Clinical Approach to Medical Management of Type 2 Diabetes

Clinical Approach to Medical 

Management of Type 2 Diabetes 

Dan V. Mihailescu, MD 

Assistant Professor of Medicine 

Director, Diabetes Program 

University of Illinois at Chicago 

UIC

Disclosures: 

• The Speaker has no financial conflict of 

interest to declare 

• The Speaker is not a consultant with any 

pharmaceutical company

Outline: 

1. Glycemic Targets in Type 2 Diabetes 

2. Overview of Antihyperglycemic Agents 

3. Treatment Guidelines for Type 2 

Diabetes

Glycemic Goals of Therapy in 

Outpatient Settings 

ADA 

AACE 

HBA1c < 7% < 6.5% 

Fasting BG 

Pre-prandial BG 

70-130 mg/dl 

< 110 mg/dl 

Post-meal BG < 180 mg/dl < 140 mg/dl 

DIABETES CARE, 35, SUPPLEMENT 1, JANUARY 2012 

ACE/AACE Diabetes Road Map Task Force. Endocr Pract. 2007

Glycemic Goals of Therapy in 

Outpatient Settings 

• Both sets of recommendations are based on the 

same clinical trial data, primarily UKPDS and 

DCCT trials 

• Both trials showed a decrease in the rate of 

microvascular complications in the intensive 

control arm ( achieved A1c 7% in UKPDS and 

7.1% in DCCT trials) 

• What about more recent trials?

Glycemic Control Strategies: 

Conventional vs. Intensive 

A1c 

(%) 

Microvascular 

Complications 

Macrovascular 

Complications 

Mortality 

ADVANCE 

(N=5571, age~66) 

6.5 vs 7.3 

(Nephropathy) 

ACCORD 

(N=10,250, age~62) 

6.4 vs 7.5 Composite 

(Retinopathy) 

VADT 

6.9 vs 8.4 

(N=892, age~60) 

UKPDS 

7.0 vs 7.9 

(N=4000, age~53)

Adjusted Hazard Ratio for Clinical Events in 

ADVANCE Trial 

End Point 

Major 

Macrovascular Event 

Major Microvascular 

Event 

Severe Hypoglycemia, 

N=231, (%) 

No Severe 

Hypoglycemia, 

N=10909, (%) 

HR (95% CI) 

15.9 10.2 3.5 (2.4-5.1) 

11.5 10.1 2.2 (1.4-3.4) 

All Cause Mortality 19.5 9.0 3.3 (2.3-4.6) 

Cardiovascular 

Mortality 

Noncardiovascular 

Mortality 

9.5 4.8 3.8 (2.4-6) 

10 4.3 2.8 (1.6-4.8) 

Zoungas et al, NEJM, 2010

Benefit assessment of long-term blood 

glucose lowering to near-normal levels in 

patients with type 2 diabetes mellitus 

• Systematic review of seven 

RCT including 28,000 

patients with type 2 DM 

– ACCORD 

– ADVANCE 

– VADT 

– UKPDS 

– KUMAMOTO 

– UGDP 

– Van der Does 

• The primary outcome was 

all-cause mortality 

• Secondary outcomes were 

late complications (MI, 

stroke, ESRD, amputation, 

blindness, therapy-related 

factors in terms of severe 

hypoglycemia and serious 

adverse advents) 

Institute for Quality and Efficiency in Health Care Report No. A05-07, 2011

Benefit assessment of long-term blood 

glucose lowering to near-normal levels in 

patients with type 2 diabetes mellitus 

• A benefit or harm of intensive BG lowering was not 

proven for any of the patient-relevant investigated 

outcomes – mortality or diabetes-related 

complications (fatal or non-fatal MI, fatal or non-fatal 

stroke, ESRD, amputation, or blindness) 

• The data provide indications of harm through an 

increased rate of severe hypoglycemia and serious 

adverse events independent of hypoglycemia 

Institute for Quality and Efficiency in Health Care Report No. A05-07, 2011

A1C Goal < 7% 

7% 

Inzucchi et al, www.care.diabetesjournals.org, accessed April 23, 2012

Outline: 


