DIABETES PHARMACOTHERAPY

PHILIP BERRY, MD Caspar David Friedrich

Woman in the Morning Light
Nothing to Disclose
Objectives

Review each common class of medication

– Basics
– Mechanism of action
– CVD trials
– Side effects and contraindications
– Dosing

Review ADA guidelines for DM2 pharmacotherapy

(please note that references are at the end of the presentation)

Metformin

Basics
 Cost per NADAC*: $2
 A1C lowering of 1-1.5%

Side benefits
 0-6 lb weight loss
  ASCVD risk
 Used in US since 1995, so >25 years of clinical experience.

* Based off National Average Drug Acquisition cost database on 11/13/18.

Metformin
mechanisms of action

¯ Liver glucose output by inhibition of hepatic gluconeogenesis

Inhibits mitochondrion-specific isoform of glycerophosphate dehydrogenase, resulting in  conversion of
lactate & glycerol to glucose.

Stimulation of enterocytes to  secretion of GLP-1 and peptide YY.

Increased transport of glucose from the circulation into stool.

Metformin
Randomized clinical trials with CVD outcomes

1. UKPDS (1998)
o prespecified subgroup of 1704 overweight pts.
o MI: HR 0.61 (p 0.01)
o all-cause mortality: 0.64 (p not reported)
o In contrast, UKPDS comparing SU or insulin vs diet, neither showed CV advantage.

2. HOME (2009)
o 390 patients with DM2 on insulin. Metformin vs placebo
o Expanded MACE* HR 0.61 (p = 0.02)

3. SPREAD-DIMCAD (2013)
o 304 patients w DM2 & CAD. Metformin vs placebo.
o Expanded MACE HR 0.54 (p = 0.026)

THE RELATIVE RISK REDUCTION FOR CARDIOVASCULAR END POINTS IS ~ 40%

* Expanded MACE = Myocardial infarction, acute coronary syndrome, coronary or peripheral revascularization, electrocardiogram changes, heart failure,
stroke/transient ischemic attack.
Metformin
side effects

Bloating, abdominal discomfort, diarrhea

– Only 5% of trial subjects d/c drug due to GI effects
– Dose with food, extended release, reduce dose
• You get 70% of the A1C reduction at 50% of the dose

B12 deficiency
–  intestinal absorption of B12 up to 30%
– 1 in 5 patients will have B12 deficiency within 5 years
– ADA recommends periodic B12 monitoring

Lactic acidosis
– Risk of LA in all patients with DM2 = 6/100,000 pt yrs
– Additional risk of LA due to metformin only in pts with predisposing factors
• Systematic review of 347 trials showed 0 cases of lactic acidosis
• Community based cohort of 75,413 pts: metformin assc’d with LA only at GFR < 30
Metformin
contraindications

Metformin is contraindicated if there are predisposing factors to

metformin-induced lactic acidosis
• eGFR < 30
dose should be ↓ to 1000mg or less if GFR < 45.

• Active or progressive liver disease

ok to use in NAFLD and compensated cirrhosis

• Active alcohol abuse

• Unstable or acute heart failure at risk of hypoperfusion and hypoxemia

ok to use in stable heart failure

• Decreased tissue perfusion or hemodynamic instability

Sulfonylureas

Basics
 Cost per NADAC: $2
 Drugs in the class: Glipizide, Glimepiride. Do not use glyburide.
 Expected A1C lowering effect : 1.0 – 2.0%.

Side benefits
• None
Sulfonylureas
mechanism of action
K+ K+

Pancreatic beta cell

KCa 7 KV
1
Mitochondria
Glucose GLUT2 8 Membrane repolarization

6
2 METABOLISM EXOCYTOSIS
Vesicles

 ATP:ADP

3 KATP VDCC 5
Membrane depolarization
4
K +
Ca2+
Sulfonylurea
Sulfonylureas
Randomized clinical trials with CVD outcomes

CAROLINA (glimepiride vs linagliptin)

 6033 patients with DM2 and elevated CV risk, median 6.2 years.
 composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was similar
in the two groups (11.8 versus 12 percent with glimepiride, hazard ratio [HR] 0.98, 95% CI 0.84-1.14)

SPREAD-DIMCAD (glipizide vs metformin)

• 304 patients with h/o CVD and DM2, median of 5 years.
• composite outcome (nonfatal MI, stroke, arterial revascularization, death from cardiovascular or any cause)
was lower in the metformin group (total events 43 vs 60, HR 0.54)

Meta-analyses of cardiovascular safety for sulfonylureas*

o A meta-analysis of 115 trials comparing sulfonylureas with an active comparator in patients with DM2,
there was no difference in the incidence of major cardiovascular events, although overall mortality was
increased (odds ratio [OR] 1.22, 95% CI 1.01-1.49)
o A meta-analysis of 47 trials comparing sulfonylureas with diet, placebo, or an active comparator,
sulfonylureas were not associated with an increased risk of overall mortality, cardiovascular mortality,
myocardial infarction, or stroke.

SULFONYLUREAS HAVE NEUTRAL IMPACT ON CARDIOVASCULAR RISK

* Note that the trials in the meta-analyses were not specifically designed to evaluate cardiovascular safety
Sulfonylureas
Side effects and contraindications

Side effects
• Hypoglycemia
– metabolites are renally excreted, and some (particularly w glyburide) are active.
– If you must use in CKD, choose a short-acting sulfonylurea with mostly inactive
metabolites (glipizide, glimepiride).
• Dizziness (2%), Headache (2%) Nausea (5%)
• Modest weight gain (on the order of ~3-5 pounds)

Contraindications
• None
• Can be used in advanced CKD, but only use in pts on hemodialysis with
extreme caution.
Sulfonylureas
dosing

Duration Total daily dose

Drug Dosing per day
(hours) (mg)
Glipizide 14 to 16 2.5 to 10 Once or divided*
Glipizide XL 24 5 to 10, up to 20 Once
mg
Glyburide 20 to 24+ 2.5 to 10 Once or divided
Glimepiride 24+ 2 to 4, up to 8 Once (can give 4 mg twice daily
instead of 8 mg once daily)

* Some patients may be effectively controlled on a once-daily regimen (2.5, 5, or 10 mg once daily) before the largest meal. Most have a better
response with divided dosing (5 or 10 mg twice daily), depending on eating pattern.
Pioglitazone

Basics
 Cost per NADAC: $3
 Drugs in the class: Pioglitazone
 Expected A1C lowering effect : 0.5 – 1.4%

Side benefits
 Decreased ASCVD risk
 Decreased liver inflammation
Pioglitazone
mechanism of action

 insulin sensitivity
 by acting on adipose tissue and muscle to increase glucose uptake.
 Pioglitazone binds/activates one or more peroxisome proliferator-activated receptors
(PPARs), mostly PPAR-gamma, which alters the transcription of multiple genes involved in
glucose and lipid metabolism

 lipolysis

 expression of genes associated with inflammation, such as IL-6

The mechanism is not fully understood.

