells cannot utilize glucose due to either insulin resistance or deficiency or
both, the accumulating glucose in the blood must be excreted. However it
cannot be excreted alone – it must be excreted with water and thus, due to the
excess glucose, there is polyuria, which in turn, causes dehydration and
polydipsia.
Mr. Sweet is 5'6“ tall and he weighs 230 lbs. He is currently on no medications, however,
he is allergic to sulfa drugs. His physical examination shows:
● BP: 170/95 mmHg - repeated and confirmed

● HR: 90 bpm and regular
● Fundi: Multiple retinal hemorrhages
● Chest: Few bibasilar crackles, (bubble bursting sound)
● Extremities: Mild edema to mid calf
● Feet: Decreased sensation to monofilament
● Capillary blood glucose (non-fasting): 250 mg/dL (normal ~120mg/dL)
Question 2: Generate hypotheses about Mr. Sweet's condition.
● Symptoms of hyperglycemia consistent with a diagnosis of diabetes

● Symptoms of congestive heart failure (likely related to coronary artery disease)

American Diabetes Asson. Criteria for Diagnosis of Diabetes
● 1) A1C ≥6.5 percent. The test should be performed in a laboratory using certified & standardized
methods.
OR
● 2) FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least eight hours.
OR
● 3) Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT. The test should be
performed as described by the World Health Organization, using a glucose load containing the
equivalent of 75-gram anhydrous glucose dissolved in water.
OR
● 4) Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of
hyperglycemia or hyperglycemic crisis.
In the absence of unequivocal hyperglycemia, criteria 1 to 3 should be confirmed by repeat testing.
Abbreviations: A1C - glycated hemoglobin; FPG - fasting plasma glucose; OGTT - oral glucose
tolerance test.
● Question 3: What are the risk factors for diabetes?

❍obesity
❍age
❍insulin resistance
❍ethnic background (more common in Native Americans, African-American, Hispanic, some Asian
Americans)
❍family members whose first-degree relatives (mother, father, siblings, children) have diabetes
❍hypertension
❍dyslipidemia
❍gestational diabetes (in women)
● Question 4: What is the incidence of diabetes in the USA?

❍As of 2014 ~29.1 million Americans, or 9.3% of the population (niddk.nih.gov - Feb 2017);
increasing in prevalence as the population ages and becomes more obese and more sedentary.
Type 2 diabetes is now being seen in the young as well. Approximately 90% of people with
diabetes have type 2 diabetes, and the vast majority of these will die of CAD.
● Question 5: What are your clinical diagnoses at this stage?

❍Diabetes with evidence of complications: retinopathy, neuropathy and congestive heart failure as
well as hypertension and obesity.
Laboratory Analysis (Fasting) Reveals:

● Plasma glucose: 200 mg/dL (normal: 80-110)

● HgbA1C: 12% (normal: 4-6)
● Electrolytes: within normal limits
● Creatinine: 1.6mg/dL (normal: 0.8-1.3)
● Liver function tests: within normal limits
● Urine microalbumin: 200 mg/g creatinine (<30 mg/g is normal)

● Total cholesterol: 240mg/dL (normal <200)
● Triglycerides: 200mg/dL (normal <150)
● HDL: 30mg/dL (normal >45 males, >55 females)
● LDL: 170mg/dL (normal <100)
● Question 6: What is HgbA1C? What is your treatment goal?

