CLASSIFICATION AND DIAGNOSIS OF DIABETES

Classification

Diabetes can be classified into the following general categories:

1. Type 1 diabetes (due to autoimmune ß-cell destruction, usually leading to absolute
insulin deficiency)
2. Type 2 diabetes (due to a progressive loss of ß-cell insulin secretion frequently on
the background of insulin resistance)
3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third
trimester of pregnancy that was not clearly overt diabetes prior to gestation)
4. Specific types of diabetes due to other causes, e.g., monogenic diabetes
syndromes (such as neonatal diabetes and maturity-onset diabetes of the young
[MODY]), diseases of the exocrine pancreas (such as cystic fibrosis and
pancreatitis), and drug- or chemical-induced diabetes (such as with glucocorticoid
use, in the treatment of HIV/AIDS, or after organ transplantation)
Table 2.2
CLASSIFICATION AND DIAGNOSIS OF DIABETES

Classification and Diagnosis of Diabetes:

Standards of Medical Care in Diabetes - 2020. Diabetes Care 2020;43(Suppl. 1):S14-S31
Promedio de glucosa mg/dl = 28.7 x A1c - 46.7
GLYCEMIC TARGETS

Glycemic Targets:
Standards of Medical Care in Diabetes - 2020. Diabetes Care 2020;43(Suppl. 1): S66-S76
2019 AACE Glycemic Control Algorithm
13

NICE: Algorithm for Blood Glucose
Lowering Therapy in Adults with T2D
If A1C rises to 48 mmol/mol (6.5%) on lifestyle interventions: If standard-release metformin is
• Offer standard-release metformin not tolerated, consider a trial of
• Support the person to aim for an A1C level of 48 mmol/mol (6.5%) modified-release metformin
FIRST INTENSIFICATION: If triple therapy is not effective, not
If A1C rises to 58 mmol/mol (7.5%): tolerated, or contraindicated,
• Consider dual therapy with: consider combination therapy with
- Metformin and a DPP4i metformin, an SU, and a GLP-1
- Metformin and pioglitazone mimetic for adults with T2D who:
- Metformin and an SU • Have a BMI of 35 kg/m2 or
- Metformin and SGLT2i higher (adjust accordingly for
• Support the person to aim for an A1C level of 53 mmol/mol (7.0%) people from black, Asian, and
other minority ethnic groups)
and specific psychological or
other medical problems
SECOND INTENSIFICATION: associated with obesity, or
If A1C rises to 58 mmol/mol (7.5%): • Have a BMI lower than 35
• Consider triple therapy with: kg/m2, and for whom insulin
- Metformin, a DPP4i, and an SU therapy would have significant
- Metformin, pioglitazone, and an SU occupational implications or
- Metformin, pioglitazone or an SU, and a SGLT2i weight loss would benefit
• Insulin-based treatment other significant
• Support the person to aim for an A1C level of 53 mmol/mol (7.0%) obesity-related complications
Metformin Contraindicated or Not
Tolerated
If A1C rises to 48 mmol/mol (6.5%) on
lifestyle interventions:
• Consider one of the following:
- A DPP4i, pioglitazone, or an
SU
- An SGLT2i instead of a DPP4i if
an SU or pioglitazone is not
appropriate
• Support the person to aim for an
A1C level of 48 mmol/mol (6.5%)
for people on DPP4i, SGLT2i, or
pioglitazone, or 53 mmol/mol (7%)
for people on an SU
FIRST INTENSIFICATION:
If A1C rises to 58 mmol/mol (7.5%):
• Consider dual therapy with:
- A DPP4i and pioglitazone
- A DPP4i and an SU
- Pioglitazone and an SU
• Support the person to aim for an
A1C level of 53 mmol/mol (7.0%)
SECOND INTENSIFICATION:
If A1C rises to 58 mmol/mol (7.5%):
• Consider insulin-based treatment
• Support the person to aim for an
A1C level of 53 mmol/mol (7.0%)

A1C, glycated hemoglobin; DPP4i, dipeptidyl peptidase-4 inhibitors; GLP-1, glucagon-like peptide; NICE, National Institute for Health and Care Excellence;
SLGT2i, sodium-glucose cotransporter 2 inhibitors; SU, sulfonylureas; T2D, type 2 diabetes.
NICE guideline. Updated May 2017. https://www.nice.org.uk/guidance/ng28.

14
 Mechanism of Action of
Antihyperglycemic Agents
Pancreas

Muscle Decreased insulin Liver

secretion from
Increase glucose uptake Increased endogenous
β-cells
TZD glucose production
GLP1 RA, DPP4i, SU, GLN Metformin, TZD,
GLP1 RA, DPP4i
Adipose (fat)
Increased FFA production The Ominous Octet Digestive tract
Decreased incretin effect
TZD GLP1 RA, AGis,
Colesevelam
GLP1 RA, DPP4i

Brain Increased glucagon Kidney

Neurotransmitter dysfunction secretion from Increased glucose reabsorption
α-cells
GLP1 RA SGLT2i
Bromocriptine Pancreas
DeFronzo RA. Diabetes. 2009;58:773-795
 Noninsulin Agents Available for T2D
Class Primary Mechanism of Action Agent(s) Available as
α-Glucosidase ∙ Delay carbohydrate absorption Acarbose Precose or generic
inhibitors from intestine Miglitol Glyset

∙ Decrease HGP
Glucophage or
Biguanide ∙ Increase glucose uptake in Metformin
generic
muscle

∙ Increase glucose-dependent Alogliptin Nesina

Linagliptin Tradjenta
DPP4 inhibitors insulin secretion
Saxagliptin Onglyza
∙ Decrease glucagon secretion Sitagliptin Januvia

Nateglinide Starlix or generic

Glinides ∙ Increase insulin secretion
Repaglinide Prandin

DPP4, dipeptidyl peptidase; HGP, hepatic glucose production.

Garber AJ, et al. Endocr Pract. 2017;23:207-238.
ADA. Diabetes Care. 2017;40:S64-S74. Continued on next slide 16
 Noninsulin Agents Available for T2D
Class Primary Mechanism of Action Agent(s) Available as
∙ Increase glucose-dependent Albiglutide Tanzeum
insulin secretion Dulaglutide Trulicity
GLP1 receptor
∙ Decrease glucagon secretion Exenatide Byetta
agonists
∙ Slow gastric emptying Exenatide XR Bydureon
∙ Increase satiety Liraglutide Victoza

Canagliflozin Invokana
∙ Increase urinary excretion of
SGLT2 inhibitors Dapagliflozin Farxiga
glucose
Empagliflozin Jardiance

Glimepiride Amaryl or generic

Glipizide Glucotrol or generic
Sulfonylureas ∙ Increase insulin secretion Glyburide Diaβeta, Glynase,
Micronase, or
generic
∙ Increase glucose uptake in muscle
Pioglitazone Actos
Thiazolidinediones and fat
Rosiglitazone Avandia
∙ Decrease HGP

GLP1, glucagon-like peptide; HGP, hepatic glucose production; SGLT2, sodium glucose cotransporter 2.
Garber AJ, et al. Endocr Pract. 2017;23:207-238.
ADA. Diabetes Care. 2017;40:S64-S74. Continued from previous slide 17
 Current Insulin Options
Type Basal Insulins Prandial Insulins Premixed Insulins
Human U-100 NPH U-100 regular human insulin U-100 70/30 RHI
U-500 regular human insulin
Technosphere inhaled insulin

Analog U-100 glargine U-100 lispro U-100 50/50 lispro

U-100 glargine equivalent* U-100 aspart U-100 75/25 lispro
U-100 detemir U-100 glulisine
U-100 degludec
U-300 glargine

• Analogue insulins are associated with less hypoglycemia than human insulins, although
these differences are not always statistically significant

*In the US, U-100 glargine equivalent is not approved as a biosimilar product.
Singh SR, et al. CMAJ. 2009;180:385-397. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. FDA.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm. 18
PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT
 Metformin
Recommended for All Patients, Unless Contraindicated or Not Tolerated

Hypoglycemia Neutral

Weight Slight loss

Contraindicated if eGFR <30 mL/min/1.73
Renal / Genitourinary
m2
Gastrointestinal adverse
Moderate
effects
Cardiac Neutral

Bone Neutral

Ketoacidosis Neutral
Few adverse events or possible benefits Use with caution ?
Likelihood of adverse effects Uncertain effect

eGFR = estimated glomerular filtration rate.