Pioglitazone
Randomized clinical trials with CVD outcomes

PROactive trial (pioglitazone vs placebo, 2005)

• 5238 pts with DM2 and ASCVD (2.8 years)
– Primary outcome failed (All-cause mortality, non fatal MI, stroke,
endovascular or surgical intervention in the coronary or leg arteries, and
above-ankle amputation).
• HR 0.90, (95% CI 0.80-1.02, p =0.095).
– Main secondary endpoint showed benefit (all-cause mortality, nonfatal
MI, or nonfatal stroke) in the pioglitazone group
• (11.6% vs 13.6%, HR 0.84, 95% CI 0.72-0.98, p = 0.027), NNT 50.
Pioglitazone
Randomized clinical trials with CVD outcomes

IRIS (Pioglitazone vs placebo, 4.8 years, 2016).

Study population
• 3876 non-diabetic patients who had had a recent ischemic stroke or TIA, pio
45mg vs placebo

Outcomes
– Stroke or MI, ARR 2.8%. NNT 36
– Develop diabetes, ARR 3.9%, NNT 26

Adverse outcomes
– Weight gain > 4.5 kg, ARI 18.5%, NNH 5
– Bone fracture ARI 1.9%, NNH 53
Pioglitazone
studies showing cardiovascular benefit

Study Type of study Outcome NNT

Vallarino Retrospective Cohort MI and/or stroke 54
Dormandy (PROactive) RCT Death, MI, stroke 50
Lincoff Meta-analysis Death, MI, stroke 77
Tzoulaki Retrospective cohort All cause mortality 256
Patel Meta analysis Restenosis after stent 4
Althouse (BARI-2D) RCT Peripheral artery disease (composite of new low ABI <0.9, a lower- 14
extremity revascularization, lower-extremity amputation)
Yang Retrospective cohort All cause mortality 14
Heneke Prospective cohort Dementia (<2yrs exposure) 125
Dementia (>2yrs exposure) 48
Yokoyama Prospective cohort Death, Coronary heart disease, ischemic stroke, peripheral artery 200
disease
Tanaka (J Spirit) RCT Recurrent stroke 13
Kernan (IRIS) RCT Recurrent stroke 36
Pioglitazone:
hepatic side benefits

NASH patients:  fibrosis/inflammation/steatosis in multiple RCTs

Study Outcome NNT

Sanyal Improved histology 7
Resolution of NASH 4
Belfort Decreased hepatic fat content (on MRI) 2
Decreased histological necroinflammation 2
Cusi Decreased hepatic triglyceride content 12
Decreased histological necroinflammation 2
Resolution of NASH 3
Pioglitazone
Side effects

• Peripheral edema:
– occurs in 4 to 6% of patients treated with TZDs (compared with 1 to
2% with placebo).
• Congestive heart failure (RR 1.32)
•  fracture risk
• Weight gain:
– dose-and time-dependent, up to 12 pounds.
– Up to 75% of this weight gain is fluid
Pioglitazone
Is there a risk of bladder cancer?

• In preclinical studies, pioglitazone was

associated with bladder tumors in
male rats.
• PROactive trial: 14 vs 5 cases of
bladder cancer.
– 10-year follow-up: no increased risk of
bladder cancer (HR 1.06, 95% CI 0.89-
1.26)
• Meta-analyses:
– One meta analysis found no increased risk
(HR 1.07, 95% CI 0.96-1.18)
– Another meta-analysis found that
8 bladder cancers dx in first 12 months of
pioglitazone assc’d with 5 cases per
study in pio arm, 3 in placebo arm.
100,000 patient years (NNH of 20,000)

Bottom line: If there is a risk of bladder cancer, it is extremely small. The hepatic and
CV benefits of this inexpensive medicine are significant.
Pioglitazone
contraindications

• Heart failure
 Active or history of bladder cancer
 Discontinue in patients who develop macular edema
Pioglitazone
Dosing

• Start at 15mg
• If insufficient effect, increase to 30.
• Most endocrinologists avoid 45mg dose
DPP-4 Inhibitors

Basics
 Cost per NADAC: $391-412
 A1C lowering of 0.5-0.8%

Side benefits
 Weight neutral
 Very low side effect profile
DPP-4 Inhibitors
Mechanism of action

DPP-4 is a ubiquitous enzyme expressed on the surface of most

cell types that deactivates a variety of peptides, including GLP-1.
DPP4 inhibitors
Randomized clinical with CVD outcomes

CARMELINA (linagliptin)
SAVOR-TIMI 53 (saxagliptin)
EXAMINE (alogliptin)
TECOS (sitagliptin)

DPP4 INHIBITORS HAVE NEUTRAL IMPACT ON CARDIOVASCULAR RISK

DPP4i
side effects

Common side effects

 (5%) upper respiratory tract infection, nasopharyngitis
 Diarrhea, Nausea

Rare side effects

 Myalgias, arthralgias
 Serious allergic reactions (anaphylaxis, angioedema, SJS, bullous
pemphigoid)
 Inflammatory bowel disease
 19 per 100,000 person-years
 Pancreatitis
 1 case per 834 patients treated for 2.4 years (meta-analysis of 3 large RCTs)
DPP4i
contraindications

• History of pancreatitis
• History of severe allergic reaction to another DPP4i
GLP-1 agonists

Basics
 Cost per NADAC*: $678-835
 A1C lowering of 0.5-1.8%
 Agents in class:
– Byetta/Bydureon (Exenatide), Victoza (Liraglutide), Trulicity (Dulaglutide), Ozempic
(Semaglutide), Rybelsus (Oral Semaglutide), Xultophy (Degludec/liraglutide), Soliqua
(Glargine/lixisenatide)
GLP-1 agonists
Side benefits

Significant weight loss

Blood pressure reduction

Decreased hepatic fat and hepatic inflammation.

