Newer OHA and insulin

Newer oral hypoglycemic agents
and newer insulins
Dr. Namrata Vithalani
(DNB Resident General Medicine)

Diabetes mellitus
 Definition: a syndrome of disordered metabolism due to a
combination of hereditary and environmental causes

SGLT2 Inhibitors
(Gliflozins)
Sodium-glucose
co-transporter-2
(SGLT-2)
inhibitors

Actions
 SGLT2, a protein , is the predominant transporter
responsible for the reabsorption of glucose from
the glomerular filterate back into the circulation.
 There are two such transporters.
SGLT1 : Distal portion of PCT
SGLT2 : Proximal portion of PCT
SGLST1SGLT : Distal portion of PCT
 SGLT2: Proximal portion of PCT

SGLT 2
Renal Handling of Glucose
(180 L/day) (1000 mg/L) = 180 g/day
10%
90%
NO
GLUCOSE
S3
S1
SGLT1

 SGLTs-Na+/D-glucose co-transporters( secondary
active transporters) are located at the luminal
membrane of the tubular cells.
 This active tranporter, hydrolyzes ATP and uses
the released energy for the transportation of
sodium ions out of the cell into interstitium.
This mechanism is responsible for low sodium
concentration and the negative potential of the
tubular cells. After entering the cells, glucose
exists across the basolateral membranes.

Glucose Transport in Tubular Epithelial Cells
G Glucose
Na+ Sodium K Potassium
BloodLumen
S1 Proximal Tubule
G
Na+
K
GLUT2
ATPase
SGLT2
High
Capacity
Low
Affinity
BloodLumen
S3 Proximal Tubule
G
2Na+
2K
GLUT1
ATPase
SGLT1
Low
Capacity
High
Affinity
Adapted from Bakris GL et al. Kidney Int 2009;75:1272-7
Marsenic O. Am J Kidney Dis. 2009;53:875-83

SGLT2 Inhibition Reduces Renal Glucose Reabsorption and
Increases Urinary Glucose Excretion
Decreased glucose reabsorption into
systemic circulation
Glucose SGLT1SGLT2 SGLT2 inhibitor
Glomerulus Proximal Convoluted Tubule
Early Distal
Glucose in urine
Adapted with permission from Rothenberg PL et al.
SGLT = sodium-glucose co-transporter.
1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. 2. Rothenberg PL et al. Poster presented at: 46th European Association
for the Study of Diabetes Annual Meeting; September 20-24, 2010; Stockholm, Sweden. 3. Cowart SL, Stachura ME. In: Walker HK et al, eds. Clinical Methods: The
History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA: Butterworths; 1990:653-657. 4. Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14(6):782-
790. 5. Oku A et al. Diabetes. 1999;48(9):1794-1800.

Glucose
SGLT2
SGLT1
SGLT2i
P
C
T
– Selective SGLT2 inhibitorsb reduce blood
glucose levels by increasing renal
excretion of glucose((UGE) ~ 77-119
grams/day, thereby reducing plasma glucose.
– UGE induction results in increased caloric loss
(320-480 kcal/day ) (1g glucose=4kCal )
leading to weight loss ( Composite
benefits).
– Osmotic effect with the diuretic effect leading
to reduction in systolic blood
pressure.
↓ Blood
Glucose
Glucosuria
Figure Developed by Janssen India MAF
↑ Blood
Glucose
Mechanism of Action
Inhibition of Glucose Reabsorption in the PCT
SGLT2=sodium glucose co-transporter 2.

 Forxiga ( Dapagliflozin)
Invokana ( Canagliflozin)
Jardiance ( Empagliflozin)

Urinary glucose excretion- Core mechanism
Reference:
prescribing information Data just represent the UGE loss by each drug from their respective Prescribing
information

Mechanism of Action
Effect on Renal Threshold for Glucose (RTG)
• Renal Threshold for Glucose (RTG )
in healthy human is ~180 mg/dL.
• RTG is increased in T2DM from 180
to ~240 mg/dL
• Inhibition of SGLT2 transporters
lowers RTG to 70 – 90 mg/dL.
– Decreased RTG increases
Urinary Glucose Excretion
(80-120 g/day).
– Mechanism of Action is
Independent of Insulin
1. Nomura S, et al. J Med Chem. 2010; 53(17):6355-6360.
2. Sha S, et al. Diabetes Obes Metab. 2011;13(7):669-672.
3. Liang Y, et al. PLoS One. 2012; 7(2):e30555.
4. Devineni D, et al. Diabetes Obes Metab. 2012.
5. Rosenstock J, et al. Diabetes Care. 2012
0
50
100
150
200
250
300
RenalThresholdforGlucose
(mg/dL)
Till BG ~ 180mg/dL,
no glycosuria.
Till BG ~ 240mg/dL,
no glycosuria.
At BG >70-90mg/dL,
there is glycosuria.
Leading to increased
Urinary Glucose
Excretion and decreased
HbA1c
BG: Blood Glucose
Healthy T2DM SGLT2i
SGLT2=sodium glucose co-transporter 2.

Side effects
Hypotension
Recurrent vulvovaginal
infections
Weight loss

Advantages
 Hypoglycemia rare with monotherapy (action
is independent of insulin)
 Causes weight loss
 Reduces blood pressure ( both systolic and
diastolic)
 Can be combined with other oral drugs,
insulin.
 A novel mode of action

SGLT2 Inhibition: Meeting Unmet
Needs In Diabetes Care
Corrects a Novel
Pathophysiologic
Defect
Reduces
HbA1c
Promotes
Weight Loss
Complements
Action of Other
ADA
Reduces
Blood
Pressure
No
Hypoglycemia
Improves
Glycemic
Control
and CVRFs
Reversal of
Glucotoxicity
CVRF: CardioVascular Risk Factors
ADA: Anti Diabetic Agents

SGLT2 INHIBITOR: WHERE DO THEY FIT IN THE
TREATMENT ALGORITHM
● 2nd line:Add-on to: MET, SU, PIO
● 3rd line :Add-on to oral combo therapy
● 4th /5th line :Double/Triple combo therapy
● Add-on to any insulin in T2DM
● ?Cannot be combined with GLP 1 agonists(ADA-
2016)
??? 1st line:Monotherapy
CURRENTLY ONLY IN T2DM

Second line therapy
ADA Guidelines : 2016
( American diabetic
association)

First line therapy
AACE/ACE Guidelines : 2015
AACE ( American aasociation of clinical Endocrinologists)/ ACE ( American college
of Endocrinology) Comprehensive Diabetis Management Algorithm

AACE/ACE Comprehensive Diabetes Management Algorithm
2015
AACE(American Association of Clinical Endocrinologists)/ACE (American College of Endocrinology)Comprehensive Diabetes Management
Algorithm, Endocr Pract. 2015;21(No. 4)
SGLT2 inhibitors are placed
above DPP4 inhibitors

Where I would not use it?
 Type 1 diabetes
 Patients > 75 years
 Patients with eGFR < 45mL/min
 Pregnancy and nursing women
 Patients with recurrent UTI/ GUI
 Patients with history of volume
depletion, dehydration, hypotension

Summary
 Novel, B cell independent mode of action
 Consistent and sustained reduction in blood
glucose and HbA1c
 Reduction in body weight
 Reduction in systolic and diastolic blood pressures
 No risk of hypoglycaemia
 Genital infections can occur
 Recommended as first or second line of treatment

Incretin based Therapies
 What is incretin effect?
 The phenomenon of an equivalent dose of
glucose producing a greater secretion of
insulin when administered orally versus
intravenously is known as 'the incretin
effect'. The incretin system is thought to be
responsible for up to 70% of insulin secretion
in response to oral glucose or a meal.

