6/6/2017

1

Management of Type 2 Diabetes: Should We Change

Our Algorithm?Drugs for Type 2 Diabetes

Robert J. Rushakoff, MDProfessor of Medicine

University of California, San Francisco

robert.rushakoff@ucsf.edu

CDC Funding

• The American Association for Diabetes Educators

• America’s Health Insurance Plans

• Black Women’s Health Imperative

• National Association of Chronic Disease Directors

• YMCA of the USA

Medicare Funding!

• Begins 1/1/2018

• 12 month intervention– At least 16 weekly core 1 hour

sessions

– Medicare Part B

– BMI >24 (Asian >22)

– HbA1c 5.7 to 6.4 or FBS 110-125

– No dx of type 1 or type 2 DM (can have hx gestational DM)

– No ESRD

• Payment structure - - TBD

• Must be recognized CDC Diabetes Prevention Recognition Program

3. ANTI‐HYPERGLYCEMIC THERAPY

• Glycemic targets

- HbA1c < 7.0% (mean PG 150‐160mg/dl [8.3‐8.9 mmol/l])

- Pre‐prandial PG <130mg/dl (7.2 mmol/l)

- Post‐prandial PG <180 mg/dl (10.0 mmol/l)

- Individualization is key:

Tighter targets (6.0 ‐ 6.5%) ‐ younger, healthier

Looser targets (7.5 ‐ 8.0%+) ‐ older, comorbidities, hypoglycemia prone, etc.

- Avoidance of hypoglycemia

PG = plasma glucose

ADA‐EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015

Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

more stringent

less stringent

Patient attitude and expected treatment efforts highly motivated, adherent,

excellent self-care capacities less motivated, non-adherent,

poor self-care capacities

Risks potentially associated with hypoglycemia and other drug adverse effects

low high

Disease duration newly diagnosed long-standing

Life expectancy long short

Important comorbidities absent severe few / mild

Established vascular complications absent severe few / mild

Readily available limited

Usually not modifiable

Potentially modifiable

HbA1c 7%

PATIENT / DISEASE FEATURES

Approach to the management of hyperglycemia

Resources and support system

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

6/6/2017

2

Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the

American College of Physicians

Recommendation 1:

ACP recommends that clinicians prescribe metformin to patients with type 2 diabetes when pharmacologic therapy is needed to improve glycemic control.

(Grade: strong recommendation; moderate-quality evidence)

Ann Intern Med. 2017;166(4):279-290.

Metformin and Lactic Acidosis

• “Metformin may provoke lactic Acidosis which is most likely to occur in patients with renal impairment. It should not be used with even mild renal impairment” 1

• Metformin probably not as unsafe as previously thought. – 25% users have relative contraindication 2

– Patient’s with lactic acidosis usually have acute renal failure 3

1. Joint Formulary Committee British National Formulary. 2006:3532. Diabet Med 2001; 18:483-4883. Diabet Med 2007; 24:494-497

Metformin: The Safest Hypoglycaemic Agent in Chronic

Kidney Disease?

• There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared with other oral hypoglycaemic treatments.

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes. Cochrane Database Syst Rev 2010;4: CD002967.

Nephron Clin Pract 2011;118:c380-c383

FDA and Metformin: 2016• Eliminated the heart failure warning in response to

2 large observational studies that suggested that metformin is safe and may be beneficial in patients with compensated heart failure.

• As a result of 2 citizen petitions, Metformin allowed in patients with:– mild to moderate kidney dysfunction, defined as an

estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2,

– but not in those with severe kidney dysfunction (eGFR<30 mL/min/1.73 m2).

6/6/2017

3

The Effect of Intravenous Contrast on Renal Function in Diabetic Patients on Metformin

SF VA - - retrospective• 130 patients

• precontrast renal function did not predict a decline in postcontrast renal function

• patients with precontrast eGFR>60 mL/min/1.73 m2 did not have any deterioration in renal function.

• no significant deterioration in renal function in patients with a precontrast eGFR <60 mL/min/1.73 m2.

UCSF - - Prospective• 40 patients

• no significant change in serum creatinine was observed (baseline range from 0.7 to 1.2 mg/dL). Notably, an additional 15 patients were recruited, but they did not obtain a postcontrast creatinine measurement despite receiving reminders.