 LEAN trial (2016) : 52 patients with NASH received liraglutide or placebo for 48 weeks, then end-
of-treatment biopsy.
 NASH more likely to resolve with liraglutide (9% vs 39%)
 Liraglutide assc’d with  progression of fibrosis (9% versus 36%)

Decreased ASCVD risk

Increased B cell proliferation and neogenesis,  B cell apoptosis (unknown whether

clinically significant)

May slow CKD progression, as has been seen in secondary endpoint in CVOTs in
LEADER and SUSTAIN-6
GLP-1 agonists
mechanisms of action

1. Increases insulin production, beta cell proliferation, and inhibits beta cell
apoptosis
2. Inhibit glucagon secretion from islet a-cells
3. Inhibits hepatic glucose production
4. Increases skeletal muscle glucose uptake
5. Improves feeding behavior
o Slowed gastric emptying and gut motility  increased gastric distension
activate gastric mechanoreceptors vagal afferent Nucleus tractus solitarii
(NTS)
o Cross the BBB and bind to receptors located in the hypothalamus, NTS, AP,
dorsal striatum, and NAc.
o Directly activate vagal afferents
 3.1% vs. 1.9% (P<0.001; NNH=83)

GLP1 agonists
RCTs with cardiovascular outcomes

LEADER (Liraglutide vs placebo, 3.8 years, 2016)

Study population
• 9340 patients
• T2DM,  50 years with known CVD, or age  60 with multiple CV risk factors
• 81% with CVD at baseline

Primary outcome
• 3-point MACE (CV mortality, nonfatal MI, or non-fatal stroke): ARR 1.9%, NNT 53 (p = 0.01)

Secondary outcomes
• All-cause mortality: ARR= 1.4%, NNT 71 (p = 0.02)
• CV mortality: ARR 1.3%, NNT 77 (p = 0.007)
• Non-fatal stroke: No significant difference
• Non-fatal MI: No significant difference
• New or worsening nephropathy: 5.7% vs. 7.2%, NNT 67 (P=0.003)

Other notable findings

• Weight change: -2.3 kg
• Systolic BP change: -1.2
• Acute gallstone disease: 3.1% vs. 1.9%, NNH=83, (P<0.001)
GLP1 agonists
RCTs with cardiovascular outcomes

SUSTAIN-6 (Semaglutide 0.5 and 1.0mg vs placebo, 2.1 years, 2016)

Study population
• 3297 patients
• T2DM,  50 years with known CVD or CKD  stage 3, or age  60 with multiple CV risk factors
• 83% with CVD at Baseline

Primary outcome
• 3-point MACE (CV mortality, nonfatal MI, or nonfatal stroke): ARR 2.3%, NNT 45 (p = 0.002)

Secondary outcomes
• CV mortality, nonfatal MI, nonfatal stroke, coronary or peripheral revascularization, hospitalization for HF or unstable
angina: 12.1% vs. 16% (P=0.002)
• Non-fatal stroke: ARR 1.1%, NNT 91
• CV mortality: No significant difference
• Non-fatal MI: No significant difference
• New or worsening nephropathy 3.8% vs. 6.1% (P=0.005)

Adverse outcomes
• Retinopathy 3% vs. 1.8%, NNH 83, (P=0.02)
• No difference in retinopathy rate in patients without baseline retinopathy.

Other notable findings

• Weight change: -4.9 kg (1.0 mg), -3.6kg (0.5 mg)
• Systolic BP change: -5.4 (1.0mg),-3.4 (0.5mg) 
• No other statistically significant outcomes other than the above
GLP1 agonists
RCTs with cardiovascular outcomes

EXSCEL (Exenatide weekly, 3.2 years, 2017)

Study population
• 14,752 patients
• T2DM,  18 years, With or w/o CVD
• 73% with CVD at baseline

Primary outcome
• 3-point MACE (CV mortality, nonfatal MI, or nonfatal stroke): ARR 9%, not
statistically significant (p=0.061)

Other notable findings

• Weight change: -1.27kg
• Systolic BP change: -1.5
GLP1 agonists
RCTs with cardiovascular outcomes

REWIND (Dulaglutide 1.5mg, 5.4 years, 2019)

Study population
• 9901 patients
• T2DM,  50 years with known CVD, or age  60 with multiple CV risk factors*
• 31% with CVD at baseline (much lower than LEADER and SUSTAIN-6)

Primary outcome
• 3-point MACE (CV mortality, nonfatal MI, or nonfatal stroke): ARR 1.37%, NNT 73 (p=0.026)

Secondary outcomes
• Non-fatal stroke: ARR 0.81%, NNT 125
• CV mortality: No significant difference
• Non-fatal MI: No significant difference
• New or worsening nephropathy: ARR 2.5%, NNT 40 (5.4 years)

Adverse outcomes
• No difference in adverse outcomes

Other notable findings

• Weight change: -1.46kg
• Systolic BP change: -1.7
* CV risk factors: 2 of following: tobacco use, dyslipidemia, HTN or abdominal obesity
GLP-1 agonists
side effects

• Nausea, vomiting and diarrhea

– 10 - 50%. 5% discontinuation rate in trials.
• Pancreatitis:
– 16 cases in 14,562 patients in GLP-1 agonist randomized trials (1 in 910)
• Sinus tachycardia
• Thyroid tumors
– Benign and malignant thyroid C cell tumors in rodent studies. Humans
have fewer C cells (than rats) and fewer expression of GLP 1 receptors
in human C cells.
• Retinopathy progression
– Ozempic assc’d with increased risk of retinopathy progression in pts
with baseline retinopathy (3 vs 1.8, NNH 83 in 2 years)
GLP1 agonists
contraindications