Insulin secretion profilesInsulinconcentration
0 10 20 30 40 50 60 70 80 90
minutes
Glucose given orally
Glucose given intravenously

Iso-glycaemic profiles
Insulinconcentration
0 10 20 30 40 50 60 70 80 90
minutes
Glucose given orally
Glucose given intravenously
to achieve the same profile
Incretin effect

Incretin hormones and their actions
 Following major incretin hormones secreted from the gut
control this gastrointestinal (GI) signalling pathway:
 glucagon-like peptide-1 (GLP-1) and
 glucose-dependent insulinotropic polypeptide (GIP).
 Release of these hormones occurrs after food intake.
Following secretion, both GLP-1 and GIP are rapidly
broken down into inactive, truncated peptides by
dipeptidyl peptidase-4 (DPP-4), a proteolytic enzyme
ubiquitously expressed on the surface of endothelium and
epithelial cells.

GLP-1 localisation
 Cleaved from proglucagon in intestinal L-cells
(and neurons in hindbrain/hypothalamus)
 Secreted in response to meal ingestion
 Cleared via the kidneys

Actions of incretins
 Incretin hormones play an integral
role in glucose haemostasis; blood
glucose is lowered through a
combination of
 potentiation of insulin synthesis
and secretion
 inhibition of glucagon release
 reduction in hepatic glucose

GLP-1 has diverse physiological roles
in addition to its effect on insulin and
glucagon secretion, which are
mediated by its specific receptor (
GLP-1R ), expressed in multiple
organs: pancreas, heart, kidney,
stomach, lungs, intestine, pituitary,
endothelium and CNS

Actions of incretin hormones
Organ Action
Pancreas  Increased insulin secretion and B cell
sensitivity
 Increased insulin synthesis
 Decreased glucagon secretion
 Increased beta cell mass
Brain Increased satiety/Decreased appetite leading
to weight loss
Liver Decreased heapatic glucose output
GIT Decreased gastric emptying helps in weight
loss
Heart Decreased systolic BP
?Cardioprotection following MI

Now for the bad News…………..

GLP-1 is short-acting
Modified fromJLarsen etal: Diabetes Care2001;24:1416-1421
After 7 days
Control
Blood glucose
profiles
24-h/dayGLP-1 s.c. infusion
16-h/dayGLP-1 s.c. infusion
100
200
300
400
04 06 08 10 12 14 16 18 20 22 00 02 04 06
BloodGlucose
(mg/dl)
Time
400
100
200
300
04 06 08 10 12 14 16 18 20 22 00 02 04 06
BloodGlucose
(mg/dl)
Time

His Ala Glu Gly Thr Phe Thr Ser Asp
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Ile Ala Trp Leu Val Lys Gly Arg Gly
Val
Ser
Glu
Phe
GLP-1
7
37
NH2
Native GLP-1 has short duration of action
(t½=2.6 minutes) when given intravenously
DPP IV

Native GLP-1 is rapidly degraded by DPP-IV
Human ileum,
GLP-1producing
L-cells
Capillaries,
DiPeptidyl
Peptidase-IV
(DPP-IV)
Adaptedfrom:Hansenetal.Endocrinology1999:140(11):5356-5363

So is that a dead-end for drug
development in this area ………….?

Incretin based therapies
A.GLP-1 Receptor Agonists
B.DPP-4 Inhibitors

GLP-1 Receptor Agonists
 The role of the incretin system in the pathophysiology of diabetes was
confirmed with data demonstrating a reduced incretin effect in subjects with
type 2 diabetes (T2D).
 Despite its pharmaceutical promise, native GLP-1 has a very short
physiological half-life because of DPP-4 degradation: approximately 1·5 min
following intravenous (IV) infusion and 1 h after subcutaneous (SC)
injection. Therefore, to be clinically effective as a diabetes therapy, native
GLP-1 would have to be given as a continuous infusion.
 For this reason, the clinical focus for potential treatments for T2D has shifted
towards long-acting GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors
(DPP-4Is).

Drugs available
 Currently, three GLP-1RAs are commercially available:
 Twice-daily (BID) exenatide
 Once-weekly exenatide extended release (exenatissde ER).
 Once-daily (OD) liraglutide
 Longer-acting GLP-1RAs are created by bioengineering of the native GLP-1
peptide; therefore, as these drugs are protein-based, they need to be
administered by SC injection.
 Exenatide is a synthetic form of exendin-4, a protein extracted from the saliva of
the Gila monster lizard.
 Similarly, liraglutide is a GLP-1 analogue, sharing 97% sequence identity with
native GLP-1; Liraglutide, is almost identical to native GLP-1 except for an amino
acid substitution and addition of a fatty acyl group (coupled with a-glutamic acid
spacer) that promote binding to albumin and plasma proteins and prolong its
half-life.

Table 1. Dose and administration of the incretin-based therapies
Therapy Dose Administration
GLP-1 receptor agonists:
Liraglutide (Victoza®,
Novo Nordisk)
0·6, 1·2, 1·8 mg† SC, OD
Exenatide
BID (Byetta®, Amylin
Pharmaceuticals)
5, 10 μg SC, BID
Exenatide
ER2 (Bydureon®, Amylin
Pharmaceuticals)
2 mg SC, QW(once every week)
DPP-4 inhibitors:*
Sitagliptin 16 (Januvia®,
Merck & Co)
25, 50, 100 mg Oral, OD
Vildagliptin 17 (Galvus®,
Novartis)
50 mg Oral, BID
Saxagliptin 18 (Onglyza®
, AstraZeneca/Bristol-
Myers Squibb)
2·5, 5 mg Oral, OD
Linagliptin 19 (Tradjenta
®, Boehringer 5 mg Oral, OD

Actions and advantages
 Low risk of hypoglycemia: These studies determined that the effect of GLP-1 on
insulin secretion is glucose-dependent, only observed when glucose levels are
normal or elevated, but not when glucose levels are low. This key discovery
highlighted that drugs targeting GLP-1 have the potential to be effective glucose-
lowering therapies for T2D with a low risk of hypoglycaemia.
 Weight loss:In addition to glycemic effects, GLP-1-based therapies have a
beneficial effect on weight, because of their inhibitory effect on appetite via the
gut–brain axis. Such a drug would have advantages over traditional antidiabetes
treatments, which are largely associated with weight gain.
 When compared with insulin glargine as an add-on to OADs, exenatide ER showed
greater reductions in glycemic control , accompanied by weight loss of 2·6 kg
compared with weight gain of 1·4 kg.