Shah et al. ENDOCRINE PRACTICE Vol 22 No. 4 April 2016

2015 American College of Radiology Manual on Contrast Media

Iodinated Contrast

Category I. (eGFR ≥30 mL/min/1.73m2)

In patients with no evidence of AKI and with eGFR ≥30

mL/min/1.73m2, there is no need to discontinue metformin either

prior to or following the intravenous administration of iodinated

contrast media, nor is there an obligatory need to reassess the

patient’s renal function following the test or procedure.

2015 American College of Radiology Manual on Contrast Media

Iodinated Contrast

Category II. (eGFR <30 mL/min/1.73m2)

In patients taking metformin who are known to have acute kidney injury or severe chronic

kidney disease (stage IV or stage V; i.e., eGFR <30 mL/min/1.73m2), or are undergoing

arterial catheter studies that might result in emboli (atheromatous or other) to the renal

arteries, metformin should be temporarily discontinued at the time of or prior to the

procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after

renal function has been re-evaluated and found to be normal.

Gadolinium-based contrast material

It is not necessary to discontinue metformin prior to contrast medium administration when the

amount of gadolinium-based contrast material administered is in the usual dose range of 0.1

to 0.3 mmol per kg of body weight.

Long term treatment with metformin in patients with type 2diabetes and risk of vitamin B-12 deficiency: randomized

placebo controlled trial

BMJ 2010;340:c2181

6/6/2017

4

Long-term Metformin Therapy and Monitoring for Vitamin B12 Deficiency Among Older Veterans

• Veterans 50 years or older with either type 2 diabetes and long-term metformin therapy (n = 3,687) or without diabetes and no prescription for metformin (n = 13,258)

• 37% of older adults with diabetes receiving metformin were tested for vitamin B12 status

• mean B12 concentration was significantly lower in the metformin-exposed group (439.2 pg/dL) compared to those without diabetes (522.4 pg/dL) (P = .0015).

• About 7% of persons with diabetes receiving metformin were vitamin B12 deficient (<170 pg/dL) compared to 3% of persons without diabetes or metformin use (P = .0001)

J Am Geriatr Soc 2017.

Metformin and B12

• Anemia may be minimal to severe

• may present only as a peripheral neuropathy, possibly being misdiagnosed as diabetic neuropathy.

Metformin: Possible Benefits

VA longitudinal Study (Wian et al - ADA 2016) • metformin exposure longer than 2 years• significant reduction in neurodegenerative disease.(reduced cognitive

decline, Parkinson's, Alzheimer's)• Metformin may be neuroprotective

Targeting Aging with Metformin (TAME) study. • Demonstrated to slow the aging process in certain microbes and mammals• The researchers will give Metformin to about 3,000 elderly people, who

either suffer from or have a high risk of developing diseases like cancer, heart disease, or cognitive problems.

Cancer• Studies on lung cancer; head and neck cancers, esophageal cancer• Affect multiple key processes related to cell growth, proliferation, and

survival. both metabolic and intracellular-signaling activity. downregulation of the Ras/Raf/MEK/ ERK and PI3K/AKT/mTOR signaling pathways. One or both of these pathways are often activated in many types of cancer cells

6/6/2017

5

Efficacy

Hypoglycemia

Adverse Effects

CostInsurance coverage

Weight Gain

Patient Acceptance

Asymptomatic Episodes of Hypoglycemia May Go Unreported

• Hypoglycemia: glucose <60 mg/dl

• In a cohort of patients with diabetes, more than 50% had asymptomatic (unrecognized) hypoglycemia, as identified by 3 day continuous glucose monitoring

• HgA1c 8 (T1) 7.4 (T2)

. Chico A et al. Diabetes Care. 2003;26(4):1153–1157.

0

25

50

75

100

All patients with diabetes

Type 1 diabetes

Pat

ien

ts,

%

Type 2diabetes

55.762.5

46.6

Patients With ≥1 Unrecognized Hypoglycemic Event, %

n=70 n=40 n=30

Patients Are Worried About the Risk of Hypoglycemia: The Diabcare–Asia 2003 Study

• Survey of 15,549 patients with diabetes

• 96% had type 2 diabetes and 4% of patients had type 1 diabetes

• 54% of respondents were anxious about the risk of hypoglycemia all or most of the time

Mohamed M. Curr Med Res Opin. 2008;24(2):507–514.