2. Properties of Selected Therapeutic 

Agents 



Antihyperglycemic Agents 

1. Biguanides (Metformin) 

2. Sulfonylurea 

3. Meglitinides 

4. Insulins 

5. Thiazolidinediones (TZDs) 

6. Dipeptidyl Peptidise-4 (DPP4) Inhibitors 

7. Glucagon-Like Peptide 1 (GLP1) Analogues 

8. Alpha-Glucosidase Inhibitors 

9. Colesevelam 

10. Bromocriptine 

11. Amylin agonists

Type 2 DM Treatment – Practical Tips: 

• All oral agents require presence of functioning 

Beta-cells as they work by either increasing 

their function or enhancing insulin sensitivity 

• Higher baseline A1c levels predicts a greater 

drop in A1c 

• Shorter duration of diabetes predicts greater 

drop in A1c level

• Diet, exercise, and education remain the foundation 

of any type 2 diabetes treatment program 

• Lifestyle Modifications Decrease HbA1c by 1-2% 

• Lifestyle management is the most difficult 

prescription that I write…

The Biguanides: 

Basic Characteristics of Metformin 

Mechanism: Decreases hepatic glucose production 

by activating AMP-kinase 

Power: Decreases HbA 1c ~ 1.5% 

Dosing: 

One to three times daily 

(aim for 2000 mg daily) 

Side effects: Diarrhea, nausea (start low), low B12 

Main risk: Lactic acidosis, very rare (1/3000 

patient-years) 

Limitations: Cr < 1.5 (M), < 1.4 (F), 

(Canada Cr cl > 60)

Relative risk reduction for 

metformin treatment (%) 

UKPDS 34: relative risk reduction with 

metformin vs conventional treatment 

0 

10 

20 

30 

40 

50 

-32 

** 

-42 

* 

-36 

* 

-39 

-41 

* 

* p < 0.05 ** p < 0.01 

N=1704 

patients 

Lancet 1998;352:854–65

10-Year Follow-up of Intensive control in Type 2 DM 

Hazard Ratios for Prespecified Clinical Outcomes 

Holman R et al. N Engl J Med 2008

Metformin: Old Drug, New Targets 

Libby et al, Diabetes Care, 2009 

• Observational Cohort Study 

in U.K. 

–4085 DM2 on MF 

–4085 DM2 comparators (matched 

to the yr of DM diagnosis) 

• Primary outcome: 

–Diagnosis of Cancer 

–297 cases (7.3%) MF group 

–474 cases (11.6%) Comparators 

• Secondary outcomes: 

– Diagnosis of colon, lung, 

breast cancer 

– All cause and cancer mortality

Metformin: Old Drug, New Targets 

Libby et al, Diabetes Care, 2009

Metformin Versus Active Comparators 

Study 

Characteristics 

N=289, 33 weeks, 

baseline A1c 8.2-8.4% 

N=486, 16 weeks, 


N=1199, 52 weeks, 

baseline A1c 8.7% 

N=1091, 24 weeks, 


N=820, 26 weeks 


Metformin 

or Placebo 

A1c Effect 

Metformin 

vs. Placebo -1.4% +0.4% 

vs. Glyburide 

vs. Glyburide/Metformin 

-1.5% -1.9% 

-2.3% 

vs. Pioglitazone -1.5% -1.4% 

vs. Sitagliptin 

vs. Sitagliptin/Metformin 

vs. Exenatide LAR 

vs. Sitagliptin 

vs. Pioglitazone 

-1.13% 

(max dose) 

A1c Effect 

Comparator 

-0.66% 

-1.90% 

-1.5% ExeLAR -1.5% 

Sita -1.2% 

Pio -1.6% 

1. Defronzo et al, NEJM, 1995 2.Garber et al, JCEM, 2003 3. Schernanter et al, JCEM, 2004 

4.Goldstein et al, Diabetes Care, 2007. 5.Russel-Jones et al, Diabetes Care, 2012