Garber AJ, et al. Endocr Pract. 2017;23:207-238.
20
 Mechanism of Action of
Antihyperglycemic Agents
Pancreas

Muscle Decreased insulin Liver

secretion from
Increase glucose uptake Increased endogenous
β-cells
TZD glucose production
GLP1 RA, DPP4i, SU, GLN Metformin, TZD,
GLP1 RA, DPP4i
Adipose (fat)
Increased FFA production The Ominous Octet Digestive tract
Decreased incretin effect
TZD GLP1 RA, AGis,
Colesevelam
GLP1 RA, DPP4i

Brain Increased glucagon Kidney

Neurotransmitter dysfunction secretion from Increased glucose reabsorption
α-cells
GLP1 RA SGLT2i
Bromocriptine Pancreas
DeFronzo RA. Diabetes. 2009;58:773-795
 Glucagon-like Peptide 1
Receptor Agonists (GLP1 RAs)
Hypoglycemia Neutral

Weight Loss
Exenatide not indicated if CrCl <30
Renal / Genitourinary mL/min
Possible benefit of liraglutide
Gastrointestinal adverse
Moderate
effects
Cardiac—CHF Possible benefit of liraglutide

Cardiac--ASCVD Possible cardiovascular benefit

Bone Neutral

Ketoacidosis
Few adverse events or possible benefits Neutral Likelihood of adverse effects Uncertain effect
Use with caution ?

ASCVD = atherosclerotic cardiovascular disease; CHF = congestive heart failure; CrCl = creatinine clearance.
Garber AJ, et al. Endocr Pract. 2017;23:207-238.
22
 Mechanism of Action of
Antihyperglycemic Agents
Pancreas

Muscle Decreased insulin Liver

secretion from
Increase glucose uptake Increased endogenous
β-cells
TZD glucose production
GLP1 RA, DPP4i, SU, GLN Metformin, TZD,
GLP1 RA, DPP4i
Adipose (fat)
Increased FFA production The Ominous Octet Digestive tract
Decreased incretin effect
TZD GLP1 RA, AGis,
Colesevelam
GLP1 RA, DPP4i

Brain Increased glucagon Kidney

Neurotransmitter dysfunction secretion from Increased glucose reabsorption
α-cells
GLP1 RA SGLT2i
Bromocriptine Pancreas
DeFronzo RA. Diabetes. 2009;58:773-795
 GLP1 Receptor Agonists

FDA-Approved Agents Key Features

• Albiglutide • Injectable administration
• Dulaglutide • Mimic action of native
• Exenatide GLP1
• Exenatide ER • Increase
• Liraglutide glucose-dependent
insulin secretion
• Lixisenatide
• Suppress glucagon
production
• Slow gastric emptying

ER, extended release; GLP1, glucagon-like peptide 1.

Garber AJ, et al. Endocr Pract. 2016;22:84-113.
 Glucose Control
with GLP1 Receptor Agonists
Placebo-Adjusted Change from Baseline
(Not Head-to-Head Trials)

Monotherapy Add-on to Metformin Add-on to SU

Alb1 Dul2 Exe3 Exe Lir5 Lix6 Alb7 Dul8 Exe9 Exe Lir11 Lix12 Alb13, Exe14 Exe Lir16
ER4 ER10 * ER15,†
Baseline A1C (%) 8.1 7.6 7.8 8.5 8.3 8.0 8.1 8.1 8.2 8.6 8.4 8.0 8.2 8.6 8.3 8.5
Placebo-adjusted
Δ A1C (%)

‡ ‡

‡
‡ ‡ ‡ ‡
‡

*Metformin with or without SU or TZD. †Metformin with or without SU. ‡Absolute change from baseline (active-controlled trial).
1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.
2. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. 3. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 4. Russell-Jones D, et al. Diabetes
Care. 2012;35:252-258. 5. Garber A, et al. Lancet. 2009;373:473-481. 6. Fonseca VA, et al. Diabetes Care. 2012;35:1225-1231. 7. Ahrén B, et al.
Diabetes Care. 2014;37:2141-2148. 8. Dungan KM, et al. Lancet. 2014;384:1349-1357. 9. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100.
10. Bergenstal RM, et al. Lancet. 2010;376:431-439. 11. Pratley RE, et al. Lancet. 2010;375:1447-1456. 12. Rosenstock J, et al. Diabetes Care.
2013;36:2945-2951. 13. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 14. Buse JB, et al. Diabetes Care. 2004;27:2628-2635.
15. Diamant M, et al. Lancet. 2010;375:2234-2243. 16. Marre M, et al. Diabet Med. 2009;26:268-278.
 Weight Change with GLP1 Receptor
Agonists
Absolute Change from Baseline
(Not Head-to-Head Trials)

Monotherapy Add-on to Metformin Add-on to SU

Alb1 Dul2 Exe3 Exe Lir5 Lix6 Alb7 Dul8 Exe9 Exe Lir11 Lix12 Alb13,* Exe14 Exe Lir16
ER4 ER10 ER15,†
Δ Weight (kg)

*Metformin with or without SU or TZD. †Metformin with or without SU.

1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.
2. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. 3. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 4. Russell-Jones D, et al.
Diabetes Care. 2012;35:252-258. 5. Garber A, et al. Lancet. 2009;373:473-481. 6. Fonseca VA, et al. Diabetes Care. 2012;35:1225-1231. 7.
Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 8. Dungan KM, et al. Lancet. 2014;384:1349-1357. 9. DeFronzo RA et al. Diabetes Care.
2005;28:1092-1100. 10. Bergenstal RM, et al. Lancet. 2010;376:431-439. 11. Pratley RE, et al. Lancet. 2010;375:1447-1456. 12. Rosenstock J,
et al. Diabetes Care. 2013;36:2945-2951. 13. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 14. Buse JB, et al. Diabetes Care.
2004;27:2628-2635. 15. Diamant M, et al. Lancet. 2010;375:2234-2243. 16. Marre M, et al. Diabet Med. 2009;26:268-278.
 Hypoglycemia with GLP1 Receptor
Agonists
Percentage of Patients Reporting Hypoglycemia
(Not Head-to-Head Trials)
Monotherapy Add-on to Metformin Add-on to SU
Alb1 Dul2 Exe3 Exe Lir5 Lix6 Alb7 Dul8 Exe9 Exe Lir11 Lix12 Alb13,* Exe14 Exe Lir16
ER4 ER10 ER15,†
Patients (%)

*Metformin with or without SU or TZD. †Metformin with or without SU.

1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB. 2. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. 3. Moretto TJ, et al. Clin
Ther. 2008;30:1448-1460. 4. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 5. Garber A, et al. Lancet. 2009;373:473-481. 6. Fonseca
VA, et al. Diabetes Care. 2012;35:1225-1231. 7. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 8. Dungan KM, et al. Lancet.
2014;384:1349-1357. 9. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 10. Bergenstal RM, et al. Lancet. 2010;376:431-439. 11. Pratley
RE, et al. Lancet. 2010;375:1447-1456. 12. Rosenstock J, et al. Diabetes Care. 2013;36:2945-2951. 13. Pratley RE, et al. Lancet Diabetes
Endocrinol. 2014;2:289-297. 14. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 15. Diamant M, et al. Lancet. 2010;375:2234-2243. 16. Marre
M, et al. Diabet Med. 2009;26:268-278.
 Systolic BP Reductions With GLP1
Receptor Agonists
Head-to-Head Trials

Exenatide BID
Exenatide BID Exenatide BID vs Liraglutide vs Liraglutide vs Liraglutide vs
vs lixisenatide vs liraglutide exenatide OW albiglutide4
1 2 3
dulaglutide5 exenatide OW6
634 464 295 841 599 912

Exe Lix Exe BID Lir Exe BID Exe OW Lir Alb Lir Dul Lir Exe OW
Δ Systolic BP (mmHg)

<1 <1

BID, twice daily; BP, blood pressure; OW, once weekly (extended release).
1. Rosenstock J, et al. Diabetes Care. 2013;36:2945-2951. 2. Buse JB, et al. Lancet. 2009;374:39-47. 3. Drucker DJ, et al. Lancet. 2008;
372:1240-1250. 4. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 5. Dungan KM, et al. Lancet. 2014;384:1349-1357. 6. Buse JB,
et al. Lancet. 2013;381:117-124.
 Nausea Rates With GLP1 Receptor
Agonists
Percentage of Patients Reporting Nausea in Head-to-Head Trials

Exenatide BID
Exenatide BID Exenatide BID vs Liraglutide vs Liraglutide vs Liraglutide vs
vs lixisenatide vs liraglutide exenatide OW albiglutide4
1 2 3
dulaglutide5 exenatide OW6
Exe Lix Exe BID Lir Exe BID Exe OW Lir Alb Lir Dul Lir Exe OW

P<0.05
P<0.05
Patients (%)

P<0.0001

BID, twice daily; OW, once weekly (extended release).