Cardiac Effects of Sulfonylurea RelatedHypoglycemia

• 30 type 2 DM patients on sulfonylureas

• Mean HbA1c 6.9

• 48 hour CGM

• Hypoglycemia (<63 mg/dl for >20 minutes) was detected in 9 of 30 subjects

• Episodes were typically nocturnal (67%) and asymptomatic (73%).

• Hypoglycemia associated QTc prolongation was seen in five of nine subjects with a large variation in individual response.

• Higher QT dynamicity, a poor prognostic factor in cardiac disease, was seen in subjects who experienced hypoglycemia compared with subjects who did not (0.193 vs. 0.159 for the nocturnal period; P = 0.01). This finding persisted after the hypoglycemic event.

• The rates of ventricular and supraventricular ectopy demonstrated a nonsignificant trend toward an increase during hypoglycemia

Diabetes Care 2017 Feb; dc161972.

6/6/2017

6

Positive Side to TZDs

• Reduction in glucose

• Reduces BP

• Reduces albuminuria

• Reduces CRP

• Possible DM prevention

• Reduces NASH

• Reduces LFT

• Reduces IMT

• Reduces stent failure

• Reduces death after CHF

• Increases adiponectin

• Increases HDL

Current TZD Side Effects

• Weight Gain: 5-12 lbs in 1 year– Blunted with metformin

– Worse with insulin

• Edema: 4-30%– Unresponsive to diuretics

• BUT:– Increased Cardiac Index

– Increased Stroke volume

– Decreased systemic resistance

– Decreased Blood Pressure

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

• multicenter, double-blind trial

• 3876 patients who had had a recent ischemic stroke or TIA

• No diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index

• received either pioglitazone (target dose, 45 mg daily) or placebo.

N Engl J Med 2016; 374:1321-1331

• Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003).

• Pioglitazone can help prevent recurrence of stroke and progression into diabetes in those patients with insulin resistance and recent cardiovascular events.

• Bone mineral density should be closely monitored in patients taking pioglitazone due to high rates of bone fracture, hospitalizations, and surgeries.

6/6/2017

7

Pioglitazone Bladder Cancer2013 Meta Analysis (1):

• hazard ratio higher in patients using pioglitazone (hazard ratio 1.23; 95% CI 1.09-1.39)

2012 Meta Analysis (2):

• hazard ratio higher in patients using pioglitazone (pooled RR 1.22, 95% CI 1.07-1.39)

2016 Population study

• 145806 patients over 14 years

• Compared with other antidiabetic drugs, pioglitazone was associated with an increased risk of bladder cancer (121.0 v 88.9 per 100 000 person years; hazard ratio 1.63, 95% confidence interval 1.22 to 2.19). Conversely, rosiglitazone was not associated with an increased risk of bladder cancer (86.2 v 88.9 per 100 000 person years; 1.10, 0.83 to 1.47). Duration-response and dose-response relations were observed for pioglitazone but not for rosiglitazone.

2016 FDA

• after updating its review of published research, which had gone back and forth on the issue.

• concluded pioglitazone may stull pose an increased risk for bladder cancer

(1) Diabet Med 2013 Jan 28. (2) CMAJ, 2012 Sep 4;184(12):E675-83

(3)BMJ 2016;352:i1541

Negative Side to TZDs

• Weight Gain

• Edema

• Bone loss

• Bladder Cancer

INCRETINS

• Gut factors that promote insulin secretion in response to nutrients

•Major incretins: GLP-1, CCK, GIP

Non-Diabetic Diabetic

Plasma Insulin Responses to Oral and Intravenous Glucose

J Clin Invest 1967; 46:1954-1962

OralIntravenous

OralIntravenous

60

Insu

lin (U

/mL

)

30

0

0 60 120 18030 90 150 0 60 120 18030 90 150

90

Insu

lin (U

/mL

)

60

30

0

90

MinutesMinutes

6/6/2017

8

Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes

Glucose

Glucagon When glucose levels approach normal values, glucagon levels rebound.