Actions and advantages
 A significant reduction in systolic blood pressure (SBP)
relative to placebo and insulin, with a weak correlation to
weight loss .
 Decreases in lipids of 20% or more have been reported
with exenatide ER, but changes in other lipids have been
less reproducible and may be related to weight loss.
 One year of treatment with exenatide BID led to
significant improvements in β-cell function, which did not
persist after cessation of therapy

Side effects and risks
 The most common adverse events are GI side effects for both
liraglutide and exenatide groups, including nausea, vomiting and
diarrhoea. Although nausea is common with all GLP-1RAs –
experienced in up to 50% of subjects – this side effect is transient,
as the proportion of subjects experiencing nausea has been shown
to reduce significantly over time.
 but nausea is less persistent with liraglutide 1·8 mg compared
with exenatide BID (P < 0·0001).
 Nausea and vomiting are less common with exenatide ER
compared with exenatide BID.[26]
 Hypoglycemia does not occur.

Side effects
 Antibodies: Liraglutide has a greater sequence identity with native GLP-1 than
exenatide (97% vs 53% identity, respectively). Potentially, this may mean that
liraglutide is less immunogenic than exenatide; Patients treated with liraglutide had
insignificant increase in antibodies while patients treated with exenatide had
significant increase in antibodies which decreased its anti hyerglycemic action.
 Medulary carcinoma of thyroid. Liraglutide carries a black box warning from the
FDA because of an increased risk of thyroid C-cell tumors in rodents and is
contraindicated in individuals with medullary carcinoma of the thyroid and multiple
endocrine neoplasia.
 Because GLP-1 receptor agonists slow gastric emptying, they may influence the
absorption of other drugs
 Pancreatitis:Noted with certain drugs but exact cause effect relation has not been
established.

Comparing Exenatide and Liraglutide
 As exenatide requires twice daily administration and does not
provide 24-h GLP-1R activation, there has been considerable
interest in development of GLP-1R analogues with more
prolonged durations of action suitable for once-daily or once-
weekly administration . Consistent with the notion that
continuous GLP-1R activation is required for optimal
glucoregulation, liraglutide administered once daily and
exenatide administered once weekly when compared with
twice-daily exenatide appear to be
 more potent glucose-lowering agents, relative to
 Furthermore, they seem to be associated with better
tolerability and patient-reported outcomes as well as trends
toward greater benefit on cardiovascular disease risk factors.

Exenatide BID Liraglutide/Exenatid
e ER
Reduction in HbA1C Less More
Effects on FBS Less More
Effects on PPBS More Less
Weight reduction Less More(3.7kg)
B cell function
improvement
Less More
Side effects:Nausea More persistent Less persistent
Immunogenecity More Less
Rodent medullary
thyroid cancer
No Reported with
liraglutide
Renal failure Avoid or dose
reduction
Safe(Liraglutide)
Administration Twice daily Daily or once weekly

 As GLP-1 (and GIP) is degraded by DPP-4, modulation of native GLP-1 levels
through inhibition of DPP-4 represents another potential antidiabetes therapy.
DPP-4Is are small molecule oral treatments that compete with DPP-4
substrates for the active site of the enzyme.
 Drugs available are:
Sitagliptin/Saxagliptin/Linagliptin/Vildagliptin

Indications
 an adjunct to diet and exercise to improve glycaemic control in subjects with
T2D as monotherapy for whom metformin is contraindicated, or
 as combination therapy with metformin
 and/or a TZD
 and/or an SU
 and/or insulin.

 Advantages
 Weight neutral(no increase or decrease)
 No risk of hypoglycemia
 Side effects
 Nasopharyngitis
 Allergic reactions

Comparing DPP-4Is
 At present, no DPP-4I has shown superiority over the others available, as
results are broadly similar for linagliptin, vildagliptin, saxagliptin and
sitagliptin.
 Linagliptin does not need dose adjustment in renal failure while all other
need adjustment or are to be avoided.
 Teneligliptin also is safe in renal and hepatic failures.It is the cheapest gliptin
available at present.

Comparing GLP-1RAs and DPP-4Is
 GLP-1RAs and DPP-4Is modulate the incretin system using different modes of
action: GLP-1RAs via pharmacological doses of exogenous GLP-1 mimetics
and DPP-4Is by enhancing physiological levels of endogenous GLP-1. As a
result, GLP-1RAs have a more potent efficacy profile than DPP-4Is, but are
associated with increased GI side effects.

GLP1
analogues
DPP-4 inhibitors
Levels of GLP1achieved in blood Pharmacological Physiological
Hypoglycemic action More Less
Reduction in HbA1C More(0.8 to 1.9) Less(0.5 to1.0)
Inhibition of gastric emptying Yes Marginal
Effect on bodyweight Decreased No effect(Weight
neutral)
Blood pressure Decreased(1-7mm of
Hg)
No efect
Lipids(Triglycerides) Decreased(12-
40mg/dl)
No effect
Side effects:Nausea Yes No
Side effects:Nasopharyngitis No Yes
Side efects:Allergy Yes Yes
Side efects :Antibody formation 30-67%E,8%L No
Side efects: Medullary carcinoma of
thyroid
Found in animal
studies with
Liraglutide hence
black box warning
for liraglutide
No
Route of administration Subcutaneous Oral
Cost Expensive Cheap

Sitagliptin - Overview
 1st approved member of a new class of OAHA - DPP-4 inhibitor
 Potent, highly selective, reversible and competitive inhibitor of DPP-
4 enzyme
 Approved by the FDA on October 17 2006. EU approval March 2007
N
ONH2
N
N
CF3
F
F
F
N

Clinical Pharmacology of Sitagliptin: Pharmacokinetics
and Drug Interactions
 Pharmacokinetics
 Tmax (median): 1 to 4 hours postdose
 Apparent t½ (mean): 12.4 hours
 Metabolism: approximately 79% excreted unchanged
in urine
 Based on in vitro data, sitagliptin does not inhibit CYP isozymes CYP3A4, 2C8, 2C9,
2D6, 1A2, 2C19, or 2B6 or induce CYP3A4
59
33

Adverse Experiences Reported in ≥3% of Patients
and Greater than Placeboa
Sitagliptin 100
mgc
n = 1082
Placeboc
n = 778
Upper Respiratory
Tract Infection
6.8 6.7
Nasopharyngitis 4.5 3.3
Diarrhea 3.0 2.3
†Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA
48

Summary – Safety + Tolerability
7 specific AEs
Chills
Naso-pharyngitis
Meniscus lesions
Nasal congestion
Contact dermatitis
Osteoarthritis
TremorPooledsafety. Stein et al. ADA2007

Sitagliptin AUC0–inf Increased With
Decreasing Creatinine Clearance
AUC GMR increase <2-fold
when CrCl >50 mL/min
Dose adjustments
<30 mL/min:¼ dose (25mg OD)
30–50 mL/min:½ dose (50mg OD)
>50 mL/min:full dose (100mg OD)
Dose-Adjusted(to50mg)AUC,μM/h
0
4
8
12
16
20
24
28
Creatinine Clearance, mL/min
10 30 50 70 90 110 130 150 170 190 210 230