❍The most widely used clinical test is measurement of glycated hemoglobin (also called A1C,
hemoglobin A1C, glycohemoglobin, or HbA1C). Hemoglobin formed in new red blood cells enters
the circulation with minimal glucose attached. However, red cells are freely permeable to
glucose. As a result, glucose becomes irreversibly attached to hemoglobin at a rate dependent
upon the prevailing blood glucose. Approximately one percent of erythrocytes are destroyed
every day, while an equal number of new ones are formed. Thus, the average amount of A1C
changes in a dynamic way and indicates the mean blood glucose concentration over the life span
of the red cell. Although the A1C reflects mean blood glucose over the entire 120-day lifespan of
the red blood cell, it correlates best with mean blood glucose over the previous 8 to 12 weeks. It
is now also being used to diagnose DM and pre-DM. The ADA recommends HgbA1C less than 7%.
Be aware that HgbA1C may not be accurate in individuals with conditions that may affect the normal
lifespan of hemoglobin.
● Falsely high values: Low cell turnover leads to a disproportionate number of older red cells and
falsely high HgbA1C values. This problem can occur in patients with iron, vitamin B12, or folate
deficiency anemia.
● Falsely low values: rapid red cell turnover leads to a greater proportion of younger red cells and
falsely low A1C values. Examples include patients with hemolysis or anemia and those treated for
iron, vitamin B12, or folate deficiency, and patients treated with erythropoietin.
● Falsely high/low: A1C values may be falsely elevated or decreased in those with chronic kidney
disease. False elevations may be due in part to analytical interference from carbamylated
hemoglobin formed in the presence of elevated concentrations of urea, leading to false elevations in
the A1C level with some assays. False decreases in measured A1C may occur with hemodialysis and
altered red cell turnover, especially in the setting of erythropoietin treatment.
● In such situations, fructosamine can be used to assess glycemic control.
Fructosamine
Many proteins other than hemoglobin also undergo nonenzymatic glycation,
leading to the formation of advanced glycosylation end products which may
play a direct role in the development of diabetic microvascular complications.
The serum concentration of some of these proteins can also be used to
estimate glycemic control. The term fructosamine has been applied to the
ketoamines formed in this process. Serum fructosamine values reflect mean
blood glucose values over a much shorter period of time (one to two weeks)
● Question 7: Should this patient be treated for nephropathy?

❍Yes. 30-300 mg microalbumin/g creatinine defines microalbuminuria, which is the earliest stage
of nephropathy. It is an indication for starting an ACE-inhibitor or an angiotensin receptor blocker

(ARB), even in normotensive patients. Other interventions that slow progression of nephropathy
are blood pressure control and smoking cessation.
Diabetes & kidney disease:

In diabetes, the small blood vessels in the body get injured. When the blood
vessels in the kidneys are injured, your kidneys cannot “clean your blood
properly”, and diabetes is the most common cause of kidney failure. One of the
earliest signs of diabetic kidney disease is an increased excretion of albumin in
the urine. Hypertension is an additional major cause of kidney problems in
people with diabetes. Antihypertensive drugs can slow the progression of
kidney disease significantly. Two specific types of antihypertensive drugs,
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs), have proven effective in slowing the progression of kidney
disease. Many patients require two or more drugs to control their blood
pressure. In addition to an ACE inhibitor or an ARB, a diuretic can be very
useful. Beta blockers, calcium channel blockers, and other blood pressure
drugs may also be needed. The benefits of ACE inhibitors & ARBs extends
beyond their ability to lower blood pressure. There is evidence that
they can directly protect the kidney's glomeruli. ACE inhibitors can
reduce proteinuria and slow the rate of deterioration even in diabetic patients
who do not have high blood pressure.
● Question 8: What is your blood pressure goal?

❍As recommended by the ADA in January 2015:
People with diabetes and hypertension should be treated to a systolic blood pressure (SBP)
■
goal of <140 mmHg.

Lower systolic targets, such as <130 mmHg, may be appropriate for certain individuals, such
■
as younger patients, if it can be achieved without undue treatment burden.

Patients with diabetes should be treated to a diastolic blood pressure (DBP) <90 mmHg.
■
● Question 9: What is the first line agent for controlling his hypertension?
❍ACE inhibitor (i.e., Ramipril); The American Diabetes Association lists 4 agents as first-line for
type 2 diabetes: ACE inhibitors, ARBs, beta blockers, calcium channel blockers and diuretics; ACE
inhibitor is best in this patient.
● Question 10: What is your goal for this patient’s lipids?

❍Treatment guidelines are based on LDL. For patients WITHOUT overt CVD, goal is LDL<100mg/dL
and for those WITH overt CVD, the goal is less than 70mg/dL.
● Question 11: What is first line treatment for the patient’s dyslipidemia?
❍A statin. The patient may also need niacin &/or a fibric acid derivative later on. Niacin can also
have the added benefit of increasing HDL but it also causes insulin resistance and may increase
glucose levels. Niacin can also cause symptoms of flushing – can give ASA 30 minutes before to
decrease this side effects.
● Question 12: What are your treatment options for controlling his hyperglycemia? What
should you try first?
❍Diet and exercise are often/typically tried first, although when a patient's A1C is
relatively high, diet and exercise can be used in conjunction with a first line agent.
❍When successful, lifestyle modification is very rewarding to both the patient and the
health care provider and can result in a marked improvement in overall health status.
When feasible, a trial of lifestyle modification also avoids the risks and costs of
pharmacologic therapy and allows newly diagnosed patients to adapt to the large
amount of new information they are receiving about their diabetes e.g., learning to

monitor their blood sugars and critically evaluating their diet.