When glucose levels approach normal values,insulin levels decreases.

*P <0.05Patients with type 2 diabetes (N=10)

mm

ol/L

15.012.510.07.55.0

250

200

150

100

50

mg

/dL*

* ** * * *

pm

ol/L

25020015010050

40

30

20

10

0

mU

/L

* ** ** * *

*

Infusion

Minutes

pm

ol/L

20

15

10

5

0 60 120 180 240

* * * *

pm

ol/L

20

15

10

5

Placebo

GLP-1

Insulin

2.50

0

0 0

0

Adapted with permission from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.

–30

Incretin Drugs GLP Agonists

Exenatide Liraglutide Semaglutide Albiglutide Taspoglutide Exenatide Lar Lixsenatide Dulaglutide

DPP 4 Inhibitors Vildagliptin Sitagliptin Saxagliptin Alogliptin Linagliptin Dutogliptin Metogliptin

Gemigliptin Anagliptin Trelagliptin Teneligliptin Omarigliptin

(1/week)

Glycemic outcome.Change from baseline in hemoglobin A1c level.

Buse J B et al. Ann Intern Med 2011;154:103-112

Use of Twice-Daily Exenatide in Basal Insulin–Treated Patients With Type 2 Diabetes

Buse J B et al. Ann Intern Med 2011;154:103-112

Use of Twice-Daily Exenatide in Basal Insulin–Treated Patients

With Type 2 Diabetes

Changes in body weight and glucose levels over 30 weeks.

Data are least-squares means estimated from a mixed model, in which the postbaseline response variable = treatment + pooled investigator + visit + baseline + baseline hemoglobin A1c stratum (≤8.0% or >8.0%) +(treatment × visit), and the participant is treated as a random effect with an unstructured covariance matrix.

6/6/2017

9

Incretin Agents: Safety Concerns

• Thyroid Cancer and Neoplasia:

– Thyroid C-cell tumors in rodent models

– Not recommended for use in patients with a personal or family history of MTC or MEN 2A or 2B

• Pancreatitis

• Pancreatic Cancer

Incretin Drugs: Pancreatitis

• Patients without Diabetes– General Population in US

• 0.33-0.44 events per 1000 adults per year (1)

• Severe disease in 15-20% of these cases (2)

• Death in 2-4% of cases (2)

• Type 2 Diabetes Patients– Epidemiology study shows 3 times risk

compared to subjects without diabetes (3)

1. Frey et al Pancreas. 2006. 33:336-3442. Forsmark et al Gastroenterology 2007 132:2022-2044

3. Noel et al Diabetes Care 2009 May;32(5):834-8

Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin

A retrospective observational pharmacy claims analysis

Diabetes Care 33:2349–2354, 2010

Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin

A retrospective observational pharmacy claims analysis

Diabetes Care 33:2349–2354, 2010

6/6/2017

10

Risks of Pancreatitis and Pancreatic Cancer with Incretin therapies

• FDA and EMA independent reviews of patient data and

animal studies have identified no evidence for causal

relationship but maintain that the risks should be

disclosed and further investigated (Egan et al NEJM

2014; EMA Report 2013).

• No prospective studies have identified a causal

relationship thus far

• Represents an area of ongoing investigation

DPP-4 Inhibitor–Related Pancreatitis: Rare but Real!

• Large-scale CVOTs have now been reported for three DPP-4 inhibitors: saxagliptin, alogliptin, and sitagliptin

• There were clear numerical imbalances, with more cases of acute pancreatitis occurring with each of the three DPP-4 inhibitors than in the control groups, which failed to reach statistical significance in each of the individual trials

• The estimated odds ratio for an increased risk of acute pancreatitis with DPP-4 inhibitors was 1.79 with an absolute increased risk of 0.13%

• translates to one to two additional cases of acute pancreatitis for every 1,000 patients treated for 2 years.

• Translated to 1 million users in the U.S., a very conservative estimate, this would result in ∼750 additional cases of acute pancreatitis per year.

Diabetes Care 2017;40:161–163

Diabetes Care 2017 Feb; 40(2): 284-286.