Patients With Renal Insufficiency
Renal
Insufficiency
Mild Moderate
Severe and
ESRD*
Increase in
Plasma
AUC of
Sitagliptin†
~1.1 to
1.6-fold
increase‡
~2-fold
increase
~4-fold
increase
Recommend
ed Dose
100 mg
no dose
adjustment
required
50 mg 25 mg
S
e
c
t
i
o
n
s
2;
12.3

Sitagliptin Has a
Weight Neutral Profile
 Monotherapy studies
 No increase in body weight from baseline with sitagliptin
compared with a small decrease in the placebo group
 Add-on to metformin
 A similar decrease in body weight for both treatment groups
 Add-on to pioglitazone
 No significant difference in body weight between treatment
groups
 Noninferiority vs Sulfonylurea
A significant reduction in body weight with sitagliptin versus
weight gain with glipizide
46

Saxagliptin
Review of Safety and Tolerability

Saxagliptin: Incidence of Adverse Events
Overall Incidence of Adverse Events Was Similar to Placebo
 Hypersensitivity-related
events (such as urticaria and
facial edema) were reported
in 1.5% who received
Saxagliptin 5 mg, Saxagliptin
2.5
Pooled Analysis of Adverse Reactions
Occurring in ≥5% of Patients and More
Commonly Than Placebo
Saxagliptin
5 mg
(N=882)
Placebo
(N=799)
Upper
respiratory
tract infection
7.7% 7.6%
Urinary tract
infection
6.8% 6.1%
Headache 6.5% 5.9%
In Monotherapy and Add-On Therapy Studies*
Percent of Patients
*Prespecified pooled analysis of 2 monotherapy studies, the add-on to MET study, the add-on to the SU glibenclamide study,
and the add-on to a TZD study; 24-week data regardless of glycemic rescue.

Incidence of Adverse Events in Initial
Combination With MET
Adverse Reaction Occurring in ≥5%
Patients and More Commonly Than
MET Plus Placebo
Saxagliptin
5 mg
+ MET
(N=320)
MET +
Placebo
(N=328)
Headache 7.5% 5.2%
Nasopharyngi
tis
6.9% 4.0%
In Initial Combination With MET Study*
Percent of Patients
*Metformin was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2000 mg daily.
Jadzinsky M et al. Diabetes Obes Metab. 2009;11:611-622.

Saxagliptin: Discontinuation of Therapy Due
to Adverse Events
 Discontinuation of therapy due to adverse events occurred in 3.3% and 1.8% of patients receiving Saxagliptin and placebo, respectively
 There was a dose-related mean decrease in absolute lymphocyte count observed with Saxagliptin
Most Common Adverse Events Associated
With Discontinuation of Therapy*
Saxagliptin
5 mg
(N=882)
Saxagliptin
2.5 mg
(N=882)
Comparato
r (N=799)
Lymphopenia 0.5% 0.1% 0.0%
Rash 0.3% 0.2% 0.3%
Blood creatinine increase 0.0% 0.3% 0.0%
Blood creatine
phosphokinase increase
0.2% 0.1% 0.0%
Percent of Patients
*Reported in at least 2 patients treated with Saxagliptin

Drug Interactions and Use in Specific Populations
Drug Interactions
Saxagliptin should be limited to 2.5 mg when coadministered with a
strong CYP3A4/5 inhibitor (e.g., atazanavir, clarithromycin, indinavir,
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir,
saquinavir, and telithromycin).
Use in Specific Populations
Pregnant and Nursing Women: There are no adequate and well-
controlled studies in pregnant women
Pediatric Patients: Safety and effectiveness of Saxagliptin in pediatric
patients have not been established.

Saxagliptin: Renal Impairment
 Mild Impairment, creatinine clearance [CrCl] ≤50 mL/min:
No dosage adjustment
 Moderate or severe renal impairment, or with end-stage
renal disease (ESRD) requiring hemodialysis (creatinine
clearance [CrCl] ≤50 mL/min). Saxagliptin 2.5 mg is
recommended.
 Saxagliptin should be administered following hemodialysis
when used in that scenario. Saxagliptin has not been studied
in patients undergoing peritoneal dialysis.
 Assessment of renal function is recommended prior to
initiation of Saxagliptin and periodically thereafter.

Saxagliptin: Hepatic Impairment
 In subjects with hepatic impairment (Child-Pugh classes
A, B, and C)
 Mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively,
compared to healthy matched controls following administration of a single 10 mg dose
of saxagliptin.

 The corresponding Cmax and AUC of the active metabolite were up to 59% and 33%
lower, respectively, compared to healthy matched controls.
 These differences are not considered to be clinically
meaningful.
 No dosage adjustment is recommended for patients with
hepatic impairment

Patients at risk
Control 1,251 935 860 774 545 288 144 123 102 57
All
saxagliptin 3,356 2,615 2,419 2,209 1,638 994 498 436 373 197
Cardiovascular events:
Saxagliptin controlled Phase 2b/3 pooled population
Time to onset of first primary Major Adverse Cardiovascular Event
(MACE)*
All saxagliptin
Control
0 24 37 50 63 76 89 102 115 128
0
1
2
3
4
5
Weeks
Firstadverseevent(%)
* Primary MACE was defined as was defined as stroke (cerebrovascular accidents), MI, and CV death

Comparing the Gliptins
Sitagliptin Vildagliptin Saxagliptin
Dosing OD BD OD
Renal Failure Approved Not Approved Approved
Hepatic Failure No info No info Safe
With Insulin Not Approved Approved Studies Pending
On Bone Improved BMD? Unknown Unknown
Infections Slight increase Neutral Neutral
UTI, URI
Cardiac Impact Reduced Neutral ?reduced CV mortality
post ischaemic stunning

Where do Incretin-based
Therapies Fit in Current
Treatment Strategies?(Current
status of Incretin-based
therapies)

ADA guidelines-2016
 GLP 1 agonists and DPP4 inhibitors cannot be combined.
 SGLT2 inhibitors and GLP 1 agonists cannot be combined.
 Although not yet approved for this indication, incretin-
based therapies have potential in the treatment of type 1
diabetes (T1D) as an add-on to insulin.

Conclusions
 Drugs that target the incretin system use an alternative mode of action compared
with traditional antidiabetes therapies, enhancing insulin secretion only when
glucose levels are high. Clinical trials have demonstrated that both GLP-1RAs and
DPP-4Is are attractive therapies for the treatment of T2D, offering effective
glycaemic control with an inherent low risk of hypoglycaemia.
 As a class, the strengths of the GLP-1RAs are as follows: considerable reductions
in HbA1c [between 0·8 and 1·9% (8·7–20·8 mmol/mol)], alongside significant weight
loss (up to 3·7 kg over 52 weeks), with potential benefits for CV and β-cell
function. In most patients, these benefits outweigh the potential disadvantages of
GI side effects and the fact that administration is via SC injection.
 In contrast, the adverse event profile and the route of administration are two of
the key benefits of the DPP-4Is. Glycaemic control provided by DPP-4Is is
moderate [0·5–1·0% (5·5–10·9 mmol/mol)], albeit not as effective as GLP-1RAs,
and on balance, DPP-4Is appear weight-neutral.