1. Rosenstock J, et al. Diabetes Care. 2013;36:2945-2951. 2. Buse JB, et al. Lancet. 2009;374:39-47. 3. Drucker DJ, et al. Lancet. 2008;
372:1240-1250. 4. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 5. Dungan KM, et al. Lancet. 2014;384:1349-1357. 6. Buse JB,
et al. Lancet. 2013;381:117-124.
 Safety Considerations
with GLP1 Receptor Agonists
• Common
GI adverse
• Usually dose dependent and transient
events • Usually reduced with dose titration
• Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal
relationship has been established
• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of
Pancreatitis increased pancreatic risk with incretins vs other agents
• Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected
• Labeling for GLP1 receptor agonists suggests consideration of other therapies for patients with a history of
pancreatitis
• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of
Pancreatic
increased pancreatic risk with incretins vs other agents
cancer • Further assessments required from long duration-controlled studies or epidemiological databases
• Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment,
but confirmatory population studies are lacking
Medullary • Labeling for albiglutide, dulaglutide, exenatide ER, and liraglutide:
thyroid • Patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of thyroid
cancer tumors
• Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia
syndrome type 2
• Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea,
Renal or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. Exenatide
impairment should not be used in patients with severe renal insufficiency or ESRD. Liraglutide was found to be safe in
patients with moderate renal impairment and may confer a beneficial effect.
ER, extended release.
Garber AJ, et al. Endocr Pract. 2016;22:84-113. ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news
release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June
28, 2013. http://www.diabetes.org/newsroom/press-releases/2013/recommendations-for.html. Davies MJ, et al. Diabetes Care. 2016;39:222-230.
Marso SP, et al. N Engl J Med. 2016;375:311-322.
 Dulaglutide: Adverse Events
Patients (%)
Dulaglutide 1.5 mg Dulaglutide 0.75 mg Placebo
Adverse Events* (n=834) (n=836) (n=568)
Nausea 21.1 12.4 5.3
Diarrhea 12.6 8.9 6.7
Vomiting 12.7 6.0 2.3
Abdominal pain 9.4 6.5 4.9
Decreased appetite 8.6 4.9 1.6
Dyspepsia 5.8 4.1 2.3
Fatigue 5.6 4.2 2.6
*Adverse events occurring in ≥5% of patients receiving dulaglutide.

Trulicity (dulaglutide) injection prescribing information. Indianapolis, IN: Eli Lilly and Company; 2014.
 Liraglutide: Adverse Events
Patients (%)
Monotherapy + Met + Glim + Met + TZD
Adverse Lir Glim Lir PBO Lir PBO Lir PBO
Events* (n=497) (n=248) (n=724) (n=121) (n=695) (n=114) (n=355) (n=175)
Nausea 28.4 8.5 15.2 4.1 7.5 1.8 34.6 8.6
Diarrhea 17.1 8.9 10.9 4.1 7.2 1.8 14.1 6.3
Vomiting 10.9 3.6 6.5 0.8 12.4 2.9
Constipation 9.9 4.8 5.3 0.9 5.1 1.1
Headache 9.1 9.3 9.0 6.6 8.2 4.6
Dyspepsia 5.2 0.9
*Adverse events of interest occurring in ≥5% of patients receiving liraglutide.

Victoza (liraglutide) injection prescribing information. Princeton, NJ: Novo Nordisk Inc. 2013.
 Lixisenatide: Adverse Events
Patients (%)
Placebo Lixisenatide
Adverse Events* (n=1639) (n=2869)
Nausea 6 25
Vomiting 2 10
Headache 6 9
Diarrhea 6 8
Dizziness 4 7
*Occurring in ≥5% of patients receiving lixisenatide.

Adlyxin (lixisenatide) injection prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC. 2016.
 Sodium Glucose Cotransporter 2
Inhibitors (SGLT2is)
Hypoglycemia Neutral
Weight Loss
Not indicated for eGFR <45 mL/min/1.73
m2
Renal / Genitourinary Genital mycotic infections
Possible benefit of empagliflozin
Gastrointestinal adverse
Neutral
effects
Cardiac—CHF Possible benefit of empagliflozin
Cardiac--ASCVD Possible cardiovascular benefit
Bone Canagliflozin warning
Few adverse events or possible benefits Use with caution
DKA Likelihood ofin
occurring adverse
T2Deffects ?stress
Uncertain effect
in various
Ketoacidosis
settings
ASCVD = atherosclerotic cardiovascular disease; CHF = congestive heart failure; DKA = diabetic ketoacidosis; eGFR = estimated glomerular
filtration rate; T2D = type 2 diabetes.
Garber AJ, et al. Endocr Pract. 2017;23:207-238.
34
 Mechanism of Action of
Antihyperglycemic Agents
Pancreas

Muscle Decreased insulin Liver

secretion from
Increase glucose uptake Increased endogenous
β-cells
TZD glucose production
GLP1 RA, DPP4i, SU, GLN Metformin, TZD,
GLP1 RA, DPP4i
Adipose (fat)
Increased FFA production The Ominous Octet Digestive tract
Decreased incretin effect
TZD GLP1 RA, AGis,
Colesevelam
GLP1 RA, DPP4i

Brain Increased glucagon Kidney

Neurotransmitter dysfunction secretion from Increased glucose reabsorption
α-cells
GLP1 RA SGLT2i
Bromocriptine Pancreas
DeFronzo RA. Diabetes. 2009;58:773-795
 SGLT2 Inhibitors

FDA-Approved Agents Key Features

• Canagliflozin • Oral administration
• Dapagliflozin • Inhibit reabsorption of
• Empagliflozin glucose into the
bloodstream from renal
fluid

SGLT2, sodium-glucose cotransporter 2.

DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14.
 Glucose Control
with SGLT2 Inhibitors
Placebo-Adjusted Change from Baseline
(Not Head-to-Head Trials)

Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs

Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9

Baseline A1C 8.1 7.8 7.9 8.1 8.2 7.9 8.2 8.6 8.3
(%)
Placebo-adjusted
Δ A1C (%)

*Absolute change from baseline (active-controlled trial).

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 3. Roden M, et al. Lancet
Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 6.
Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8. Wilding JPH, et al. Ann Intern
Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.
 Weight Change
with SGLT2 Inhibitors
Absolute Change from Baseline
(Not Head-to-Head Trials)

Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs

Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9
Δ Weight (kg)

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 3. Roden M, et al. Lancet
Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 6.
Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8. Wilding JPH, et al. Ann Intern
Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.
 Hypoglycemia with SGLT2 Inhibitors
Percentage of Patients Reporting Hypoglycemia
(Not Head-to-Head Trials)

Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs

Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9
Patients (%)

<1

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 3. Roden M, et al. Lancet
Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 6.
Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8. Wilding JPH, et al. Ann Intern
Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.
 Safety Considerations
with SGLT2 Inhibitors
Genitourinary
• Increased incidence; patients should be monitored and treated if necessary
infection

Increased LDL-C • Small increases in LDL-C have been observed in clinical trials
• Increased incidence of bladder cancers in patients receiving dapagliflozin

Bladder cancer • Dapagliflozin labeling recommends not using in patients with active bladder
cancer and should be used with caution in patients with a history of bladder
cancer

Renal • Monitor kidney function during therapy, especially in patients with GFR <60
impairment mL/min/1.73 m2
• Increased incidence of bone fractures in canagliflozin and dapagliflozin clinical
Bone fractures trials
• Canagliflozin labeling includes specific warning about bone fractures
• Potentially increased risk of diabetic ketoacidosis in patients with insulin
DKA
deficiency and/or those undergoing acute metabolic stress

Garber AJ, et al. Endocr Pract. 2016;22:84-113. Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company.
2015. Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2015. Jardiance (empagliflozin) prescribing
information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2015. Handelsman Y, et al. Endocr Pract. 2016;22:753-762.
 AACE/ACE Position Statement on
Association of SGLT2 Inhibitors With DKA
• DKA occurs infrequently
• Risk-benefit ratio favors continued use of SGLT2
inhibitors with no changes in current
recommendations
• DKA diagnosis may be missed or delayed due to
atypical presentation involving
lower-than-anticipated glucose levels or other
misleading laboratory values
– This atypical presentation has been seen with other
antihyperglycemic agents long before the introduction
of SGLT2 inhibitors

DKA = diabetic ketoacidosis; SGLT2 = sodium glucose cotransporter 2.

Handelsman Y, et al. Endocr Pract. 2016;22:753-762. 41
 Dipeptidyl Peptidase 4 Inhibitors
(DPP4is)
Hypoglycemia Neutral

Weight Neutral
Dose adjustment necessary (except
Renal / Genitourinary linagliptin)
Effective in reducing albuminuria
Gastrointestinal adverse
Neutral
effects
Cardiac—CHF Possible risk for saxagliptin and alogliptin

Cardiac--ASCVD Neutral

Bone Neutral

Ketoacidosis Neutral
Few adverse events or possible benefits Use with caution ?
Likelihood of adverse effects Uncertain effect

ASCVD = atherosclerotic cardiovascular disease; CHF = congestive heart failure.