Incretins (dpp-4): CVD SAVOR-TIMI 53: Saxagliptin• unexpected excess rate of hospitalization for heart failure in the saxagliptin

group (hazard ratio, 1.27; 95% CI, 1.07 to 1.51)

EXAMINE: Alogliptin• nonsignificant numerical imbalance in hospitalization for heart failure in the

alogliptin group as compared with placebo (hazard ratio, 1.19; 95% CI, 0.90 to 1.58)

TECOS: Sitagliptin, • rates of hospitalization for heart failure was no different from placebo

Retrospective (Diabetes Care 2016): • In patients with type 2 diabetes, there was no association between HF, or other

selected cardiovascular outcomes, and treatment with a DPP-4i relative to SU or treatment with saxagliptin relative to sitagliptin.

Meta-analysis of the cardiovascular outcome trials reporting the risk of HF with DPP-4 inhibitors.

Kristian B. Filion, and Samy Suissa Dia Care 2016;39:735-737

©2016 by American Diabetes Association

6/6/2017

11

Incretins (GLP-1): CVD ELIXA: Lixisenatide (N Engl J Med 2015; 373:2247-2257)

• neutral effect on heart failure and other cardiovascular problems

Liraglutide (N Engl J Med 2016; 375:311-322)• rate of the first occurrence of

death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo

Renal Glucose Reabsorption in Type 2 Diabetes

Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule

Renal glucose reabsorption is increased in type 2 diabetes

Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose

J Intern Med. 2007;261:32-43.

Rationale for SGLT2 Inhibitors Inhibit glucose reabsorption in the renal

proximal tubule Resultant glucosuria leads to a decline in

plasma glucose and reversal of glucotoxicity

This therapy is simple and nonspecific Even patients with refractory type 2

diabetes are likely to respond

• Potential Advantages

– Weight loss

– Low risk of hypoglycemia

– Possible BP lowering effect

– Effect independent of insulin

• Concerns

– Polyuria

– Electrolyte disturbances

– Bacterial UTIs

– Fungal genital infections

– Euglycemic DKA

SGLT2 Inhibitors

6/6/2017

12

Cefalu WT et al. Lancet 2013.

Glimiperide Canagliflozin100mg

Canagliflozin300mg

Body weight, kgLS mean (SE) change 0.70 (0.2) ‐3.7 (0.2) ‐4.0 (0.2)

Systolic BPLS mean (SE) change 0.2 (0.6) ‐3.3 (0.6) ‐4.6 (0.6)

Hypoglycemia (n, %) 164 (34%) 27 (6%) 24 (5%)

Bailey CJ et al. BMC Medicine 2013

Cefalu WT et al. Lancet 2013. Zinman B et al. N Engl J Med 2015;373:2117-2128

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

Primary outcome: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke

6/6/2017

13

Diabetes Care 2016 May; 39(5): 717-725

Possible mechanisms that could contribute to the reduction of CV mortality by empagliflozin in the EMPA-

REG OUTCOME study

– Increased risk for lower-limb amputations (toes)• ? Mechanism

• Limited data

• 3.4 year interim analysis of CANVAS

rate of amputations per every 1000 patients

100 mg/day: 7 300 mg/day: 5 Placebo: 3

SGLT2 InhibitorsAmputations

• 714 elderly patients with type 2 diabetes (mean age, 64 years; range, 55 - 80 years).

• At 2 years,

– Decreases in total hip BMD were seen with canagliflozin 100 and 300 mg versus placebo (-1.7%, -2.1%, -0.8%; differences of -0.9% and -1.2%)

– No bone loss at other sites, (normal age-related bone loss, ~0.5-1.0%/year).

• Fractures tended to occur as early as 12 weeks after initiating treatment and were primarily located in the distal parts of the upper and lower extremities.

• Why?

– SGLT2 inhibitors increase concentrations of phosphate in serum, probably via increased tubular reabsorption, which has the potential to adversely affect bone.

– SGLT2 inhibitors increase concentrations of parathyroid hormone (PTH). Sustained increases in PTH concentration enhance bone resorption and increase the risk for bone fractures.