❍ In this patient, so plan to also consider adding:
■ Oral agents &/or Insulin: See algorithm in Figure 16.
Management of Type 2 Diabetes
#: if not contraindicated; §: Alternative agents include: GLP-1 agonists, DPP-4 inhibitors, α-glucosidase
inhibitors & SGLT2 inhibitors.
Figure 16. Algorithm for management of Type 2 diabetes. Lifestyle interventions should be
reinforced at every visit. Check A1C every three months until A1C is <7% and then check at least
every six months thereafter. The interventions should be changed if A1C becomes ≥7%. Adapted
from Nathan et al (2009) & McCullough (2017).
After discussing treatment options with the patient, a trial of lifestyle intervention is agreed upon.
The patient enrolls in a diabetes education class for specific instruction regarding diet and exercise.
Given the patient’s obesity, a reduced-calorie diet designed to induce a slow but steady weight loss is
prescribed. Specifically, a moderate caloric restriction of 200 to 500 calories per day is recommended
with additional instruction to reduce dietary protein to 10% to 20% of total calories and dietary fat to
less than 30% of total calories, with no more than 10% of total calories to be derived from saturated
fats. The remainder of the patient’s daily caloric intake (50% to 60%) is to be derived from
carbohydrates, with emphasis on high-fiber complex carbohydrates. The patient is also instructed to
eat several small meals rather than a few large meals each day; this practice has been shown to
reduce plasma glucose and serum insulin concentrations in type 2 diabetes and to reduce LDL
cholesterol levels. Finally, the patient is instructed to increase his exercise by walking briskly for 30-

40 minutes daily.
The patient returns for follow-up 3 months later. He has gained 4 pounds despite the fact that he is
“trying to exercise” and has been watching the amount of fat in his diet. His fasting blood glucose
levels are typically between 140 and 170mg/dL, and occasional postprandial measurements have
been between 225 and 250mg/dL. Nocturia persists, and his HgbA1C remains elevated 10%. Blood
pressure is elevated at 155/95mmHg. A spot urine check reveals microalbuminuria of 66 mg/g
creatinine (reference range, 30 mg/g). A repeat fasting lipid panel reveals elevated plasma
triglycerides of 249mg/dL, total cholesterol of 220mg/dL, reduced HDL cholesterol of 33mg/dL, and a
calculated LDL cholesterol of 137mg/dL.
● Question 13: What are your treatment options for controlling his hyperglycemia at this
point? What are the advantages and disadvantages of each in this patient?
❍The patient is started on glipizide (a sulfonylurea) at 10 mg daily in an attempt to improve his
glycemic control. Three months later, the patient’s HgbA1C is 7.9%, and his creatinine is down to
1.2mg/dL. His weight has increased by an additional 8lbs, but his blood pressure is under better
at 145/90mmHg. Fasting triglycerides are 180 mg/dL and LDL cholesterol is 140mg/dL. The
patient likely has insulin resistance syndrome which is associated with obesity, hypertension,
dyslipidemia, hyperuricemia, and glucose intolerance.
● Question 14: What other medications would you consider adding at this time?
❍Options:
Metformin (if not contraindicated), a glitazone (insulin sensitizer), a GLP-1 analog, amylin
■
analog or a DPP-IV inhibitor.