Garber AJ, et al. Endocr Pract. 2017;23:207-238.
42
 Mechanism of Action of
Antihyperglycemic Agents
Pancreas

Muscle Decreased insulin Liver

secretion from
Increase glucose uptake Increased endogenous
β-cells
TZD glucose production
GLP1 RA, DPP4i, SU, GLN Metformin, TZD,
GLP1 RA, DPP4i
Adipose (fat)
Increased FFA production The Ominous Octet Digestive tract
Decreased incretin effect
TZD GLP1 RA, AGis,
Colesevelam
GLP1 RA, DPP4i

Brain Increased glucagon Kidney

Neurotransmitter dysfunction secretion from Increased glucose reabsorption
α-cells
GLP1 RA SGLT2i
Bromocriptine Pancreas
DeFronzo RA. Diabetes. 2009;58:773-795
 DPP4 Inhibitors

FDA-Approved Agents Key Features

• Alogliptin • Oral administration
• Linagliptin • Increase endogenous
• Saxagliptin GLP1 and GIP levels
• Sitagliptin • Increase
glucose-dependent
insulin secretion
• Suppress glucagon
production

DPP4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic polypeptide; GLP1, glucagon-like peptide 1.
Garber AJ, et al. Endocr Pract. 2016;22:84-113.
 Glucose Control
with DPP4 Inhibitors
Placebo-Adjusted Change from Baseline
(Not Head-to-Head Trials)

Monotherapy Add-on to Metformin Add-on to SU

Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†

Baseline A1C (%) 7.9 8.0 8.0 7.5 8.1 8.2 8.6 8.4 7.8 7.9 8.5 8.3
Placebo-adjusted
Δ A1C (%)

*SU + metformin. †With or without metformin. ‡Absolute change from baseline (active-controlled trial).
1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267.
3. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 4. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 5. Nauck MA, et al. Int J Clin
Pract. 2009;63:46-55. 6. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 7. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 8.
Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 9. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176. 10. Owens DR, et al. Diabet Med.
2011;28:1352-61. 11. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 12. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745.
 Weight Change
with DPP4 Inhibitors
Absolute Change from Baseline
(Not Head-to-Head Trials)
Monotherapy Add-on to Metformin Add-on to SU
Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†
Δ Weight (kg)

NR NR

NR, value not reported.

*SU + metformin. †With or without metformin.
1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267.
3. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 4. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 5. Nauck MA, et al. Int J Clin
Pract. 2009;63:46-55. 6. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 7. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 8.
Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 9. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176. 10. Owens DR, et al. Diabet Med.
2011;28:1352-61. 11. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 12. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745.
 Hypoglycemia with DPP4 Inhibitors
Percentage of Patients Reporting Hypoglycemia
(Not Head-to-Head Trials)
Monotherapy Add-on to Metformin Add-on to SU
Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†
Patients (%)

NR, value not reported.

*SU + metformin. †With or without metformin.
1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267.
3. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 4. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 5. Nauck MA, et al. Int J
Clin Pract. 2009;63:46-55. 6. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 7. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 8.
Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 9. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176. 10. Owens DR, et al. Diabet
Med. 2011;28:1352-61. 11. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 12. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745.
 Safety Considerations
with DPP4 Inhibitors
GI adverse
• Minimal
events
• Pancreatitis has been reported with postmarketing use of some of incretin agents,
although no causal relationship has been established
• Extensive review by FDA of studies involving >80,000 patients has not uncovered
Pancreatitis
reliable evidence of increased pancreatic risk with incretins vs other agents
• Labeling for all incretins states these agents should be immediately discontinued if
pancreatitis is suspected
• Extensive review by FDA of studies involving >80,000 patients has not uncovered
Pancreatic reliable evidence of increased pancreatic risk with incretins vs other agents
cancer • Further assessments required from long duration-controlled studies or
epidemiological databases
• Kidney function monitoring and dose reduction required for alogliptin, saxagliptin,
Renal and sitagliptin when used in patients with moderate-to-severe renal impairment
impairment • Linagliptin does not require dose adjustment or periodic monitoring of drug-related
kidney function

• Potentially increased risk of congestive heart failure hospitalization with alogliptin

CHF
and saxagliptin

Garber AJ, et al. Endocr Pract. 2016;22:84-113. White W, et al. N Engl J Med. 2013;369:1327-1335. Scirica BM, et al. Circulation.
2014;130:1579-1588. ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA:
American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, 2013.
http://www.diabetes.org/newsroom/press-releases/2013/recommendations-for.html.
 Linagliptin: Adverse Events

Patients (%)
Linagliptin 5 mg Placebo
Adverse Events* (n=3625) (n=2176)
Nasopharyngitis 7.0 6.1
Diarrhea 3.3 3.0
Cough 2.1 1.4
*Occurring in ≥2% of patients receiving linagliptin 5 mg and more commonly
than in placebo-treated patients.

Tradjenta (linagliptin) prescribing information. Ridgefield, CT: Boehringer Ingelheim, Inc.; 2014.
 Alpha Glucosidase Inhibitors (AGis)

Hypoglycemia Neutral

Weight Neutral

Renal / Genitourinary Neutral

Gastrointestinal adverse
Moderate
effects
Cardiac Neutral

Bone Neutral

Ketoacidosis Neutral

Few adverse events or possible benefits Use with caution ?

Likelihood of adverse effects Uncertain effect

ASCVD = atherosclerotic cardiovascular disease; CHF = congestive heart failure.

50
Garber AJ, et al. Endocr Pract. 2017;23:207-238.
 Mechanism of Action of
Antihyperglycemic Agents
Pancreas

Muscle Decreased insulin Liver

secretion from
Increase glucose uptake Increased endogenous
β-cells
TZD glucose production
GLP1 RA, DPP4i, SU, GLN Metformin, TZD,
GLP1 RA, DPP4i
Adipose (fat)
Increased FFA production The Ominous Octet Digestive tract
Decreased incretin effect
TZD GLP1 RA, AGis,
Colesevelam
GLP1 RA, DPP4i

Brain Increased glucagon Kidney

Neurotransmitter dysfunction secretion from Increased glucose reabsorption
α-cells
GLP1 RA SGLT2i
Bromocriptine Pancreas
DeFronzo RA. Diabetes. 2009;58:773-795
 Thiazolidinediones (TZDs)*
Hypoglycemia Neutral

Weight Gain

Renal / Genitourinary Neutral

Gastrointestinal adverse
Neutral
effects
Cardiac—CHF Moderate

Cardiac--ASCVD May reduce stroke risk

Bone Moderate fracture risk

Ketoacidosis Neutral

Few adverse events or possible benefits Use with caution ?

Likelihood of adverse effects Uncertain effect

*Moderate dose (pioglitazone 30 mg).

ASCVD = atherosclerotic cardiovascular disease; CHF = congestive heart failure.
Garber AJ, et al. Endocr Pract. 2017;23:207-238.
52
 Mechanism of Action of
Antihyperglycemic Agents
Pancreas

Muscle Decreased insulin Liver

secretion from
Increase glucose uptake Increased endogenous
β-cells
TZD glucose production
GLP1 RA, DPP4i, SU, GLN Metformin, TZD,
GLP1 RA, DPP4i
Adipose (fat)
Increased FFA production The Ominous Octet Digestive tract
Decreased incretin effect
TZD GLP1 RA, AGis,
Colesevelam
GLP1 RA, DPP4i

Brain Increased glucagon Kidney

Neurotransmitter dysfunction secretion from Increased glucose reabsorption
α-cells
GLP1 RA SGLT2i
Bromocriptine Pancreas
DeFronzo RA. Diabetes. 2009;58:773-795
 Secretagogues
SU GLN
Hypoglycemia Moderate / severe Mild
Weight Gain
Renal / Genitourinary More hypoglycemia risk
Gastrointestinal adverse effects Neutral
Cardiac—CHF More CHF risk
Cardiac--ASCVD ?
Bone Neutral
Ketoacidosis Neutral

Few adverse events or possible benefits Use with caution ?

Likelihood of adverse effects Uncertain effect

ASCVD = atherosclerotic cardiovascular disease; CHF = congestive heart failure; GLN = glinide; SU = sulfonylurea.
Garber AJ, et al. Endocr Pract. 2017;23:207-238.
54
 Mechanism of Action of
Antihyperglycemic Agents
Pancreas

Muscle Decreased insulin Liver

secretion from
Increase glucose uptake Increased endogenous
β-cells
TZD glucose production
GLP1 RA, DPP4i, SU, GLN Metformin, TZD,
GLP1 RA, DPP4i
Adipose (fat)
Increased FFA production The Ominous Octet Digestive tract
Decreased incretin effect
TZD GLP1 RA, AGis,
Colesevelam
GLP1 RA, DPP4i

Brain Increased glucagon Kidney

Neurotransmitter dysfunction secretion from Increased glucose reabsorption
α-cells
GLP1 RA SGLT2i
Bromocriptine Pancreas
DeFronzo RA. Diabetes. 2009;58:773-795
 Colesevelam and
Bromocriptine Mesylate
Colesevelam BCR-QR
Hypoglycemia Neutral Neutral
Weight Neutral Neutral
Renal / Genitourinary Neutral Neutral
Gastrointestinal adverse
Mild Moderate
effects
Cardiac—CHF Neutral Neutral
Cardiac--ASCVD Benefit Safe
Bone Neutral Neutral
Ketoacidosis Neutral Neutral
Few adverse events or possible benefits Use with caution ?
Likelihood of adverse effects Uncertain effect

ASCVD = atherosclerotic cardiovascular disease; BCR-QR = bromocriptine mesylate quick release; CHF = congestive heart failure.
Garber AJ, et al. Endocr Pract. 2017;23:207-238.
56
 Mechanism of Action of
Antihyperglycemic Agents
Pancreas

Muscle Decreased insulin Liver

secretion from
Increase glucose uptake Increased endogenous
β-cells
TZD glucose production
GLP1 RA, DPP4i, SU, GLN Metformin, TZD,
GLP1 RA, DPP4i
Adipose (fat)
Increased FFA production The Ominous Octet Digestive tract
Decreased incretin effect
TZD GLP1 RA, AGis,
Colesevelam
GLP1 RA, DPP4i

Brain Increased glucagon Kidney

Neurotransmitter dysfunction secretion from Increased glucose reabsorption
α-cells
GLP1 RA SGLT2i
Bromocriptine Pancreas
DeFronzo RA. Diabetes. 2009;58:773-795
PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT
 Insulin
Hypoglycemia Moderate to severe

Weight Gain

Renal / Genitourinary More hypoglycemia risk

Gastrointestinal adverse
Neutral
effects
Cardiac—CHF More CHF risk

Cardiac—ASCVD Neutral

Bone Neutral

Ketoacidosis Neutral

Few adverse events or possible benefits Use with caution ?