Injectable amylin analogues
 Actions:
 slow gastric emptying
 supresses glucagon
 Pramlintide ( the only clinically available amylin analogue
: administered by s.c. injection )
 Adverse effect : nausea
 Typical reductions in HbA1c are 0.5- 1 %

Before Insulin
Before insulin was discovered in 1921, everyone with type 1 diabetes
died within weeks to years of its onset
© 2004, John Walsh, P.A., C.D.E.
JL on 12/15/22 and 2 mos later

Insulin analogues
 Insulin analogues are created by genetic engineering by
chanaging sequence of amino acids in insulin
molecule(lispro,aspart,glulisine,glargine) or by adding a
molecule(detemer,degludec) which slightly differs from
human insulin. This changes the pharmacokinetics of
insulin without affecting their hormonal actions.

Types
 These modifications have been used to create two types of insulin
analogs:
 Short acting: Lispro, Aspart, glulisine
 Long acting: Glargine, Detemer, Degludec
 Premixed insulins: They are obtained by mixing short acting analogues
with conventional long acting insulins or analogue long acting insulins
( Degludec).

Physical and chemical properties of
human insulin
 Human insulin is a polypeptide 51 amino acids .there are two chains Alpha(21
amino acids) amd beta(30 amino acids) linked by two disulphide bridges.
 Unmodified human and porcine insulins tend to complex with zinc in the
blood, forming hexamers. Insulin in the form of a hexamer will not bind to its
receptors, so the hexamer has to slowly equilibrate back into its monomers
to be biologically useful. Hexameric insulin delivered subcutaneously is not
readily available for the body when insulin is needed in larger doses, such as
after a meal (although this is more a function of subcutaneously administered
insulin, as intravenously dosed insulin is distributed rapidly to the cell
receptors, and therefore, avoids this problem). Zinc combinations of insulin
are used for slow release of basal insulin..

Physical and Chemical Properties of Human Insulin
α-chain
β-chain
Zn++
Zn++
Self-aggregation
in solution
Monomers
Dimers
Hexamers
(around Zn2+)
21 amino acids
30 amino acids

Insulin Analogues: Chemical Properties
Human Insulin
Dimers and hexamers
in solution
Lispro
Limited self-aggregation
Monomers in solution
Aspart
Glargine
Soluble at low pH
Precipitates at
neutral (subcutaneous) pH
Glulisine
Asp
Lys Glu
Lys Pro
Gly
Arg Arg

Insulin Analogues:Chemical Structure & Mechanism
Name Chemical structure Mechanism
Short acting Lispro Penultimate lysine and proline residues on the C-terminal end of the B-chain were reversed. Less tendency to self
aggregate leading to
less formation of
insulin dimers and
hexamers and more
insulin in monomer
form.This allows faster
absorption of insulin .
Aspart Amino acid, B28, which is normally proline, is substituted with an aspartic acid residue.
Glulisine Amino acid lysine in position B29 is replaced by glutamic acid and the asparagine at position B3 is
replaced by lysine.
Basal
(Long
acting)
Glargine  Asparagine at position 21 in the A-chains replaced by glycine.
 Two positively charged arginine molecules were added to the C-terminus of the B-chain.
Shifts the isoelectric
point from 5.4 to 6.7,
making glargine more
soluble at a slightly
acidic pH and less
soluble at a
physiological pH.
Detemir  Fatty acid tail added (myristic acid) to lysine at B29. Binds to albumin in
blood from where it is
slowly released
Degludec  Amino acid threonine at position B3wa s re m o ve d a n d a 1 6 - c a r bo n f a tty d ia
-c i d c h a i n hexadecandioyl was added at B29 via a glutamic acid spacer (linker ) L-γ-
Glutamate.
Formation of long
chain multihexamers
results in heavy
molecular weight
complex and slow
release of insulin
monomers to the blood
stream.

Rapid acting
 Above physiological concentrations, such as those present in the injectable
preparations, native human insulin self aggregates & forms dimers and
hexamers, which inhibit its rapid absorption from the injection site .
Therefore, by changing the amino acid sequence of human insulin , analogs
are developed with a decreased tendency to self-aggregate and thus
decreased tendency to form dimers and hexamers.
 This facilitates absorption and helps achieve rapid action.

Absorption rates depend on the size of
molecule

96
Short-acting (regular) insulins
e.g. Humulin R, Novolin R
Uses Designed to control postprandial
hyperglycemia & to treat
emergency diabetic ketoacidosis
Physical
characteristics
Clear solution at neutral pH
Chemical
structure
Hexameric analogue
Route & time of
administration
S.C. 30 – 45 min before meal
I.V. in emergency
(e.g. diabetic ketoacidosis)
Onset of action 30 – 45 min ( S.C )
Peak serum levels 2 – 4 hr
Duration of action 6 – 8 hr
Usual
administration
2 – 3 times/day or more
Ultra-Short acting insulins
e.g. Lispro, aspart, glulisine
Similar to regular insulin but
designed to overcome the
limitations of regular insulin
Clear solution at neutral pH
Monomeric analogue
S.C. 5 min (no more than 15 min)
before meal
I.V. in emergency
(e.g. diabetic ketoacidosis)
0 – 15 min ( S.C )
30 – 90 min
3 – 4 hr
2 – 3 times / day or more

Rapid acting
 Rapid onset of action,rapid clearence from circulation
 Can be administered immediately before meals and sometimes even after
meals(Regular insulin has to be given half an hour before the meal)
 Closely match circulating insulin levels seen physiologically after a
carbohydrate rich meal)
 The rapidity of action is also of benefit in situations where rapid reduction of
glycaemia is required, as, for example, in diabetic keto-acidosis, or post
acute myocardial infarction.
 Shorter duration of action reduces chances of hypoglycemia.

102
Intermediate - acting insulins
e.g. isophane (NPH)
Turbid suspension
Injected S.C.(Only)
Onset of action 1 - 2 hr
Peak serum level 5 - 7 hr
Duration of action 13 - 18 hr
Insulin mixtures
75/25 70/30 50/50 ( NPH / Regular )

103
3. Intermediate - acting insulins (contd.)
Lente insulin
Turbid suspension
Mixture of 30% semilente insulin (smaller particles
and amorphous) and 70% ultralente insulin (large
particles insoluble in water)
Injected S.C. (only)
Onset of action 1 - 3 hr
Peak serum level 4 - 8 hr
Duration of action 13 - 20 hr

104
3. Intermediate - acting insulins (contd.)
Lente and NPH insulins
Are roughly equivalent in biological effects.
They are usually given once or twice a day.
N.B: They are not used during emergencies
(e.g. diabetic ketoacidosis).