• H/o pancreatitis
• Personal or family history of medullary thyroid cancer or
multiple endocrine neoplasia 2A or 2B 
• Use with caution in patients with gastroparesis.
GLP-1 agonists
practical prescribing information
Victoza (18mg/3mL)
3 pens/month. Need to Rx pen needles x 30 days
• Pen dial is marked for 0.6, 1.2, or 1.8 mg.
• Dosed daily
• Titrate dose up each week as tolerated (to 1.8mg
if possible) Prescribe pen needles, dial in as with
insulin.
Bydureon (2mg powder with 0.65mL diluent)
4 pens/month, single-use pens
• 2mg dose only. Dosed weekly.
• To mix, rotate and tap up to 80x against hand
until clear
Bydureon bcise (2mg powder 0.85mL diluent)
4 pens/month, single-use pens
• 2mg dose only. Dosed weekly.
• To mix, shake for 15 seconds or until clear
Trulicity (0.75 mg/0.5 mL and 1.5 mg/0.5 mL )
4 pens/month. Single-use pens
• No wait, remove stand, no need to
reconstitute, needle is already on
• Titrate dose after 4 weeks if tolerated
Ozempic (2mg/1.5mL)
1 pen/month at 0.25-0.5mg (low dose pen)
2 pens/month at 1mg (full dose pen)
pen comes w/ needles
• Dosed weekly
• Low dose pen has markings for 0.25 and
0.5mg doses
• High dose pen has markings only for 1mg
dose
• Titrate dose every 4 weeks as tolerated. Dial
dose as with insulin.
SGLT2 inhibitors

Basics
• Cost per NADAC: $258-446
• A1C lowering of: 0.5 – 0.7
• Agents in the class:
– Canagliflozin (Invokana)
– Dapagliflozin (Farxiga)
– Empagliflozin (jardiance)
– Ertugliflozin (Steglatro)

Side benefits
  weight 2 - 3 kg
  blood pressure
  risk of death due to CVD (empa, cana)
  risk of hospitalization due to HF (empa, cana, dapa)
  risk of CKD progression (cana, dapa)
SGLT2 inhibitors
mechanism of action

DM2 nephron DM2 nephron with SGLT2i

SGLT2 inhibitors
RCTs with cardiovascular outcomes

EMPA-REG OUTCOME (Empagliflozin vs placebo, 3.1 years, 2015)

Study population
• 7028 patients 
• DM2 with High CVD risk. eGFR >30
• 99.5% CVD at baseline

Primary outcome:
• 3-point MACE (CV mortality, nonfatal MI, or nonfatal stroke): 10.5% vs. 12.1%. ARR 1.6%, NNT 62. P=0.04

Secondary outcomes
 All-cause mortality: 5.7% vs. 8.3%. NNT 38. P <0.001
 CV mortality: 3.7% vs. 5.9%. NNT 45. P<0.001
 HF hospitalization: 2.7% vs. 4.1%. NNT 71. P=0.002
 HF hospitalization or CV mortality excluding fatal stroke: 5.7% vs. 8.5%, NNT 36. P<0.001

Adverse outcomes
• No difference in UTI (18.0% vs 18.1%, NS)
• Genital infection 6.4% vs 1.8% (p<0.01) males 5% vs 1%, females 10% vs 2.6%
• No difference in AKI, ARF, DKA, or fracture

Other notable findings

• Weight change: 2kg
• Systolic BP change: -4
SGLT2 inhibitors
RCTs with cardiovascular outcomes

CANVAS (Canagliflozin, 3.6 years, 2017)

Study population
• 10,142 patients
• DM2 with high CVD risk. Mean eGFR 76.5
• 70% CVD at baseline

Primary outcome:
• 3-point MACE: 26.9 vs 31.5 per 1000 patient years. NNT 224. P=0.02

Secondary outcomes
• Hospitalization for HF: 5.5 vs. 8.7 pt with event /1000 P-Y. (P value not given)
• CV mortality and hospitalization for heart failure: 16.3 vs. 20.8 events/1000 P-Y. (P value not given)
• All-cause mortality: Not significant.
• CV mortality: Not significant.
• Hospitalization for any cause: Not significant.
• 40% reduction in eGFR, renal-replacement therapy or renal death: 5.5 vs 9.0 events per 1000 P-Y

Adverse outcomes
• Amputation of feet/toes 6.3 vs. 3.4 participants per 1000 patient-years
– This was not found in the subsequent cana trial CREDENCE or in any other SGLT2i trial
• Genital infections in men (34.9 vs 10.8 events per 1000 pt yrs)
• Genital infections in women 69 vs 18 pts events per 1000 pt/yrs

Other notable findings

• Weight change: -1.6kg
• Systolic BP change: -3.9
 NNT
4.3%
= 76
Dapagliflozin vs 5.6% Placebo (CI 0.67-0.87)
NNT = 76
SGLT2 inhibitors
RCTs with cardiovascular outcomes

DECLARE-TIMI 58 (Dapagliflozin, 4.2 years, 2019)

Study population
• 17,160 patients
• DM2 with CVD or high CVD risk*. eGFR ≥60
• 41% CVD at baseline

Primary outcome
• 3-point MACE: No significant difference

Secondary outcomes
• CV death or hospitalization for heart failure: 4.9% vs. 5.8%, NNT 111. P = 0.005
• Hospitalization for heart failure: 2.5 vs 3.3%. ARR 0.8% (P= ?)
• Death from any cause: not significant
• Myocardial infarction: Not significant
• Stroke: not significant
• Renal composite: 4.3% vs 5.6%, NNT = 76

Adverse outcomes
• Genital infection 0.9% vs 0.1% (NS)
• AKI 1.5% vs 2% (NS)

Other notable findings

•Weight change: -1.8kg
•Systolic BP change: -2.7
*at least 2 factors: Males ≥ 55 years old and females ≥ 60 years old and Dyslipidemia, hypertension OR tobacco use
SGLT2 inhibitors
RCTs with primary renal outcomes

CREDENCE (Canagliflozin, 2.6 years, 2019) trial stopped early due to positive efficacy
Study population
• 4,401 patients
• DM2. eGFR ≥30 to <90. UACR >300 to ≤5,000 mg/g.
• Stabilization on maximum labeled or tolerated dose of an ACEi or ARB (unless contraindicated)