Likelihood of adverse effects Uncertain effect

ASCVD = atherosclerotic cardiovascular disease; CHF = congestive heart failure.

Garber AJ, et al. Endocr Pract. 2017;23:207-238.
60
 Effects of Antihyperglycemic Therapies
on Blood Pressure
Meta-analyses
∆ Systolic BP, mmHg ∆ Diastolic BP, mmHg
Class
(95% CI) (95% CI)
Newer therapies
-3.57 -1.38
GLP1 receptor agonists1 (-5.49 to -1.66) (-2.02 to -0.73)
-0.1
DPP4 inhibitors2 (-1.2 to 0.8) —

-3.77 -1.75
SGLT2 inhibitors3
(-4.65 to -2.90) (-2.27 to -1.23)
Older therapies
-1.09 -0.97
Metformin4 (-3.01 to 0.82) (-2.15 to 0.21)
-4.70 -3.79
TZDs5 (-6.13 to -3.27) (-5.82 to -1.77)

1. Vilsbøll T, et al. BMJ. 2012 Jan 10;344:d7771. doi: 10.1136/bmj.d7771.

2. Monami M, et al. Diabetes Obes Metab. 2013;15:112-120.
3. Vasilakou D, et al. Ann Intern Med. 2013;159:262-274.
4. Wulffelé M, et al. J Intern Med. 2004;256:1-14.
5. Qayyum R, Adomaityte J. J Clin Hypertens (Greenwich). 2006;8:19-28.
Glycemic Management of Type 2 Diabetes

INSULIN THERAPY

62
 Early Insulin Use in Type 2 Diabetes
ORIGIN
(N=12,537 patients with CV risk factors + prediabetes or T2D)

ORIGIN, Outcome Reduction With an Initial Glargine Interventionl T2D, type 2 diabetes.
ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328. 64
 Insulin Concentrations
Concentration Units/mL Units/vial Units/pen
1000 300
U-100 100
(10 units per vial) (3 mL/pen)
600
U-200 200 Not available in vials
(3 mL/pen)
450
U-300 300 Not available in vials
(1.5 mL/pen)
10,000 1500
U-500 500
(20 units/vial) (1.5 mL/pen)

• Insulin pens significantly reduce the risk of dosing errors and hypoglycemic events
• Pens completely eliminate the need for converting doses based on the volume of
insulin injected
• Dosing errors with U-500 insulin vials are common and dangerous but can be avoided
with newly available pens
– 5-fold higher insulin dose relative to the same volume of a U-100 insulin

Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. Newton C, et al. AACE Annual Meeting. 2013 [abstract

271]. Segal AR, et al. Am J Health Syst Pharm. 2010;67:1526-1535. 65
 Efficacy and Safety of U-100
Glargine Equivalent
Patients With T2D*
(N=756)
Overall Nocturnal Severe
(BG <70 mg/dL or S/S) (between bedtime and waking) (Requiring assistance)

†
Episodes per

Episodes per
†
patient-year

patient-year

No. events
A1C Insulin Dose Weight
†
†

Δ Weight (kg)
U/kg/day
Δ A1C (%)

BL = 8.3 8.3

†
*Mean age = 59 y; duration of diabetes = 11-12 y; baseline BMI = 32 kg/m2. †Not significant vs glargine.
BMI = body mass index; Glar-Eq = glargine equivalent (n=376); Glar = insulin glargine (n=380); S/S = signs and symptoms; T2D = type 2
diabetes.
Rosenstock J, et al. Diabetes Obes Metab. 2015;17:734-741. 66
 Efficacy and Safety of Glargine
U-300
Insulin-Naive T2D Patients*
(N=878)
Overall Nocturnal Severe
(BG <70 mg/dL) (between midnight and 6:00 am) (Requiring assistance)
†
Patients (%)

Patients (%)

Patients (%)
P<0.05
†

A1C Insulin Dose Weight

†

Δ Weight (kg)
†
U/kg/day
Δ A1C (%)

BL = 8.5 8.6

*Mean age = 58 y; duration of diabetes = 9.8 y; baseline BMI = 33 kg/m2. †Not significant vs glargine U-100.
BMI = body mass index; NS = not significant; T2D = type 2 diabetes.
Bolli GB, et al. Diabetes Obes Metab. 2015;17:386-394. 67
 Efficacy and Safety of Degludec and
Glargine U-100
Insulin-Naive T2D Patients*
(N=1030)
Overall Nocturnal Severe
(BG <70 mg/dL or S/S) (between bedtime and waking) (Requiring assistance)

Episodes per
Episodes per

Episodes per

patient-year
patient-year

patient-year
P=0.038
P=0.017

A1C Insulin Dose Weight

† †

Δ Weight (kg)
U/kg/day
Δ A1C (%)

BL = 8.2 8.2

*Mean age = 59 y; duration of diabetes = 9 y; baseline BMI = 31-32 kg/m2; degludec (n=773); glargine (n=257). †Not significant vs glargine.
BMI = body mass index; Deg = degludec; Glar = glargine; NS = not significant; T2D = type 2 diabetes.
Zinman B, et al. Diabetes Care. 2012;35:2464-2471.
 Inhaled Insulin

• Inhaled administration
• Rapid-acting insulin
– Peak levels achieved in ~15 minutes

Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212.

 Glucose Control with
Inhaled Insulin

Add-on to Metformin and/or Other OAs

24 Weeks
Placebo Inhaled insulin
N 353
Baseline A1C (%) 8.3 8.3
Δ A1C (%)

*Difference from placebo (95% CI): -0.40% (-0.57% to -0.23%).

Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
 Weight Change with
Inhaled Insulin

Add-on to Metformin and/or Other OAs

24 Weeks
Placebo Inhaled insulin
N 353
Δ Weight (kg)

Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
 Hypoglycemia with
Inhaled Insulin
Add-on to Metformin and/or Other OAs
24 Weeks
N 353
Nonsevere Severe
PBO II PBO II
Hypoglycemia
Patients With

(%)

II, inhaled insulin.

Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
 Safety Considerations
with Inhaled Insulin

• Contraindicated in asthma, COPD, and other chronic lung diseases

• Perform spirometry to assess lung function before initiating inhaled
insulin, after 6 months of therapy, and annually thereafter, even in the
Lung disease
absence of pulmonary symptoms
• Do not use in patients with active lung cancer and use with caution in
patients with a history of lung cancer or those at risk for lung cancer

• Observe for signs and symptoms of fluid retention or heart failure,

Heart failure
especially when used with TZDs

Hypoglycemia • Increase frequency of glucose monitoring

Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
 Inhaled Insulin:
Adverse Events
Patients (%)
Adverse Events* Inhaled insulin Placebo Active comparators
(n=1991) (n=290) (n=1363)
Cough 25.6 19.7 5.4
Throat pain or irritation 4.4 3.8 0.9
Headache 3.1 2.8 1.8
Diarrhea 2.7 1.4 2.2
Productive cough 2.2 1.0 0.9
Fatigue 2.0 0.7 0.6
Nausea 2.0 0.3 1.0
*Adverse events of interest occurring in ≥2% of patients receiving inhaled insulin.

Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Glycemic Management of Type 2 Diabetes

SAFETY CONCERNS:
HYPOGLYCEMIA

75
 Hypoglycemia: Risk Factors
Patient Characteristics Behavioral and Treatment
Factors
• Older age • Missed meals
• Female gender • Elevated A1C
• African American ethnicity
• Longer duration of
diabetes
• Neuropathy
• Renal impairment
• Previous hypoglycemia

Miller ME, et al. BMJ. 2010 Jan 8;340:b5444. doi: 10.1136/bmj.b5444. 76

 Symptoms of Hypoglycemia
Blood Glucose
Classification Level Typical Signs and Symptoms
(mg/dL)

• Neurogenic: palpitations, tremor, hunger,

Mild hypoglycemia ~50-70
sweating, anxiety, paresthesia

• Neuroglycopenic: behavioral changes,

Moderate hypoglycemia ~50-70
emotional lability, difficulty thinking, confusion

• Severe confusion, unconsciousness, seizure,

Severe hypoglycemia <50* coma, death
• Requires help from another individual

*Severe hypoglycemia symptoms should be treated regardless of blood glucose level.