SGLT2 InhibitorsBone Loss Generic Oral Hypoglycemic Slide

HgA1c

Time

Change from Drug A to B, C, or D

Add Drug A to B, or B to A

Add Drug C

Add Drug D

6/6/2017

14

1. Patient‐Centered Approach“...providing care that is respectful of and responsive to individual patient preferences, needs, and values ‐

ensuring   that patient values guide all clinical decisions.”

• Gauge patient’s preferred level of involvement.

• Explore, where possible, therapeutic choices. Consider using decision aids.

• Shared Decision Making – a collaborative process between patient and clinician, using best available evidence and taking into account the patient’s preferences and values  

• Final decisions regarding lifestyle choices ultimately lie with the patient.

ADA‐EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015

Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic

Review and Meta-analysis

Ann Intern Med. 2016;164(11):740-751.

204 studies analyzed

50 spanned several continents, while others were conducted across Europe, Asia and the United States.

Most of the studies were short term, with only 22 mostly observational studies lasting more than two years

Pooled between-group differences in the change in HbA1c for comparisons of monotherapies and metformin-based combination therapies.

Ann Intern Med. 2016;164(11):740-751.

Pooled between-group differences in the change in weight for comparisons of monotherapies and metformin-based combination therapies.

Ann Intern Med. 2016;164(11):740-751.

6/6/2017

15

Pooled odds ratios for mild and moderate hypoglycemia for comparisons of monotherapies and metformin-based combination therapies.

Ann Intern Med. 2016;164(11):740-751.

Pooled odds ratios for GI side effects for monotherapies and metformin-based combination therapies.

Ann Intern Med. 2016;164(11):740-751.

Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the

American College of Physicians

Recommendation 2:ACP recommends that clinicians consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is considered.

(Grade: weak recommendation; moderate-quality evidence.)

ACP recommends that clinicians and patients select among medications after discussing benefits, adverse effects, and costs.

Ann Intern Med. 2017;166(4):279-290.

Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the American

College of Physicians

Ann Intern Med. 2017;166(4):279-290.

6/6/2017

16

Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the American

College of Physicians

Ann Intern Med. 2017;166(4):279-290.

Drug Cost ComparisonDrug and Dose Cost/month

(2014) 2017Glucose Strips (2 per day) $66

Sulfonylurea $4-14/$50-90Rapaglinide 2 mg tid $38-275nateglinide 120 tid $58-145Acarbose 100 mg tid $30-77Metformin 1000 bid $ 4-32 /120Canagliflozin 300 mg/d (342) $433-535Pioglitazone 45 mg/d (12/$480) $12/$715Sitagliptin/Saxagliptin (300) $400-450Dulaglutide1.5 /Liraglutide 1.2mg (L-400) $750/515-650Glargine, 45 U/d /(pen) (236) $360Aspart/lispro/apidra (30 U/d)

vial (180) $300Pens (225) $390

24 hour fitness center $35YMCA $65Cross Fit $300Personal Trainer $1000

Clinical Inertia in People with Type 2 Diabetes

• 81000 people with Type 2 DM

• Followed from 2004-2011

• Median time to add another drug

Diabetes Care. 2013. 36:3411

HbA1c On 1 drug On 2 drugs Adding insulin if

on 1-3 oral

>7 2.9 7.2 8.7

>7.5 1.9 7.2 9.1

>8 1.6 6.9 9.7

ClassGeneric Name(Brand Name)

Mechanism of Action

Dosage RelativeEffective-

ness

Major Side Effects / Interactions / Uses

Weight Effects

(average)

Cost

Sulfonylureasglyburide(Micronase)glipizide(Glucotrol)glimepiride(Amaryl)

Stimulate insulin release from beta cells of the pancreas

2.5-20 mg bid

5-20 mg bid

0.5-4 mg bid

1

1

1

HypoglycemiaGain 2 lbs

$

Meglitinidesrepaglinide(Prandin)

nateglinide(Starlix)

Stimulate insulin release from beta cells of the pancreas

0.5-2 mg tid(before meals)

60-360 mg tid(before meals)

1

1

HypoglycemiaUseful in pts on glucocorticoids and in pts with renal failure who often have good FBS and high BS over the course of the dayPrandin is short-acting. Starlix is very short-acting