Primary outcome
• Composite of ESRD, doubling of baseline serum creatinine, renal mortality, or CV mortality: 11% vs. 15%. NNT 25, p = 0.00001
– Doubling of creatinine: 20.7 vs 33.8 events/1000 P-Y P < 0.001
– ESRD: 20.4 vs 29.4 events/1000 P-Y. P < 0.001
– Renal mortality: 0.3 vs. 0.9 events/1000 P-Y. P value not given.
– CV mortality: 19.0 vs. 24.4 events/1000 P-Y. P= 0.05

Secondary outcomes
 CV death or hospitalization for heart failure: 31.5 vs. 45.4/1000 P-Y . NNT 75. P<0.001
 CV death, MI or stroke: 38.7 vs. 48.7/1000 P-Y. NNT=40. P=0.01
 HF hospitalization 15.7 vs. 25.3/1000 P-Y , NNT 106. (p < 0.001)

Adverse outcomes
• Amputation 12.3 vs 11.2/1000 P-Y (NS)
• Genital mycotic infections (males) 8.4 vs 0.9/1000 P-Y
• Genital mycotic infections (females) 12.6 vs 6.1/1000 P-Y

Other notable findings

•Weight change: -0.8kg
•Systolic BP change: -3.3
SGLT2 inhibitors
RCTs with primary renal outcomes

DAPA-CKD (Dapagliflozin, 2.4 years, 2020) trial stopped early due to positive efficacy
Study population
• 4304 patients
• CKD, eGFR 25 - 75. UACR 200 -5,000 mg/g.
• 67% of patients had DM2
• On max tolerated dose of an ACEi or ARB (unless contraindicated)

Primary Outcomes
 ESRD, >50% decrease in eGFR, renal mortality, or CV mortality: 9.2% vs 14.5%. NNT 18.9 p < 0.001.
• >50% decrease in eGFR: 5.2% vs 9.3%
• ESRD: 2.5% vs 3.8%
• Renal mortality: 0.0% vs 0.1%
• CV mortality: 1.4% vs 1.7%
• Subgroup analysis
• Patients with diabetes: 11.9% vs. 15.7% (HR 0.64; 95% CI 0.52-0.79)
• Patients without diabetes: 6.45% vs. 10.5% (HR 0.50; 95% CI 0.35-0.72)

Secondary Outcomes
 Composite (ESRD, >50% decrease in eGFR, renal mortality): 3.3% vs 5.8%, p < 0.001
 Composite (CV mortality, hospitalization for HF): 4.6% vs 6.4%, NNT 56, p= 0.009
 Death from any cause: 2.2 vs 3.1% p 0.004, NNT 111 (P = 0.004)

Other notable findings

•Adverse outcomes were all negative.
SGLT2 inhibitors
RCTs with primary renal outcomes

EMPA-KIDNEY (Empagliflozin, 2022)

Study population
• DM2 with eGFR ≥20 to <45 OR eGFR ≥45 to <90 with UACR ≥200 mg/g.
• Clinically appropriate dose of an ACEi or ARB (unless contraindicated)
SGLT2 inhibitors
side effects

Vulvovaginal candidiasis
– 9.5% versus 2.6% in controls.
– Trials do not show an increased risk of UTI.

Hypotension
– Theoretically could cause AKI, but studies have not shown an association .
– Caution in elderly patients as they may be more susceptible to dizziness and dehydration
from this drug.

Decreased GFR
– Temporary lowering of GFR for the first few months after starting this medication is
common.
SGLT2 inhibitors
side effects

Heerspink HJL, et al. Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3): a
multinational observational cohort study. Lancet Diabetes Endocrinol. 2020.
SGLT2 inhibitors
rare side effects

Euglycemic diabetic ketoacidosis (<0.1%) Amputations (controversial)

• (DKA with BG < 250) • CANVAS: 5.9 vs 2.8 per 1000 patient-years, NNH
• Check serum ketones in any patient on SGLT2i 324 over 5.7 years
with nausea/vomiting • CANVAS-R: 7.5 vs 4.2 per 1000 patient-years NNH
305 over 2.1 years.
Fournier’s Gangrene (controversial) • CREDENCE: no significant difference
• rarely seen in patients on SGLT2i, unclear • EMPA-REG: no significant difference
whether it is causal. • DECLARE-TIMI: no significant difference
• A case control study of patients in the Truven • DAPA-CKD: no significant difference
Health MarketScan database did not find
association of SGLT2i with FG
– All pts with DM2 admitted to hospitals since
2013
– 216 cases of FG. Of these, 9 were on SGLT2i.
– Incidence of FG in DM2 is 5.2 events/100,000
pt yrs.
SGLT2 inhibitors
contraindications

• Type 1 diabetes
• (for treatment of hyperglycemia) Type 2 diabetes and eGFR <60
(ertugliflozin) or <45 (canagliflozin, dapagliflozin, empagliflozin)
• Prior DKA
• Use caution in the following scenarios
– Frequent bacterial urinary tract infections or genitourinary yeast infections
– Postmenopausal women ( risk of genitourinary infections)
– Elderly patients (particularly those who are increased fall risk)
– Active foot ulceration or significant peripheral vascular disease
– Factors predisposing to DKA (ketosis-prone type 2 diabetes, ketogenic diet,
pancreatic insufficiency, drug or alcohol addiction)
– When used in conjunction with other medications that predispose to acute renal
injury such as NSAIDs, ACEIs, ARBs, diuretics.
SGLT2 inhibitors
dosing

  Canagliflozin Empagliflozin Dapagliflozin Ertugliflozin

(Invokana) (Jardiance) (Farxiga) (Steglatro)
GFR cutoff 45 45 60 60
(30 in CREDENCE) (25 in DAPA-CKD)
Dosing 100mg 10mg 5mg 5mg
300 mg 25 mg 10 mg 15 mg

A1c lowering vs 100 mg – 0.77% 10 mg – 0.7% 5 mg – 0.8% 5 mg – 0.7%

placebo* 300 mg – 1.03% 25 mg – 0.8% 10 mg – 0.9% 15 mg – 0.8%

Weight loss* 100 mg – 2.5 kg 10 mg – 2.8 kg 5 mg – 2.5 kg 5 mg – 2.8 kg

300 mg – 3.4 kg 25 mg – 3.2 kg 10 mg – 2.9 kg 15 mg – 3.0 kg

* from package inserts

ADA Treatment Algorithm
The ADA recommends a patient-centered approach to the
choice of medications1.