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 77

 Hypoglycemia: Clinical
Consequences
Acute Long-term
• Symptoms (sweating, • Recurrent hypoglycemia
irritability, confusion) and hypoglycemia
• Accidents unawareness
• Falls • Refractory diabetes
• Dementia (elderly)
• CV events
– Cardiac autonomic
neuropathy
– Cardiac ischemia
– Fatal arrhythmia
– Angina
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 78
 Potential Consequences of
Hypoglycemia
• Neurogenic symptoms
– Tremor, palpitations, anxiety, sweating, hunger (weight gain),
paresthesias
• Neuroglycopenia morbidity
– Cognitive impairment, psychomotor abnormalities, abnormal
behavior, seizure, coma, mortality (brain death)
• Rebound hyperglycemia, brittle diabetes
• Barrier to glycemic control and adherence to treatment
secondary to fear of hypoglycemia
• Greater risk of dementia
• Prolonged QT interval with increased risk of dysrhythmias,
sudden death
• Harm to property or to others (eg, if driving)

Cryer PE. J Clin Invest. 2007;117:868-870.

Cryer PE. Diabetes Care. 2003;26:1902-1912. 79
 Treatment of Hypoglycemia
Hypoglycemia symptoms
(BG <70 mg/dL)

Patient severely confused or

Patient conscious and alert
unconscious (requires help)

• Consume glucose-containing foods • Glucagon injection, delivered

(fruit juice, soft drink, crackers, milk, by another person
glucose tablets); avoid foods also
• Patient should be taken to
containing fat
hospital for evaluation and
• Repeat glucose intake if SMBG result treatment after any severe
remains low after 15 minutes
episode
• Consume meal or snack after SMBG
has returned to normal to avoid
recurrence

BG = blood glucose; SMBG = self-monitoring of blood glucose.

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 80

 Frequency of Severe Hypoglycemia With
Antihyperglycemic Agents
Percentage of Patients Treated in 1 Year

6% Mixtures, rapid-acting, basal-bolus

5% Insulin

4% Basal

3%

2% Sulfonylureas
Glinides
1%
DPP4 inhibitors, GLP1 receptor agonists,
0 Metformin, TZDs, SGLT2 inhibitors

Moghissi E, et al. Endocr Pract. 2013;19:526-535. 81

 Relative Rates of Severe
Hypoglycemia with Insulin
Increasing rates
of hypoglycemia

Prandial Human insulin

Most
and Prandial analogs and inhaled insulin
frequent premixed Premixed (70/30, 75/25)

More Basal plus 2-3 prandial

Basal +
frequent Basal plus 1 prandial

NPH
Less Basal Basal analogs (glargine, detemir)
frequent only Pipeline basal analogues
(degludec, pegylated lispro)

Moghissi E, et al. Endocr Pract. 2013;19:526-535. 82

 Hypoglycemia and Mortality
ACCORD Posthoc Analysis

Risk of Hypoglycemia with Each 1% Risk of Mortality in Patients with

Change in Updated A1C Severe Hypoglycemia
2.9X

76%
Standard
Intensive
28%
15%

14%
28%

1% Decrease 1% Increase

83
Miller ME, et al. BMJ. 2010;340:b5444-b5444.
 Glucose Control and Mortality
ACCORD Posthoc Analysis

Adjusted Log (Hazard Ratio) by Treatment Strategy

Relative to Standard at A1C of 6%

Mortality Risk Intensive

Risk increase with each
1% increase in A1C
Log (Hazard Ratio)

1 P Value
66% <0.0001

0
14% 0.17
Standard
-1
Mortality Benefit
6 7 8 9
Average A1C (%)

Riddle MC, et al. Diabetes Care. 2010;33:983-990. 84

Glycemic Management of Type 2 Diabetes

SAFETY CONCERNS: WEIGHT

85
 Antidiabetic Agents and Weight
Class Agent(s) Weight Effect
Amylin analog Pramlintide ↓
Biguanide Metformin ↓
Albiglutide, dulaglutide, exenatide, exenatide XR,
GLP1 receptor agonists
liraglutide
↓
SGLT-2 inhibitors Canagliflozin, dapagliflozin, empagliflozin ↓
α-Glucosidase inhibitors Acarbose, miglitol ↔
Bile acid sequestrant Colesevelam ↔
DPP4 inhibitors Alogliptin, linagliptin, saxagliptin, sitagliptin ↔
Dopamine-2 agonist Bromocriptine ↔
Glinides Nateglinide, repaglinide ↑
Sulfonylureas Glimepiride, glipizide, glyburide ↑
Aspart, detemir, glargine, glulisine, lispro, NPH, regular,
Insulin
inhaled
↑↑
Thiazolidinediones Pioglitazone, rosiglitazone ↑↑
• Risk of additional weight gain must be balanced against the benefits of the agent
– Sulfonylureas may negate weight loss benefits of GLP1 receptor agonists or
metformin
– Insulin should not be withheld because of the risk of weight gain
Garber AJ, et al. Endocr Pract. 2017;23:207-238.
ADA. Diabetes Care. 2017;40:S64-S74.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
86
Type 2 Diabetes Glucose Goals and Complications
Management

INDIVIDUALIZED GOALS

87
 AACE Comprehensive Diabetes
Care: Glucose Goals
Parameter Treatment Goal for Nonpregnant Adults
A1C (%) Individualize targets:
• ≤6.5 if it can be achieved without substantial
hypoglycemia or other unacceptable
consequences
• >6.5% to 8% for those at risk*
FPG (mg/dL) <110
2- hour PPG (mg/dL) <140

*As long as patient remains free of polydipsia, polyuria, polyphagia, or other

symptoms of hyperglycemia. Factors indicating a higher A1C target include
• Risk for hypoglycemia • Long-standing T2D in which the
• History of severe hypoglycemia A1C goal has been difficult to
• Limited life expectancy attain despite intensive efforts

Handelsman Y, et al. Endocr Pract. 2015;21(suppl 1):1-87. Garber AJ, et al. Endocr Pract. 2018;24:91-120.
88
 Algorithm for Individualizing
Glycemic Targets
Most intensive Less intensive Least intensive
6.0% 7.0% 8.0%

Psychosocioeconomic considerations
Highly motivated, adherent, knowledgeable, Less motivated, nonadherent, limited
excellent self-care capacities, and insight, poor self-care capacities, and
comprehensive support systems weak support systems

Hypoglycemia risk
Low Moderate High
Patient age, years
40 45 50 55 60 65 70 75

Disease duration, years

5 10 15 20
Other comorbid conditions
None Few or mild Multiple or severe

Established vascular complications

None Cardiovascular disease
Early microvascular Advanced microvascular

Ismail-Beigi F, Moghissi E, et al. Ann Intern Med. 2011;154:554-559. 89

 ADA-Recommended
Glucose Goals
Parameter
A1C (%)
Preprandial glucose (mg/dL)
Peak postprandial glucose (mg/dL)
*Appropriate patients
• Short duration of diabetes
• T2D treated only with lifestyle or
metformin
• Long life expectancy
• No significant cardiovascular disease
ADA. Diabetes Care. 2018;41:S55-S64.
Treatment Goal for Nonpregnant Adults
Individualize
• <7.0% for most nonpregnant adults
• <6.5 if it can be achieved without
significant hypoglycemia or other
adverse effects of treatment*
• <8% for those at risk†
80-130
<180
†
At risk patients
• History of severe hypoglycemia
• Limited life expectancy
• Advanced micro- or macrovascular
complications
• Extensive comorbid conditions
• Long-standing T2D in which A1C goal has
been difficult to attain despite intensive efforts
90
 ADA-Recommended Approach to
Management of Hyperglycemia
More stringent A1C 7% Less stringent

Risks potentially associated

with hypoglycemia, other Low High
drug adverse events

Disease duration Newly diagnosed Long-standing

Life expectancy Usually not

Long Short modifiable

Important comorbidities
Absent Few/mild Severe

Established vascular
complications Absent Few/mild Severe

Patient attitude and

Highly motivated, adherent, Less motivated, nonadherent, Potentially
expected treatment efforts excellent self-care capacities poor self-care capacities
modifiable
Resources, support system
Readily available Limited
ADA. Diabetes Care. 2018;41:S55-S64.
91
 Macrovascular Benefits of Glycemic Control
Depend on Duration of Diabetes
Veterans Affairs Diabetes Trial

Effect of intensive glycemic control

4.0
Neutral Reduced Neutral Elevated
3.5 risk risk
3.0
Hazard ratio

2.5
2.0
1.5
1.0
0.5
0
0 3 6 9 12 15 18 21 24 27 30
Years with diabetes

VADT, Veterans Affairs Diabetes Trial.