105
4. Long – acting insulins
e.g.Insulin glargine
Onset of action 2 hr
Absorbed less rapidly than NPH&Lente insulins.
Duration of action upto 24 hr
Designed to overcome the deficiencies of intermediate acting
insulins
Advantages over intermediate-acting insulins:
Constant circulating insulin over 24hr with no pronounced peak.
More safe than NPH&Lente insulins due to reduced risk of
hypoglycemia(esp.nocturnal hypoglycemia).
Clear solution that does not require resuspention before administration.

Long acting(basal) insulins
 Basal insulin is the amount the body needs through the day excluding the
amount needed after meals
 Glargine(Lantus)
 Detemir(Levemir)
 Degludec(Tresiba-Novo)

108
Profile of Insulin Glargine vs NPH
Glargine
NPH

Glargine
 Structure:
 Asparagine at position 21 in the A-chains replaced by glycine.
 Two positively charged arginine molecules were added to the C-terminus of the B-
chain.
 Normal unmodified insulin is soluble at physiological pH.Glargine is designed in
such a way that its isoelectric point is shifted from ph 5.4 to 7.4, thus making it
insoluble at physiological ph and more soluble at acidic ph.
 Glargine is compleely soluble at the acid(4.0) ph of its injectable solution.After
subcutaneous injection, it gets precipitated in the physiological ph of the
body.From this microprecipitates,small amounts of insulin glargine are
continuously released,providing smooth peakless profile and prolonged duration of
action.
 The onset of action of subcutaneous insulin glargine is somewhat slower than NPH
human insulin. It is a clear solution as there is no zinc in formula.

Detemir: the weird one
• Fatty acid tail (myristic acid) added to human insulin
• Complexes with albumin>20 hour action
http://www.nature.com/nrd/journal/v1/n7/images/nrd836-i2.gif

Detemir
 Fatty acid tail added (myristic acid) to lysine at B29.

Insulin analogues
 Structure/Properties/Advantages/disadvantages
 Rapid acting
 Basal(Long acting)
 Premixed

 Amino acid threonine at position B30 wa s re moved a n d a 16-
carbon
 f a tty d ia c i d c h a i n hexadecandioyl was added at B29 via a
glutamic acid spacer (linker ) L-γ-Glutamate.
 In the formulation:
 Insulin degludec is a soluble basal insulin analogue with neutral pH
which in the presence of zinc, chloride and phenol tends to self-
associate into stable, soluble di-hexamers.7 Phenol at either ends
of di-hexamers prevent further association of individual di
hexamers and stabilises the molecule in formulation.

After injection
 Once insulin degludec is injected, phenol disperses and the ends of di-
hexamers are free to associate with other di-hexamers with the help
of fatty acid and glutamic acid spacer to form long chains of multi-
hexamers. This can be described as string of pearls like structure in
the S.C. space.
Zinc now slowly is absorbed from the multi hexamers at the either end
and the gradual decrease in zinc concentration causes the bonds
between the zinc ions and the fatty diacid side chains to break, thus
allowing the continuous dissociation of insulin degludec monomers from
the ends of these multi-hexamer chains.
 This results in a slow and continuous delivery of insulin monomers
from the subcutaneous injection site into the circulation.

Glucose lowering effect of Degludec at three different
dose levels
0.4, 0.6 and 0.8U/kg which increases steadily with
increasing doses

Comparison with Detemir/Glargine
 Longer duration of action
 Stable, ‘truly peakless’
 Minimum hour-hour and day to day variability

Advantages of long acting insulin
 24 hour duration of action hence single prick is required to give basal insulin.
 ‘Peakless’ insulin.
 A bedtime injection of insulin glargine produces a much lower frequency
 of nocturnal hypoglycaemia, but similar glycaemic control (as judged
 by the HbA1C ).
 Furthermore, there is less weight gain than when using bedtime NPH.
 Can be given at any time of the day.(But the time of the day for a particular
individual must be fixed)

Disadvantages
 Glargine cannot be mixed with other forms of insulin as it is in an acid
solution, and would alter the absorption kinetics of those insulins.Hence
multiple injections are required.
 Expensive
 Note:When switching over from conventional insulin to analogue long acting
insulin,approximately 80% of the conventional insulin dose is required for
analogue insulins.

Premixed insulins
 Premixed insulins increase the convenience of insulin dosing, which may
improve compliance, long-term control and outcome.
 IDegAsp:Degludec(70%)+Aspart(30%):
 Detemer and Glargine structures are such that they are incompatible with
short acting insulins.Hence till now a coformulation of long acting analogue
with short acting insulin was not possible.Degulec is compatible with short
acting analogues hence such combined product is available.

Pre mixed insulins
Onset, h Peak, h Effective
Duration, h
Conventional insulins
70/30–70% NPH, 30% regular 0.5–1 Dualb 10–16
Analogue insulins
75/25–75% protamine lispro, 25% lispro
(Humalog® Mix75/25™ [75% insulin lispro
protamine suspension and 25% insulin lispro
injection, ]Humalog:75.25(Novo)
<0.25 1.5 h Up to 10–16
70/30–70% protamine aspart, 30% aspart
((70% insulin aspart protamine suspension
and 30% insulin aspart injection, [rDNA
origin])) Humalog:70.30(Novo)
<0.25 1.5 h Up to 10–16
50/50–50% protamine lispro, 50% lispro <0.25 1.5 h Up to 10–16
IDegAsp:Degludec(70%)+Aspart(30%)
(Ryzodeg-Novo)
5-15min 30-90 min >24 hrs

 Advantages over 70% biphasic insulin, 30% aspart:
 Superior reductions in fasting plasma glucose
 Decreasd incidence of hypoglycemia
 Reduced daily insulin dose
 Comparable reductions in HbA1C

Analogue regimen
 Following three are the commonly used insulin regimen.Insulin regimen
containing long acting analogue(A) provides much more physiological control
than one containing NPH(B).

Figure 344-12(Harrison) Representative insulin regimens for the
treatment of diabetes. For each panel, the y-axis shows the amount of insulin
effect and the x-axis shows the time of day. B, breakfast; L, lunch; S, supper; HS,
bedtime; CSII, continuous subcutaneous insulin infusion. *Lispro, glulisine, or
insulin aspart can be used. The time of insulin injection is shown with a vertical
arrow. The type of insulin is noted above each insulin curve. A. A multiple-
component insulin regimen consisting of long-acting insulinA glargine or detemir
may be required each day) to provide basal insulin coverage and three shots of
glulisine, lispro, or insulin aspart to provide glycemic coverage for each meal. B. The
injection of two shots of long-acting insulin (NPH) and short-acting insulin [glulisine,
lispro, insulin aspart (solid red line), or regular (green dashed line)]. Only one
formulation of short-acting insulin is used. C. Insulin administration by insulin
infusion device is shown with the basal insulin and a bolus injection at each meal.
The basal insulin rate is decreased during the evening and increased slightly prior to
the patient awakening in the morning. Glulisine, lispro, or insulin aspart is used in
the insulin pump.