Gain 1 lb $

Biguanidemetformin(Glucophage)

Primarily inhibits hepatic gluconeogenesis

500-2000 mg daily with meals

1 Diarrhea, nausea, vomitingIncreased risk of lactic acidosis if impaired renal or hepatic function or heavy EtOH use. B12 deficiency

Loss2-3 lbs

$

Bile Acid Sequestrants

Colesevelam(Welchol)

unknown3.75 g/d

(3- 625 mg tabs bid)

0.7

esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea,constipation neutral $$$

Bromocriptine/Cyclset

improved glucose tolerance (enhanced stimulated insulin-mediated glucose disposal).

0.25– 0.5 mg/d1.6-4.8 mg/d

.5

Nasal Stuffiness, Nausea, headache, constrictive pericarditis, neuroleptic malignant syndrome, hypotension

---- $$-$$$

ClassGeneric Name(Brand Name)

Mechanism of Action

Dosage RelativeEffective-

ness

Major Side Effects / Interactions / Uses

Weight Effects

(average)

Cost

Alpha-glucosidaseInhibitoracarbose(Precose)

Inhibits enzymes needed to break down glucose in the small intestine

50 mg with 1st bite of each meal (start at 12.5 mg and titrate up over weeks)

0.7Gas/ GI upsetNeed to use glucose to treat hypoglycemia (not a complex CHO)

Loss1-2 lbs

$

Thiazolidinediones

rosiglitazone(Avandia)

pioglitazone(Actos)

Insulin sensitizers—Activate receptor molecules inside cell nuclei to decrease insulin resistance

4-8 mg daily

15-45 mg daily

1

1

Weight gain, edema which is resistant to diuretic therapyAssociated with bone loss and fractures.

Gain 12 lbs

$

Incretinsexenatide(Byetta)(Bydureon)

Liraglutide(Victoza)

Albiglutide(Tanzeum)

Dulaglutide(Trulicity)

sitagliptin(Januvia)

saxagliptin(Onglyza)

linagliptin(Trajenta)

Alogliptin(nesia)

Mimics GLP-1 (gut hormone which affects insulin, glucagon, gastric emptying and satiety)

DPP-4 inhibitor (enzyme that breaks down GLP-1)

5-10 mcg bid SQ2mg/week

0.6-1.8 mg qd SQ

30-50 mg SC weekly

0.75/1.5 mg SQ weekly

100, 50, or 25 mg daily (dose by Cr Cl)

5, 2.5 mg (for decrease creat)

5 mg (no change for creat

25, 12.5, or 6.25 mg daily (dose by Cr Cl)

1

0.7-1

Nausea, Vomiting, constipation, pancreatitis (?) Renal failureWeight loss achieved through appetite suppression

Thyroid C-cell tumors at clinically relevant exposures in rodents.

Side effects are rare. Occ GI side effects.

Loss 8 lbs

Neutral

$$$

$$$

ClassGeneric Name(Brand Name)

Mechanism of Action

Dosage RelativeEffective-

ness

Major Side Effects / Interactions / Uses

Weight Effects

(average)

Cost

SGLT 2 Inhibitor

Canagliflozin (Invokana)

Dapagliflozin (Farxiga)

Empagliflozin(Jardiance)

Inhibit glucose reabsorption in the renal proximal tubule

100/300 mg daily

5 mg daily

10/25 mg daily

1 Dehydration, urinary tract infections, genital mycotic infection, bone loss

Loss4 lbs $$$

Preop management program: ucsf.logicnets.com

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk neutral/loss GI / lactic acidosis low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk gain edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk neutral rare

high

DPP-4 inhibitor

highest high risk gain hypoglycemia variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+ TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione +

SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk loss GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk gain hypoglycemia low

SGLT2 inhibitor intermediate low risk loss GU, dehydration high

SU

TZD

Insulin§

GLP-1 receptor agonist +

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk Weight Side effects Costs

Dual therapy†

Efficacy* Hypo risk Weight Side effects Costs

Triple therapy

or

or

DPP-4 Inhibitor +

SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

Insulin (basal)

+

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442