Add another antihypertensive drug to better control his BP (beta-blocker, diuretic or calcium
■
channel blocker, as recommended by the ADA).

give a lipid-lowering drug, such as a statin (e.g. simvastatin).
■
Discussion points:
●
Insulin resistance is primarily an impaired metabolic response to insulin. There are many
❍
therapeutic agents that address all of the known pathogenetic factors in type 2 diabetes:
impaired β-cell function (sulfonylureas, meglitinides, insulin), inappropriate hepatic
glucose production (biguanides), obesity (intestinal lipase inhibitors, appetite
suppressants), and peripheral insulin resistance (thiazolidinediones). As a result,
achievement of target glycemic goals is now a realistic possibility for most patients with
the disease. There is no consensus on how these agents should be used in any given
patient or, for that matter, in what order they should be used.
There are many criteria that can potentially be applied to assist in this choice. For
❍
example, thiazolidinediones (glitazones) would be a logical choice for most patients with
insulin resistance.
Metformin was the only drug to significantly decrease the risk of myocardial infarction
❍
and mortality in obese patients in a large clinical trial (UKPDS). In most patients,
metformin would be the first drug for DM. Metformin has effects mainly on the liver and
acts to decrease hepatic glucose production. In this patient, however, metformin is
inappropriate because of probable CHF and creatinine levels greater than 1.5mg/dL.
Most patients with type 2 diabetes will ultimately require combination therapy to achieve
❍
target glycemic goals.
● Question 15: What are the goals of therapy in type 2 diabetes?

❍Normalize blood glucose concentrations with HgbA1c <7%
❍BP control – goal SBP <140 and even lower with nephropathy SBP<120
❍Body weight reduction
❍LDL cholesterol reduction

❍ daily aspirin
❍ Yearly retinal eye examinations
CASE 2
A 25-year-old African-American female presents to the emergency department

complaining of 2 months of polyuria, polydipsia and a 10 lb weight loss. She has no other
medical problems. On physical exam she is obese. You suspect she has diabetes.
Questions:
1. What test would you order to make the diagnosis?

2. What type of diabetes do you think she has? Why?
3. What test would you order to help you decide which type of diabetes she has?
4. She has an identical twin. Do you think her twin also will have diabetes?
5. Which acute diabetic complication should you be concerned about at this time? What are the acute
complications of diabetes?
6. Do you suspect she will have chronic diabetic complications at this time? Why or why not? What
are the chronic complications of diabetes?
7. What will be your strategy to prevent chronic diabetic complications in this patient?
8. Assuming she doesn’t have an acute complication of diabetes at this time, how would you treat
this patient?
Case 2 - Answers
1. FPG > 126 mg/dL on 2 separate occasions or random blood glucose > 200 mg/dL or Hb A1C >/=
6.5% (on 2 separate occasions).
2. Type 2 diabetes. Obesity is associated with insulin resistance. African American individuals (and
other susceptible minorities) are at increased risk for type 2 diabetes.
3. The presence of autoantibodies (IAA, GAD, IA2,) increases the likelihood of Type 1 diabetes. C-
peptide may be low with Type 1 diabetes but may be low, normal of high in Type 2 diabetes.
4. 90-100% concordance of Type 2 diabetes in MZ twins. Concordance of Type 1 variable (30-70%) in
MZ twins.
5. You want to make sure she does not have hyperosmolar hyperglycemic nonketotic state. You also
would check for evidence of infection.
Acute complications
❍
1. Diabetic Ketoacidosis (DKA) in Type 1 diabetes

The initial treatment of ketoacidosis is to administer SHORT ACTING INSULIN i.v.,
●
since this treats the cause of the problem, vs its symptoms.

2. Hyperosmolar hyperglycemic non-ketotic state in Type 2 diabetes
3. Infections and poor wound healing in all diabetics
6. In type 2 diabetes complications are present in approximately 50% of patients at the time of
diagnosis. Hyperglycemia frequently has been present for years before the disease was diagnosed.
In Type 1 DM chronic complications do not occur until after 5 years.
Chronic complications
❍
1. Retinopathy
2. Neuropathy

3. Nephropathy
4. Coronary artery disease
5. Peripheral vascular disease
6. Gastroparesis
7. Strategy to prevent chronic diabetic complications:
Tight glycemic control. Normal A1C levels.
❍
Aggressive treatment of all risk factors for macrovascular disease (smoking cessation, ASA for
❍
procoagulant state, treatment of dyslipidemia, hypertension and obesity).

Screening for and treatment of microalbuminuria/proteinuria
❍
Retinopathy screening and treatment.