 Problems:----------------------------------------------------------------------------------------
--
 Expensive
 ?Carcinogenecity
 ?Efficacy:
 Expensive:Much more expensive than human insulins.
 ?Carcinogenicity:
 All insulin analogs must be tested for carcinogenicity, as insulin engages in cross-
talk with IGF pathways, which can cause abnormal cell growth and tumorigenesis.
Modifications to insulin always carry the risk of unintentionally enhancing IGF
signalling in addition to the desired pharmacological properties.. Recently there
has been concern with the carcinogenicity of glargine but is yet to be proven. The
FDA has instructed for a large scale study evaluating the carcinogenicity of
glargine. The study result is expected in a few years.

Newer insulin delievery devices
 Insulin syringes: Prefilled disposable syringes with regular
or modified insulins
 Pen devices : Fountain pen like : insulin cartridges
 Inhaled insulin : Fine powder delievered through
nebulizer, rapid absorption
 Insulin pumps: Portable infusion devices connected to
subcutaneously placed cannula ( continuous insulin
infusion )
 Insulin patch-pen: A small ( two inches long, one inch wide
and ¼ inch thick) plastic device is designed to be worn on
the skin like a bandage.

 Implantable pumps : electromechanical mechanism regulates insulin
delievery from percutaneously refillable reservoir
 Mechanical pumps, fluorocarbon propellents and osmotic pumps are
also being developed.
 Under clinical trials:
oral ( liposome/ impermeable polymer coating)
rectal
intraperitoneal
nasal
insulin jet injectors
ultrasound pulses

INSULIN PENS AND PEN NEEDLES
 Often the size and shape of a large marker, insulin pens carry insulin in a self-
contained cartridge. They are easy to use and growing in popularity.
 Some users use insulin pens for all their injections, while others carry them
when they are "on the go" and rely on less-expensive and more versatile
syringes when they are:
 mixing different insulins
 taking an insulin that is not available in a pen
 at home
 Insulin pens are used with pen needles that are sold separately. A new pen
needle should be used each time you inject.

Insulin Pen Types
 While there are a number of different brands and models available, most
insulin pens fall into one of two groups: reusable pens and disposable pens.
 Before using a reusable insulin pen, you must load it with a cartridge of
insulin (sold separately in boxes of five cartridges). Cartridges used in the
U.S. today hold 150 or 300 units of insulin. Depending on the size of your
doses, a cartridge may give you enough insulin to last for several days of
injections. When the cartridge is empty, you throw it away and load a new
cartridge. With good care, a reusable pen can often be used for several years.
 Disposable insulin pens come filled with insulin and are thrown away when
they are empty. Most disposable pens used in the U.S. today hold 300 units of
insulin and are sold in boxes of five. Disposable pens are generally more
convenient than reusable pens because you do not need to load any
cartridges, but they usually cost more to use than reusable pens and cartridge

 Pen brands and models differ from one another in many ways. When working
with your healthcare team to select a pen, there are many factors to keep in
mind, including:
 The brands and types of insulin that are available for the pen.
 The number of units of insulin that the pen holds when full.
 The largest size dose that can be injected with the pen.
 How finely the dose can be adjusted by the pen. For example, one pen may
dose in two-unit increments (2, 4, 6, etc.), another in one-unit increments (1,
2, 3, etc.) and yet another in half-unit increments (1/2, 1, 1 1/2).

 The way the pen indicates whether or not there is enough insulin left in it for your
entire dose.
 The styling and appearance of the pen and the material (plastic or metal) that the
pen is made of.
 The size of the numbers on the pen dose dial and whether they are magnified.
 The amount of strength and dexterity required to operate the pen.
 How to correct a mistake if you dial the wrong dose into the pen.
 The way the pen indicates whether or not there is enough insulin left in it for your
entire dose.

Advantages and Disadvantages of Insulin
Pens
 The reasons why some insulin users prefer insulin pens include:
 Insulin pens are portable, discreet, and convenient for injections away from
home.
 They save time because there is no need to draw up insulin from a bottle - it
is already pre-filled in the self-contained cartridge.
 They usually let you set an accurate dose by the simple turn of a dosage dial,
and that may make it easier to set an accurate dose for people who have
vision or dexterity problems.

 Insulin pens should only be used for self-injection. This is because the pen
needle must be removed from the pen after each injection, and there is no
way to completely protect the person giving the injection from getting
accidentally stuck by the needle while he or she is removing it from the pen

Disadvantages
 There are also reasons why insulin pens are not right for all users, including:
 Insulin in pens and cartridges is often more expensive than insulin in bottles for
use in syringes.
 Some insulin is wasted when pens are used: one to two units of insulin are lost
when the pen is primed before each injection; and there is usually some insulin
left in the pen or cartridge (but not enough to inject) when they are used up.
 Not all insulin types are available for use in insulin pen cartridges.
 Insulin pens do not let you mix insulin types, which means that if the insulin
mixture you need is not available as a pre-mix, two injections must be given - one
for each type of insulin.

COMPLICATIONS OF INSULIN THERAPY
1. Severe Hypoglycemia (< 50 mg/dl )– Life threatening
Overdose of insulin
Excessive (unusual) physical exercise
A meal is missed
How it is treated ?
2. Weight gain
3. Local or systemic allergic reactions (rare)
4. Lipodystrophy at injection sites
5. Insulin resistance
6. Hypokalemia

Noncompliance is not a patient
problem.
It is a system failure.
Dr. Paul Farmer
First to successfully use complex drug regimens to treat AIDs
and TB in Haiti
Our Current Diabetes Approach
Does Not Work

When a system is not working for
patients, trying harder will not
work.
Only changing the care system or
our approach to care will work.

Convergence Toward Automation
I
n
s
u
l
i
n
M
o
n
i
t
o
r
i
n
g
HCP Self Management Automation
Insulin & syringes
Pumps
Pens
Connectivity
Clinic Monitoring
Home Monitors
Data Management
Advice/Feedback
Open Loop
D
e
l
i
v
e
r
y
Closed Loop
You are here

Dumb
Smart
Intelligent
Automatic
Results over Features!
Do not judge a device by how cool it is,
but by whether it lowers the A1c.

Today’s Smart Pumps
 Carb boluses
 Personalized carb factors for different
times of day
 Easy carb bolus calculations
 Personalized carb database (soon)
 Correction boluses
 Personalized correction factors for different times
 Easier and safer correction of high BGs
 Reveal when correction bolus is high, ie > 8% of TDD
 Combined carb/correction boluses
 Automatic bolus reduction for Bolus On Board
(BOB)© 2004, John Walsh, P.A., C.D.E.