92
Duckworth WC, et al. J Diabetes Complications. 2011;25:355-361.
Type 2 Diabetes Glucose Goals and Complications
Management

MICROVASCULAR
COMPLICATIONS

93
 Microvascular Complications of
Diabetes

Nephropathy Retinopathy Neuropathy

94
 Microvascular Complications
Increase With Increasing A1C
Diabetes Control and Complications Trial

20
Retinopathy
18
Nephropathy
16
Neuropathy
14
Relative Risk

Microalbuminuria
12
10
8
6
4
2
0
6 7 8 9 10 1 12
A1C (%) 1

Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254. 95

 Reducing A1C Reduces
Microvascular Risk
United Kingdom Prospective Diabetes Study

10
Microvascular Complications

P<0.0001
Hazard Ratio

1 37% Decrease
per 1% reduction in A1C
0.5
0 5 6 7 8 9 10
Updated Mean A1C

Stratton IM, et al. BMJ. 2000;321:405-412. 96

 Prevalence of CKD in Diagnosed
Diabetes
Diabetic Kidney Disease Is the Leading Cause of Kidney Failure in the United States

NKF
Description GFR
Stage
Kidney damage* with
1 ≥90
normal or ↑ GFR
Kidney damage* with
2 60-89
mild ↓ GFR
3 Moderate ↓ GFR 30-59
4 Severe ↓ GFR 15-29
Kidney failure or <15 or
5
ESRD dialysis

*Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.
ESRD, end-stage renal disease; GFR, glomerular filtration rate (mL/min/1.73 m2); NKF, National Kidney Foundation.
CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.
Plantinga LC, et al. Clin J Am Soc Nephrol. 2010;5:673-682. 97
 Development of
Diabetic Nephropathy
Hyperglycemia Hyperfiltration Breakdown of
Micro-albuminu
Hypertension Enlarged glomerular
ria
↑Angiotensin II kidneys filtration barrier

Genetically susceptible individuals

Protein
reabsorption and Capillary Decreasing Macro-albumin
accumulation in occlusion GFR uria
renal epithelial cells

Release of Tubular atrophy

Tubule and Renal
vasoactive and and fibrosis,
inflammatory
podocyte
podocyte failure
cytokines damage
destruction

Radbill B, et al. Mayo Clin Proc. 2008;83:1373-1381.

Remuzzi G, Bertani T. N Engl J Med. 1998;339:1448-1456. 98
 CV Risk Increases With Comorbid
Diabetes and CKD

x 2.8
x 2.0

x 2.1
x 1.7
x 2.5

x 2.3

AMI, acute myocardial infarction; ASVD, atherosclerotic vascular disease; CHF, congestive heart failure;
CVA/TIA, cerebrovascular accident/transient ischemic attack; PVD, peripheral vascular disease.
*ASVD was defined as the first occurrence of AMI, CVA/TIA, or PVD.
Foley RN, et al. J Am Soc Nephrol. 2005;16:489-495. 99
 Risk of Cardiovascular Mortality with
Decreasing eGFR and Increasing
Albuminuria

D e ath
c ular
Relative Risk

s
rd i ova
o f Ca
Risk

ACR (mg/g)

eGFR (mL/min/1.73 m2)

ACR = albumin-creatinine ratio; eGFR = estimated glomerular filtration rate.

100
Handelsman Y, et al. Endocr Pract. 2015;21(suppl 1):1-87. NKF. Kidney Int Suppl. 2013;3:1-150.
 Staging and Monitoring
of CKD in Diabetes
Persistent albuminuria categories
Description and range

A1 A2 A3
Previous
Guide to frequency of monitoring Normal to mildly Moderately Severely
NKF CKD
(number of times per year) by GFR increased increased increased
stage
and albuminuria category
<30 mg/g 30-300 mg/g >300 mg/g
<3 mg/mmol 3-30 mg/mmol >30 mg/mmol

GFR 1 G1 Normal or high ≥90 1 if CKD 1 2

categ
ories 2 G2 Mildly decreased 60-89 1 if CKD 1 2
(mL/
min/1 Mild to moderately
.73
G3a
decreased
45-59 1 2 3
m2) 3
Desc Moderately to
riptio
G3b
severely decreased
30-44 2 3 3
n
and 4 G4 Severely decreased 15-29 3 3 4+
rang
e 5 G5 Kidney failure <15 4+ 4+ 4+

CKD = chronic kidney disease; GFR = glomerular filtration rate; NKF = National Kidney Foundation.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 101
 Reducing A1C Reduces
Nephropathy Risk in T2D
UKPDS ADVANCE ACCORD

A1C reduction (%)* 0.9 0.8 1.3

Nephropathy risk
30 21 21
reduction (%)*

New New or New

onset worsening microalbuminuria
micro- nephropathy (P=0.0005)
albuminuria (P=0.006)
(P=0.033)

*Intensive vs standard glucose control.

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.
Ismail-Beigi F, et al. Lancet. 2010;376:419-430. 102
 Management of Diabetic
Nephropathy
• Optimal control of blood pressure, glucose, and
lipids
• Smoking cessation
• RAAS blockade
– ACE inhibitor, ARB, or renin inhibitor
– Do not combine RAAS blocking agents
– Monitor serum potassium
• Nephrologist referral
– Atypical presentation
– Rapid decline in eGFR or albuminuria progression
– Stage 4 CKD

ACE = angiotensin converting enzyme; ARB = angiotensin II receptor blocker; CKD = chronic kidney disease; eGFR = estimated
glomerular filtration rate; RAAS = renin angiotensin aldosterone system.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 103
 DKD Risk Factor Management
Risk Factor Goal Management Recommendation

Avoid metformin in moderate to severe CKD

Individualized A1C goals Consider need for dose reductions and/or risk of
hypoglycemia and other renal-related AEs with other
Hyperglycemia ≤6.5% for most (AACE)
antidiabetic agents
~7.0% (NKF)
Do not target A1C <7% in patients at risk of
hypoglycemia

Use ACE inhibitor or ARB in combination with other

Hypertension BP ~130/80 mmHg
antihypertensive agents as needed

Proteinuria Use ACE inhibitor or ARB as directed

LDL-C <100 mg/dL, Statin +/- ezetimibe therapy recommended for all
Dyslipidemia <70 mg/dL an option for patients except those on dialysis (NKF)
high risk Fibrate dose reduction may be required

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.

National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.
National Kidney Foundation. Am J Kidney Dis. 2012;60:850-886. 104
 Use of Antihyperglycemic Agents in
Kidney Disease
Class: Agent(s) Kidney Disease Recommendation
Amylin analog: pramlintide Not recommended for CKD stage ≥4
Biguanide: metformin Contraindicated if SCr >1.5 (men) or 1.4 (women) mg/dL
Bile acid sequestrant: colesevelam No dosage adjustment
Dopamine-2 agonist: bromocriptine Use with caution
DPP-4 inhibitors: alogliptin, linagliptin, saxagliptin, Reduce dosage for alogliptin, saxagliptin and sitagliptin if CrCl
sitagliptin <50 mg/dL
Glinides: nateglinide, repaglinide Start at lowest effective dose if GFR <30 mL/min/1.73 m2
GLP-1 receptor agonists: albiglutide, dulaglutide, Exenatide and liraglutide not recommended with GFR <30
exenatide, exenatide XR, liraglutide mL/min/
α-Glucosidase inhibitors: acarbose, miglitol Avoid if GFR <25 (miglitol) or <30 (acarbose) mL/min/1.73 m2
Insulin: aspart, detemir, glargine, glulisine, inhaled, lispro,
Adjust dose based on patient response
NPH, regular

SGLT inhibitors: canagliflozin, dapagliflozin, empagliflozin Ineffective if GFR <30 mL/min/1.73 m2

No dose adjustment for glipizide; start glimepiride

Sulfonylureas: glimepiride, glipizide, glyburide
conservatively; avoid glyburide and all other SUs
Thiazolidinediones: pioglitazone, rosiglitazone No dosage adjustment

Garber AJ, et al. Endocr Pract. 2017;23:207-238. ADA. Diabetes Care. 2017;40:S64-S74. Handelsman YH, et al. Endocr Pract. 2015;21(suppl
1):1-87. National Kidney Foundation. Am J Kidney Dis. 2012;60:850-886. 105
 Diabetic Retinopathy

NHANES 2005-2008 • All T2D patients should have a

dilated eye examination by
Adults Age ≥40 Years (N=1006)
experienced ophthalmologist
annually, starting at diagnosis to
detect clinically significant
retinopathy before vision is
threatened
• Lesion types
• Background or
nonproliferative retinopathy
• Macular edema
• Preproliferative retinopathy
• Proliferative retinopathy

*Severe NPDR, PDR, or clinically significant macular edema.

NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; T2D, type 2 diabetes.
Zhang X, et al. JAMA. 2010;304:649-656.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 106
 Reducing A1C Reduces Retinopathy
Progression in T2D
UKPDS ACCORD

A1C reduction (%) 0.9 1.3

Retinopathy risk
29 17 33
reduction (%)*

Retinopathy Retinopathy Retinopathy

onset progression progression
(P=0.003) (P=0.017) (P=0.003)

*Intensive vs standard glucose control.