❍
8. You could consider starting with diet and exercise and/or oral agent. Insulin for severe symptoms
(weight loss) or severe hyperglycemia.
Feel Like Taking A Quiz or Three?
● Insulin (10 Qs)

● Hypoglycemics (10 Qs)
● Antidiabetics (6 Qs)
References
● ADA (2017): American Diabetes Association Standards of Medical Care in Diabetes – 2017. Diabetes
Care. 40 (Suppl 1): S1-138.
● Buse JB et al (2019): 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A
Consensus Report by the American Diabetes Association (ADA) and the European Association for the
Study of Diabetes (EASD). Diabetes Care. https://doi.org/10.2337/dci19-0066
● Charbonnel B, Cariou B (2011): Pharmacological management of type 2 diabetes: the potential of
incretin-based therapies. Diabetes, Obesity and Metabolism 13:99-117.
● DeWitt DE, Hirsch IB (2003): Outpatient insulin therapy in Type 1 and Type 2 diabetes mellitus. JAMA
289(17): 2254-2264.
● Dungan K (2019): Amylin analogs for the treatment of diabetes mellitus. In: UpToDate, Basow, DS
(Ed), Waltham, MA. Cited 11/12/19
● Guo XH (2016): The value of short- and long-acting glucagon-like peptide-1 agonists in the
management of type 2 diabetes mellitus: experience with exenatide. Curr Med Res Opin. 32(1):61-
76. doi: 10.1185/03007995.2015.1103214.
● He L, Wondisford FE (2015): Metformin action: concentration matters. Cell Metab. 3;21(2):159-62.
doi: 10.1016/j.cmet.2015.01.003.
● Hollander PA et al (2001): Importance of early insulin secretion: comparison of nateglinide and
glyburide in previously diet-treated patients with type 2 diabetes. Diabetes Care. 24(6):983-8.
https://doi.org/10.2337/diacare.24.6.983
● Kendall DM et al (2009): Clinical Application of Incretin-Based Therapy: Therapeutic Potential,
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1)
there is only one biguanide available, hence the drug metformin is almost always used in place of the
“biguanide” class name
2)
older criteria were based upon creatinine clearance: >1.5 in men, >1.4 in women
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2020/01/08 20:40 1/35 Treatment of Diabetes

By the end of the self study you should be able to:

potential side effects

major advantages /disadvantages

● the list of antidiabetic drugs is growing steadily, making it very challenging to

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❍ Glinides: repaglinide, nateglinide

Short-acting: regular crystalline zinc

Long acting: glargine, detemir

Ultra-long acting: degludec

● INSULIN + GLP1 COMBINATIONS:

● Diabetes Drug Trade Names

(according to ADA Clinical Practice guidelines 2017)

5. Pre-prandial capillary plasma glucose: 80-130 mg/dl

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● Sulfonylureas (2nd Gen):

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● Sulfonylureas have once a day dosing

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DRUGS ACTING ON LIVER, MUSCLE & ADIPOSE TISSUE

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● Individuals with a significant component of insulin resistance

body tissues where glucose is stored

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● ROSIGLITAZONE & PIOGLITAZONE:

Figure 5. Glycemic mechanism of action of thiazolidinedione “insulin sensitizers” (using an adipocyte

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exerts more significant lipid-lowering effects compared to rosiglitazone (a pure PPARγ

Pharmacokinetics & Dosing:

contribute to the development of metabolic acidosis.

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BILE ACID SEQUESTRANTS

● lowers LDL cholesterol in patients with primary hypercholesterolemia. Colesevelam's mechanism of

Decreased dopaminergic tone in the hypothalamus is involved in the pathogenesis of insulin

● dizziness, vomiting, fatigue.

DPP-IV INHIBITORS (Gliptins)

Can be used as monotherapy and/or as an add-on therapy to metformin, SU or thiazolidinediones.

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● occasional reports of urticaria/angioedema, cases of pancreatitis observed, long-term safety

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● genito-urinary infections, hypotension, dehydration, potential for weight loss.

INJECTABLE NON-INSULIN HYPOGLYCEMICS

GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS

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● GI side effects: nausea, vomiting (mild to moderate; decreases with time)

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● ideally should be injected before a meal.

ADVANTAGES & DISADVANTAGES OF TREATMENT OPTIONS

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GLINIDES - insulin secretagogues

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DOPAMINE AGONIST - modulates hypothalamic regulation of metabolism

American Diabetes Assn 2020 Update

● High risk diabetic patients

● High risk for atherosclerotic CV disease

● Systolic heart failure (HFrEF) & chronic kidney disease (CKD)