 Track Bolus On Board
 Improved bolus accuracy
 Avoids stacking of bolus insulin
 Helps prevent hypoglycemia
 Requires BG reading for accuracy
 Guide whether carbs or insulin are needed
 Does not yet warn when carbs are needed

 Reminders to
 Test blood glucose after a bolus
 Warn when bolus delivery was not completed
 Test blood glucose following a low or high BG
 Give boluses at certain times of day
 Change infusion site
 Direct BG entry from meter
 Eliminates errors in data transfer
 Ensures that all blood glucose data will be entered
into a database or logbook format

Smart Pumps Do Not:
Today’s pumps collect the information needed (insulin doses, BGs,
carb intake, and timing), but they do not:
 Identify problem patterns
 Automatically test basals and boluses or warn
when they are out of balance
 Suggest dose adjustments
 Warn when excess correction boluses are used
 Account for GI differences between foods
 Guarantee an improved outcome

Intelligent Devices
Today’s “smart” pumps are migrating to better pumps, pens, and
PDAs
 Calculus rather than formulas to set bolus amounts
 Auto analysis of BG patterns
 Fuzzy and artificial intelligence
 Provide automatic (retrospective) carb/insulin balance
 Use of A1c to focus therapy

The Intelligent Device Hypothesis
Intelligent devices:
provide meaningful advice, *
improve lifestyles, *
improve medical outcomes with diabetes.*
Made by
Unidentified company here
* Yet to be proven

Smart Vs Intelligent Devices
Feature Smart Intelligent
Carb list Alphabetic By recent use
Basal testing By user Automatic
Bolus testing By user Automatic
Exercise NA Automatic
Timer Manual Automatic
Corr. bolus Ignored Redistributed
Super Bolus None Automatic
# of hypos By user Automatic
Communication Verbal Bidirectional© 2004, John Walsh, P.A., C.D.E.

Intelligent Devices
 Pumps
 Pens
 PDAs
 Smart Phones
 Meters
 A central reporting station where data is filtered for minor versus
major problems and who is to be alerted (user, guardian, MD/RN)

Demands On Intelligent Devices
 Intuitive interface and language
 Must be impartial and fair
 Outcome driven – user feels better and is more confident
about control
 Compatible with clinic workflow
 Well funded
 Able to rapidly evolve as errors appear
 Must close the data loop between user and MD

Intelligent Device Ingredients
 Automatic BG timer
 Automatic basal decrease
 Super Bolus
 Automatic basal/bolus balancing
 Automatic adjustment when correction boluses are overused
 Carb list and carb counter
 Exercise intensity and duration
 Database intelligence

Intelligent Device Benefits
 Provide immediate advice on situations
 Identify common or infrequent patterns
 Constant surveillance of data for changes
 Provide real meaning to BG values
 Integrate well with continuous monitoring and artificial
intelligence

Smart Phones And PDAs
 Fast internet & email communication
 Convenient remote insulin delivery
 Larger food and carb database
 Better graphics for BG analysis, display of patterns, etc
 Larger event database for long-term analysis

Intelligent Devices
 300 personal carb selections
with accurate carb counts
 Carb factor (1:1 TO 1:100)
 Correction factor (1:4 to 1:
400)
5 sec microdraw BG meter
0.1 unit precision motor
Non-volatile memory
3,000 events
Bluetooth data transfer

Thoughts And Developments For
The Future

Old Basal/Bolus
Concepts
 Basal insulin
 ~ 50% of daily insulin need
 Limits hyperglycemia after meals
 Suppresses glucose production between meals and overnight
 Bolus insulin (mealtime)
 Limits hyperglycemia after meals
 Immediate rise and sharp peak at 1 hour
 10% to 20% of total daily insulin requirement at each meal

New: Rapid Basal Reduction
A rapid basal reduction offsets excess BOB and
eliminates the need to eat at bedtime.

New: The Super Bolus
A Super Bolus helps cover high GI foods and prevent
postmeal hyperglycemia. A 3 or 4 hour block of basal
insulin is turned into a bolus to speed its effect.
A Super Bolus
can be
activated at a
user-selected
quantity, such
as 40 or 50
grams

New: The Super Bolus
 To ensure safety and success, the Super Bolus will require some clinical
testing:
 How long can basal delivery be stopped or reduced without increasing the risk for
clogging of the infusion line
 How long (3, 4, 5 hours?) can the basal be lowered before a rebound high will occur
once the Super Bolus is gone?
 Is a reduction of the basal delivery rather than complete stoppage a better policy?
 If a person sets their basal delivery too low or too high, will this affect a Super
Bolus?

New: High BG Super Bolus
If a pumper misjudges the carb content of a meal, a
super bolus enables a faster, safe correction.

New: A Reminder Timer
 A simple timer alerts the user 25 minutes after a
bolus that it is safe to begin eating a high GI
meal.

New: An Intelligent Reminder
An intelligent
pump alerts the
user when their
BG is likely to
cross a selected
threshold value,
such as 120
mg/dl. They can
then eat without
exposure to
extremely high
readings.

New: Less Glucose Exposure
The lower the blood
glucose is at the
start of a meal, the
less exposure to
glucose there will
be.

New: An Intelligent Reminder
An intelligent pump
alerts the user
when their blood
glucose is low
enough to begin
eating

Future Intelligent Devices
 Useful reminders

Future Pattern Management
 Finding problem patterns enables solutions
 Set BG targets
 Gather and record data
 Analyze patterns in data
 Assess factors that influence patterns
 Recommend action

Only A Few Patterns
The relatively low number of BG patterns in diabetes makes them
easy to identify:
 High most of the time
 Frequent lows
 High mornings (lunches, dinners, bedtime)
 Low mornings (lunches, dinners, bedtime)
 Postmeal spiking
 High to low
 Low to high
 Poor control with little or no pattern

Pattern Analysis: Low-High
.
38
10 pm
320
.
Overtreated low

Low High Pattern Alert
 Insulin dose suggestions and an alert about past overtreatment of
lows.

Low High Pattern Alert
 An intelligent device can provide a person’s precise carb
requirement when the blood glucose is tested.

Easy Analysis 2
232
194
217
243
178
263
222
Breakfast
Breakfast highs

Overnight Basal Patterns
bedtime 2 am breakfast
100
200
300
basal too low
Dawn
Phenomenon
just right
too high
Goal for overnight BG change = +/- 30 mg/dl
just right

User Interface – Critical Component
Despite 30 years of pump and meter development, device
communication to the user is still in it’s infancy.

 Carb database for accurate carb counts.

 Suggestion for carb intake or to limit intake based on weight/calorie/carb
goals

 A high glucose can be analyzed to determine the magnitude of the
error

 Recommended carb intake (or insulin reduction) to balance
activity.

 New dose recommendations based on A1c, % of TDD given as
correction boluses, and frequency of hypoglycemia

 Pattern alerts and advice

 Fast lab results without calling. Messaging allows physician to make
recommendations.

Pump Plus Continuous Monitor
 Automatic basal and bolus testing
 Trends allow exact short-term BG predictions for rapid
recognition of pending highs or lows
 Both user and device can relate problems to their source
Unfortunately, insulin delivery from an external pump is too
slow to create an effective artificial pancreas with this
combination

The Closed Loop Will Close Slowly
 Patents impede device development
 FDA is slow to allow medical care from a device or via
telemedicine
 Slow acceptance by medical personnel and people with
diabetes
 Liability issues
 Large financial incentives in current meter and pump
technology
Even so, truly intelligent and helpful devices
could be created soon.

Newer OHA and insulin

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Newer OHA and insulin

Similar to Newer OHA and insulin (20)

Recently uploaded

Recently uploaded (20)

Newer OHA and insulin