Comorbidities (ASCVD, CHF, CKD)

Hypoglycemia risk
Impact on weight
Cost
Risk of side effects
Patient preference

1. Recommendation 9.10 GRADE E

The recommended first agent is still metformin

1. Recommendation 9.5 GRADE A

2. Galega Officinalis (goat’s rue, French lilac)- this plant is rich in galegine, a substance with blood glucose lowering activity. Study of this plant laid the foundation for the
biguanide class of medications. Jean Sterne (1909 – 1997) was a French physician and pharmacologist who did the first studies of galegine.
2nd line treatment in pts with ASCVD

Use a GLP-1 with or an SGLT2i with evidence for CVD benefit

GLP-1 with CVD benefit SGLT2i with CVD benefit

• Victoza • Jardiance
• Ozempic • Invokana
• Trulicity • (farxiga failed to show benefit)
• (bydureon failed to show benefit)

Also consider pioglitazone, particularly if pt has h/o stroke (not in ADA guideline)

1. Marso SP, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. NEJM 2016 (LEADER trial)
2. Marso SP, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. NEJM 2016 (SUSTAIN-6 trial)
3. Holman R, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. NEJM. 2017. (EXSCEL trial)
4. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. NEJM 2015. (EMPA-REG trial)
5. Wiviott SD, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes . NEJM 2019 (DECLARE-TIMI trial)
6. Neal B, et al. Canagliflozin and cardiovascular and renal effects in type 2 diabetes. NEJM 2017. (CANVAS trial)
2nd line treatment in pts with CKD1

Use an SGLT2i with evidence for ↓ CKD progression

Invokana
• CREDENCE (primary endpoint) ARR 4%, NNT 25 (2.6 years)
• CANVAS (secondary endpoint) NNT 287.8 (3.6 yrs)

Jardiance
• EMPA-REG (secondary endpoint) ARR 6.1%, NNT 16 (3.1 yrs)

Farxiga
• DAPA CKD (primary endpoint) ARR 5.3%, NNT 18.9 (2.4 yrs)
• DECLARE TIMI-58 (secondary endpoint) ARR 1.3%, NNT 76.9 (4.2 yrs)
1. Recommendations 9.12, and 9.13, GRADE C
2. Wanner C, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. NEJM. 2016.
3. Wiviott SD, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes . NEJM 2019.
4. Neal B, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. NEJM. 2017.
Note: “new or worsening nephropathy” = sustained 40% reduction in eGFR, the need for renal replacement therapy, or death from renal causes)
2nd line treatment in pts with CKD, continued

If SGLT2i not tolerated, contraindicated, or eGFR<45, then the

ADA recommends you a use GLP-1.

Victoza Showed benefit in LEADER trial as a secondary endpoint

ARR 1.5%, NNT 67 (3.8 yrs)

Ozempic showed benefit in SUSTAIN-6 trial as a secondary endpoint

ARR 2.3%, NNT 43 (2.1 yrs)

Trulicity showed benefit in REWIND trial as a secondary endpoint

ARR 2.5%, NNT 40 (5.4 years)

* Secondary endpoint (Prevent new or worsening nephropathy)

1. Mann JFE, et al.  Liraglutide and Renal Outcomes in Type 2 Diabetes. NEJM. 2017.
2. Marso SP, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. NEJM 2016.
3. Gertstein HC, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet.2019.
2nd line treatment in pts with Heart Failure1

Use an SGLT2i with evidence for reducing risk of hospitalization due

to HF

Jardiance showed  HF hospitalization in EMPA-REG

– ARR 1.4%, NNT 71 (3.1 yrs)

Farxiga showed  HF hospitalization in DECLARE TIMI-58

– ARR 0.8%, NNT 125 (4.2 yrs)

Invokana showed  HF hospitalization in CANVAS

– 3.2 participants with event per 1000 patient-years, NNT 315 (3.6 yrs)
1. Recommendation 9.12, and 9.13, GRADE C
2. Wanner C, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. NEJM. 2016.
3. Wiviott SD, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes . NEJM 2019. (composite renal outcome = sustained 40% reduction in eGFR, the need for renal replacement
therapy, or death from renal causes)
4. Neal B, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. NEJM. 2017.
Second line agents in
patients without ASCVD, HF, or CKD

Consider the top priority for your patient:

Minimize risk of
hypoglycemia?

Promote weight
loss?

Minimize cost?
 2nd line therapy, If minimizing cost is top priority

Pioglitazone or sulfonylurea (glipizide or glimepiride)

• If on both of these + metformin and still above target

– Consider starting Relion N, the least expensive basal ($24.88 per 10mL).

– Note about hypoglycemia risk of NPH versus the modern basals:

• A retrospective observational study with 25,489 pts showed that compared to analog basal insulin,
NPH was not associated with increased risk of hypoglycemia requiring visit to ER or hospitalization1.

1. Lipska KJ, et al. Association of Initiation of Basal Insulin Analogs vs Neutral Protamine Hagedorn Insulin With Hypoglycemia-Related Emergency Department Visits or Hospital Admissions and With
Glycemic Control in Patients With Type 2 Diabetes. JAMA. 2018
Practical dosing of NPH

Dose timing
– At bedtime. This allows med to peak at breakfast rather than
middle of the night

Starting dose
– 10u for lean patients, 16u for obese patients.
– (if you want to be fancy, 0.1-0.2 u/kg)

Titration:
– Check fasting glucose daily.
– Increase dose by 1u Q2D for lean or 2u Q2D for obese
patients, until FBG < 130.
– If FBG < 70, dose should be decreased similarly.
– Once dose achieved to keep FBG < 130, then need to check
pre-lunch and pre-dinner BG to monitor for daytime
hypoglycemia
– If any pre-meal glucose < 80, then cut SU dose in half
– Check A1C after 3 months on final dose of basal insulin. If not at
goal, then consider mealtime Regular insulin.
Thank you.
(reference slides to follow)

Haunted wood
Caspar David Friedrich
Metformin references
Basics
• Maruthur NM, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-
analysis. Ann Intern Med 2016.
• Hundal RS, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000
• Kahn SE, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. NEJM 2006 (ADOPT trial)
• Holman RR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. NEJM 2008
• Maruthur NM, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and
metaanalysis.. Ann Intern Med 2016

Mechanism of action
• Madiraju AK, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014.
• Buse JB, et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-
week dose-ranging studies. Diabetes Care 2016.
• Morita Y, et al. Enhanced Release of Glucose Into the Intraluminal Space of the Intestine Associated With Metformin Treatment as Revealed by
[18F]Fluorodeoxyglucose PET-MRI. Diabetes Care 2020.