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
Ismail-Beigi F, et al. Lancet. 2010;376:419-430.
Chew EY, et al. N Engl J Med. 2010;363:233-244. 107
 Assessment of Diabetic Retinopathy
• Annual dilated eye examination by experienced
ophthalmologist or optometrist
• Begin assessment
– 5 years after diagnosis of T1D
– At diagnosis of T2D
• More frequent examinations for:
– Pregnant women with DM during pregnancy and 1
year postpartum
– Patients with diagnosed retinopathy
– Patients with macular edema receiving active therapy

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 108

 Diabetic Retinopathy Management
• Goal: detect clinically significant retinopathy before vision is threatened
• Annual dilated eye examination by experienced ophthalmologist,
starting at diagnosis for all T2D patients
Lesion Type Management Recommendation
Background or • Optimal glucose and blood pressure control
nonproliferative retinopathy
Macular edema • Optimal glucose and blood pressure control
• Ranibizumab injection therapy
• Focused laser photocoagulation guided by fluorescein
angiography
Preproliferative retinopathy • Optimal glucose and blood pressure control
• Panretinal scatter laser photocoagulation
Proliferative retinopathy • Optimal glucose and blood pressure control
• Panretinal scatter laser photocoagulation
• Vitrectomy for patients with persistent vitreous
hemorrhage or significant vitreous scarring and debris

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 109

 Prevalence of Diabetic Neuropathy
NHANES 1999-2004 • Neuropathy is a
Adults With Diabetes, Age ≥40 Years heterogeneous disorder
(N=559) • 70% to 100% of T2D patients
may have at least mild damage
to
– Proximal nerves
– Distal nerves
– Somatic nerves
– Autonomic nerves
• Neuropathy may be
– Acute and self-limiting
– Chronic and indolent

T2D, type 2 diabetes.

Gregg EW, et al. Diabetes Res Clin Pract. 2007;77:485-488.
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. 110
 Causes of Death in Diabetic
Autonomic Neuropathy
• Sudden unexplained
• Cardiac arrhythmia
• Silent myocardial infarction
– More likely to die of heart attack
– Greater incidence of cardiac failure
• Aspiration pneumonia
• Ulcers, amputations, gangrene
• Chronic renal failure

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 111

 Reducing A1C Reduces Neuropathy
Risk in T2D
ACCORD

A1C reduction (%) 1.3

Neuropathy risk
12
reduction (%)*

Loss of sensation to
light touch
(P=0.045)

*Intensive vs standard glucose control.

Ismail-Beigi F, et al. Lancet. 2010;376:419-430. 112
 Assessment of Diabetic Neuropathy

• Complete neurologic examination annually

• Begin assessment
– 5 years after diagnosis of T1D
– At diagnosis of T2D

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 113

 Diabetic Neuropathy Evaluations and
Tests
Foot inspection Foot structure and deformities
Skin temperature and integrity
Ulcers
Vascular status
Pedal pulses
Amputations
Neurologic testing Loss of sensation, using 1 and 10-g monofilament
Vibration perception using 128-Hz tuning fork
Ankle reflexes
Touch, pinprick, and warm and cold sensation
Painful neuropathy May have no physical signs
Diagnosis may require skin biopsy or other surrogate measure
Cardiovascular Heart rate variability with:
autonomic neuropathy • Deep inspiration
• Valsalva maneuver
• Change in position from prone to standing

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 114

 Diabetic Neuropathy Management
All neuropathies • Prevent by controlling blood glucose to individual targets
• No therapies proven to reverse neuropathy once it is
established
• May slow progression by maintaining optimal glucose, blood
pressure, and lipid control and using other interventions that
reduce oxidative stress
Painful neuropathy • Tricyclic antidepressants, anticonvulsants, serotonin reuptake
inhibitors, or norepinephrine reuptake inhibitors
Large-fiber • Strength, gait, and balance training
neuropathies • Orthotics to prevent/treat foot deformities
• Tendon lengthening for pes equinus
• Surgical reconstruction
• Casting
Small-fiber • Foot protection (eg, padded socks)
neuropathies • Supportive shoes with orthotics if needed
• Regular foot inspection
• Prevention of heat injury
• Emollient creams
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 115
Type 2 Diabetes Glucose Goals and Complications
Management

MACROVASCULAR
COMPLICATIONS

116
 Macrovascular Complications

• Cardiovascular disease
– Coronary artery disease
– Myocardial infarction
• Cerebrovascular disease (stroke)
• Peripheral vascular disease

117
 Diabetes and Cardiovascular Risk

P<0.001
7-Year Incidence of MI (%)

P<0.001

No prior MI Prior No prior Prior

MI MI MI
Patients without diabetes Patients with diabetes
(n=1373) (n=1059)

MI, myocardial infarction.

Haffner SM, et al. N Engl J Med. 1998;339:229-234. 118
 Lower A1C Is Associated With Lower
Risk of Myocardial Infarction
United Kingdom Prospective Diabetes Study

10
P<0.0001
Myocardial Infarction
Hazard Ratio

1 14% Decrease
per 1% reduction in A1C
0.5
0 5 6 7 8 9 10
Updated Mean A1C

Stratton IM et al. BMJ. 2000;321:405-412. 119

 Effect of Intensive Glycemic Control on
Macrovascular Risk in Older Patients With
Longer Duration of Disease
ACCORD ADVANCE VADT

T2DM duration (years) 10 8 12

A1C reduction (%)* 0.9 0.8 1.3

Macrovascular risk (%)* 10 6 12

P=0.16 P=0.32 P=0.14

(CV death, nonfatal MI, (CV death, nonfatal MI, (CV death, nonfatal MI,
nonfatal stroke) nonfatal stroke) nonfatal stroke, CHF,
vascular surgery,
inoperable coronary
disease, PVD
amputation)
*Intensive vs standard glucose control.
ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR
Controlled Evaluation; CHF, congestive heart failure; CV, cardiovascular; MI, myocardial infarction; PVD, peripheral vascular disease; VADT,
Veterans Affairs Diabetes Trial.
ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572. Duckworth W, et
al. N Engl J Med. 2009;360:129-139.
120
 Intensive Glycemic Control May Have
Macrovascular Benefit in Healthier People
Action to Control Cardiovascular Risk in
Diabetes
Secondary endpoint
Primary endpoint (CV death, nonfatal MI,
(nonfatal MI; entire
nonfatal stroke) subgroup analyses
cohort)

Baseline A1C ≤8% No prior CV events

Risk reduction (%)* 24 26 21

P=0.004 P=0.03 P=0.04

*Intensive vs standard glucose control.

CV, cardiovascular; MI, myocardial infarction.
121
ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.
 Intensive Glycemic Control Reduces
Long-term Macrovascular Risk
DCCT UKPDS
T1D, 5-6 years duration T2D, newly diagnosed
(N=1441) (N=4209)
42% risk reduction 15% risk reduction
0.12 P=0.02 1.0 P=0.01
Cumulative incidence

Proportion With MI
0.10 0.8
CV Outcome

0.08
Conventional 0.6
Randomized Randomized
0.06
treatment treatment Conventional
0.4
0.04
0.2 Intensive
0.02 Intensive
0.00 0.0
0 5 10 15 20 0 5 10 15 20 25
Years Years

CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; MI, myocardial infarction;
T1D, type 1 diabetes; T2D, type 2 diabetes; UKPDS, United Kingdom Prospective Diabetes Study.
Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Holman RR, et al. N Engl J Med. 2008;359:1577-1589. 122
 Long-Term Effect of Intensive
Glycemic Control on Macrovascular
Risk
VADT Follow-up Study
1.0
Probability of No Event

0.75
Intensive

Randomized
17% risk reduction
0.50 P=0.04
treatment Standard

0.25

0
0 2 4 6 8 10 12 14

Years

VADT, Veterans Affairs Diabetes Trial.

123
Hayward RA, et al. N Engl J Med. 2015;372:2197-2206.
 Effects of Intensive Glucose Control on
Macrovascular Risk in T2D
Meta-analysis of 5 Prospective RCTs Assessing Effect of Intensive
Glucose Lowering on CV Outcomes
(ACCORD, ADVANCE, PROactive, UKPDS, VADT)

Event Odds ratio Relative risk

Nonfatal MI 0.83 (0.75-0.93) -17%

Any CHD event 0.85 (0.77-0.93) -15%
Stroke 0.93 (0.81-1.06) -7% (NS)
All-cause mortality 1.02 (0.87-1.19) +2% (NS)

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

Intensive treatment better Standard treatment better

ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron
MR Controlled Evaluation; NS, not significant; PROactive, Prospective Pioglitazone Clinical Trial in Macrovascular Events;
T2D, type 2 diabetes; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.
Ray KK, et al. Lancet. 2009;373:1765-1772. 124
 Macrovascular Risk Reduction in
Type 2 Diabetes
• Individualized glucose control
• Hypertension control
• Dyslipidemia control
• Smoking cessation
• Aspirin therapy
• Diagnosis and management of:
– Autonomic cardiac neuropathy
– Kidney disease

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 125