RCTs with CVD outcomes

• Maruthur NM, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and
metaanalysis.. Ann Intern Med 2016
• UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with
type 2 diabetes (UKPDS 34). Lancet 1998.
• UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment
and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998.
• Kooy A, et al. Long-term effects of metformin on metabolism and micro-vascular and macrovascular disease in patients with type 2 diabetes mellitus.
Arch Intern Med 2009.
• Hong J, et al.; SPREAD-DIMCAD Investigators. Effects of metformin versus glipi-zide on cardiovascular outcomes in patients with type 2 diabetes and
coronary artery disease. Diabetes Care 2013.
• Roumie CL, et al. Comparative effectiveness of sulfonylurea and metfor-min monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort
study. Ann Intern Med 2012.
• Johnson JA, et al. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care
2002.
• Claesen M, et al. Mortality in individuals treated with glucose-lowering agents: a large, controlled cohort study. JCEM 2016.

Side effects
• Hirst JA et al. Quantifying the Effect of Metformin Treatment and Dose on Glycemic Control. Diabetes Care 2012
• Aroda VRT et al. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. JCEM 2016
• * ADA 2020 Recommendation 9.7 GRADE B
• Salpeter SR, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Sys Rev 2010.
• Lazarus B et al. Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study. JAMA
intern med 2018.
Sulfonylurea references
Basics
• Rydberg T, et al. Hypoglycemic activity of glyburide (glibenclamide) metabolites in humans.Diabetes Care 1994
• Hermann LS, et al. Therapeutic comparison of metformin and sulphonylurea, alone and in various combinations. A double-blind controlled study.
Diabetes Care 1994..

Mechanism of action
• Pearson, ER, et al. Switching From Insulin to Oral Sulfonylureas in Patients With Diabetes Due to Kir6.2 Mutations. NEJM 2006.

RCTs with cardiovascular outcomes

• Rosenstock J, et al. Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA
Randomized Clinical Trial. JAMA 2019.
• Monami M, et al. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013.
• Varvaki Rados D, et al. The Association between Sulfonylurea Use and All-Cause and Cardiovascular Mortality: A Meta-Analysis with Trial Sequential
Analysis of Randomized Clinical Trials. PLoS Med 2016.
• Hong J, et al. SPREAD-DIMCAD Investigators. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and
coronary artery disease. Diabetes Care 2013.
• Simpson SH, et al. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study.. CMAJ
2006.
• Roumie CL, et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort
study. Ann Intern Med 2012.
• Schramm TK, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or
without a previous myocardial infarction: a nationwide study. Eur Heart J. 2011.
• Roumie CL, et al. Association of Treatment With Metformin vs Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and
Reduced Kidney Function. JAMA 2019.
• Azoulay L, Suissa S. Sulfonylureas and the Risks of Cardiovascular Events and Death: A Methodological Meta-Regression Analysis of the Observational
Studies. Diabetes Care 2017.
Pioglitazone references
Basics
• Aronoff S, et al. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-
response study. The Pioglitazone 001 Study Group. Diabetes Care 2000.
• Yki-Jarvinen H. Thiazolidinediones. NEJM 2004
• Yki-Jarvinen H. Thiazolidinediones. NEJM 2004.
• Petersen KF, et al. Mechanism of troglitazone action in type 2 diabetes. Diabetes 2000.

Mechanism of action
• Yki-Jarvinen H. Thiazolidinediones. NEJM 2004.
• Petersen KF, et al. Mechanism of troglitazone action in type 2 diabetes. Diabetes 2000.

RCTs with CVD outcomes

• Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In
macroVascular Events): a randomised controlled trial. Lancet. 2005.
• Kernan WN, et al. Pioglitazone after ischemic stroke or transient ischemic attack. NEJM. 2016

Cardiovascular side benefits

• Davidson MD, Pan D. An updated meta-analysis of pioglitazone exposure and bladder cancer and comparison to the drug’s effect on cardiovascular disease and non-alcoholic
steatohepatitis. Diabetes Research and Clinical Practice. 2018
• Vallarino C, et al. Comparing pioglitazone to insulin with respect to cancer, cardiovascular and bone fractures endpoints, using propensity score weights. Clin Drug Investig 2013
• Dormandy JA, et al. Secondary preventionErdman E, et al. he effect of pioglitazone on recurrent myocardial infarction in 2445 patients with type 2 diabetes and previous myocardial
infarction. J Am Coll Cardiol 2007.
• Lincoff Am, et al. oioglitazone and risk of cardiovascular events in patient with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007
• Tzoulaki J, et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK
general practice research database. BMJ. 2009.
• Patel D, et al. Role of pioglitazone in the prevention of restenosis and need for revascularization after bare-metal stent implantation: a meta-analysis. JACC Cardiovasc Interv 2011.
• Althouse AD, et al. Favorable effects of insulin sensitizers pertinent to peripheral arterial disease in type 2 diabetes: results from the Bypass Angioplasty Revascularization Investigation
2 Diabetes (BARI 2D) trial. Diabetes Care 2014.
• Yang J, et al. A comparison of all-cause mortality with pioglitazone and insulin in type 2 diabetes: an expanded analysis from a retrospective cohort study.. Curr Med Res Opin. 2014.
• Heneke MT, et al. Effect of pioglitazone medication on the incidence of dementia. Ann Neurol 2015.
• Yokoyama H, et al. Pioglitazone treatment and cardiovascular event and death in subjects with type 2 diabetes without established cardiovascular disease. Diabetes Clin Res Pract.
2015
• Tanaka R, et al. Effects of pioglitazone for secondary stroke prevention in patients with impaired glucose tolerance and newly diagnosed diabetes: the J-SPIRIT study. J Atheroscler
Thromb 2015.
• Kernan WN, et al. Pioglitazone after ischemic stroke or transient ischemic attack. NEJM. 2016

Hepatic Side benefits

• Davidson MD, Pan D. An updated meta-analysis of pioglitazone exposure and bladder cancer and comparison to the drug’s effect on cardiovascular disease and non-alcoholic
steatohepatitis. Diabetes Research and Clinical Practice. 2018
• Sanyal AJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone of the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004.
• Belfort R, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. NEJM . 2006.
• Cusi K, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus. Ann Intern Med 2016.

Side effects
• Davidson MD, Pan D. An updated meta-analysis of pioglitazone exposure and bladder cancer and comparison to the drug’s effect on cardiovascular disease and non-alcoholic
steatohepatitis. Diabetes Research and Clinical Practice. 2018
• Sanyal AJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone of the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004.
• Belfort R, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. NEJM . 2006.
DPP4 inhibitor references
Basics
• Drucker DJ. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action.
Diabetes care. 2007.

Mechanism of action
• Drucker DJ. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action.
Diabetes care. 2007.

RCTs with CVD outcomes

• Scirica BM, et al. SAVOR-TIMI 53 Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. NEJM
2013.
• Scirica BM, et al. SAVOR-TIMI 53 Investigators. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53
randomized trial. Circulation 2014.
• White WB, et al. EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. NEJM. 2013.
• Zannad F, et al. EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus
placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015.
• Green JB, et al. TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. NEJM. 2015.
• Rosenstock J, et al. CARMELINA Investigators. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2
Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA 2019.

Side effects
• Scirica BM, et al. SAVOR-TIMI 53 Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. NEJM
2013.
• Scirica BM, et al. SAVOR-TIMI 53 Investigators. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53
randomized trial. Circulation 2014.
• White WB, et al. EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. NEJM. 2013.
• Zannad F, et al. EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus
placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015.
• Green JB, et al. TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. NEJM. 2015.
• Rosenstock J, et al. CARMELINA Investigators. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2
Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA 2019.
GLP1 agonist references
Basics
• Armstrong MJ, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
Lancet 2016.
• Muskiet MHA, et al. The gut–renal axis: do incretin-based agents confer renoprotection in diabetes? Nat Rev Nephrol. 2014

Mechanism of action
•Kreymann B, et al. Glucagon-like peptide-1 7-36: a physiological insulin incretin in man. Lancet. 1987
•Mojsov S, et al. Insulinotropin: glucagon-like peptide (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. Journal of clinical
investigation. 1987
•Drucker DJ, et al. Glucagon-like peptide 1 stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. PNAS. 1987.
•Holz GG, et al. Pancreatic B-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1 (7-37). Nature. 1993.
•Nauck, MA, et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 17–36 amide in type 2 (non‑
•dependent) diabetic patients. Diabetologia 1993.
•Hansen L, et al. Somatostatin restrains the secretion of glucagon-like peptide‑ 1 and 2 from isolated perfused porcine ileum. Am. J. Physiol. Endocrinol. Metab. 2000.
•Cervera, A. et al. Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 2008.
•Hvidberg, A. et al. Effect of glucagon-like peptide-1 (pro-glucagon 78-107amide) on hepatic glucose production in healthy man. Metabolism. 1994.
•Cersosimo, E. et al. Effect of exenatide on splanchnic and peripheral glucose metabolism in type 2 diabetic subjects. JCEM. 2011.
•Vahl, T.P. et al. Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats.
Endocrinology. 2007.
•Armstrong, M.J. et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016.
•Prigeon, R.L. et al. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am. J. Physiol. Endocrinol. Metab. 2003.
•Luque MA, et al. Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes. Journal of Endocrinology. 2002.
•Jansen P, et al. The role of gastric motility in the control of food intake. Alimentary Pharmacology and therapeutics. 2011.
•Marthe CS, et al. Effects of GLP-1 and incretin-based therapies on gastrointestinal motor function. Experimental Diabetes Research. 2011.
•Shugrue PJ, et al. Glucagon-like peptide-1 receptor (GLP1-R) mRNA in the rat hypothalamus. Endocrinology. 1996
•Merchenthaler I, et al. Distribution of pre–pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. Journal of Comparative
Neurology. 1999.
•Abbott CR, et al. The inhibitory effects of peripheral administration of peptide YY(3–36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal–brainstem–
hypothalamic pathway. Brain Research. 2005.
•Plamboeck A, et al. The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. American Journal of Physiology. Gastrointestinal and
Liver Physiology. 2013.

RCTs with CVD outcomes

1. Marso SP, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. NEJM 2016 (LEADER trial)
2. Marso SP, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. NEJM 2016 (SUSTAIN-6 trial)
3. Vilsbol T, et al. Semaglutide, reduction in glycated haemoglobin, and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018
4. Holman R, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. NEJM. 2017. (EXSCEL trial)

Side effects
• Vilsbol T, et al. Semaglutide, reduction in glycated haemoglobin, and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018
• Shyangdan, DS, et al. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011.
• Li L, et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. BMJ.
2014.
SGLT2 inhibitor references

Basics

RCTs with CVD outcomes

1. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. NEJM 2015. (EMPA-REG trial)
2. Wiviott SD, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes . NEJM 2019 (DECLARE-TIMI trial)
3. Neal B, et al. Canagliflozin and cardiovascular and renal effects in type 2 diabetes. NEJM 2017. (CANVAS trial)

RCTs with renal outcomes

Side effects
• Clar C, et al. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012.
• Li D, et al. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A
meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017.
• Kumar S, et al. Fournier's gangrene in a man on empagliflozin for treatment of Type 2 diabetes. Diabet Med. 2017
• Bersoff-Matcha SJ, et al. Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous
Postmarketing Cases. Ann Intern Med. 2019.
• Wang T, et al. SGLT2 Inhibitors and the Risk of Hospitalization for Fournier’s Gangrene: A Nested Case–Control Study. Diabetes Ther.
2020.
• Nadkarni GN, et al. Acute Kidney Injury in Patients on SGLT2 Inhibitors: A Propensity-Matched Analysis. Diabetes Care. 2017.
• Fralick M, et al. Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. NEJM 2017.
• Inzucchi SE, et al. Empagliflozin and Assessment of Lower-Limb Amputations in the EMPA-REG OUTCOME Trial. Diabetes Care. 2018.
• Puckrin R, et al. SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials. Acta
Diabetol. 2018.