Secretagogues: 

Sulfonylureas and the Meglitinides 

Mechanism: 

Depend upon: 

Increase basal and postprandial 

insulin secretion 

Functioning -cells, bind to different 

receptors 

Power: Decrease HbA 1c ~1.5% 

Dosing: 

Side effects: 

Main risk: 

Once to three times daily 

Weight gain 

Hypoglycemia, especially if CKD

Insulin Secretagogues – Classification: 

1. First Generation Sulfonylureas 

• Chlorpropramide 

2. Second Generation Sulfonylureas 

• Glibenclamide (Glyburide) 

• Glipizide 

• Glimepiride 

3. Meglitinides 

• Repaglinide (Prandin) 

• Nateglinide (Starlix)

Secretagogues: 

Sulfonylureas and the Glinides 

• Avoid using first generation SU agents and Glyburide 

- higher risk of hypoglycemia, especially in elderly 

(partially active metabolites) 

• Glimepiride -significant biliary and fecal excretion of 

the metabolites 

• For patients with CKD or with unpredictable meal 

schedule use meglitinides BID - TID with meals

10-Year Follow-up of Intensive control in 

Type 2 DM (Holman et al, NEJM, 2008)

Sulfonylurea Versus Newer Agents: 

Glimepiride and Sitagliptin 

Srivastava et al, JAPI, 2012

Sulfonylurea Versus Newer Agents: 

Glimepiride and Liraglutide 

• Minor Hypoglycemia: 3% Liraglutide vs. 17% Glimepiride 

• No Major Hypoglycemia was reported in any groups 

• Nausea: 19% Liraglutide vs. 4% Glimepiride 

Nauck et al, Diabetes Care, 2009 (LEAD 2)

Basic Characteristics of Glitazones 

• Enhance muscle and adipose tissue response to 

insulin, modulate PPAR-γ receptor 

• Depends upon presence of insulin, appear to have a 

more durable effect on the glycemic control 

compared with SU 

• Decrease HbA 1c ~ 1.0 % 

• Side effects: edema, CHF, weight gain, bone 

fractures

Rosiglitazone 

• Rosiglitazone is associated 

with an increased risk of CV 

events, removed from the 

market in Europe, use 

restricted by the FDA 

– Must prove other medications 

are not effective or 

Rosiglitazone is the only 

alternative 

Nissen et al, Arch Intern Med, 2010

Pioglitazone 

• Is not associated with an increased CV risk 

• Is associated with an increased risk of urinary bladder 

cancer 

– removed from the market in France, Germany 

recommended not to be started in new patients 

– FDA (August 2011): “Interim results…suggested that 

taking ACTOS longer than 12 months increased the 

relative risk of developing bladder cancer…by 40% which 

equates to an absolute increase of 3 cases in 10,000 (from 

approximately 7 in 10,000 [without ACTOS] to 

approximately 10 in 10,000 [with ACTOS])”

Pioglitazone 

• Durable Glycemic Control 

• Favorable Lipid Effects 

( TG, HDL) 

• Possible CVD Risk Reduction 

• CHF 

• Bone Fractures 

• Edema 

• Bladder Cancer

The α-Glucosidase Inhibitors: 

Basic Characteristics of Acarbose and 

Miglitol 

Mechanism of action: Delays carbohydrate 

absorption 

Targets: 

Postprandial 

hyperglycemia 

Strength: Decrease HbA 1c 0.5 - 1% 

Dosing: 

Three times daily 

Side effects: Flatulence 

Main risk: LFT elevation (rare) 

4-7

STOP-NIDDM Trial 

To evaluate the effect of decreasing postprandial hyperglycemia 

with acarbose on the risk of CVD and HTN in patients with IGT 

N=1429 

RRR 49% 

Chiasson et al, JAMA, 2003

Types of Insulins 

• Basal insulin 

– Human: NPH 

– Analogs: glargine, detemir 

• Mealtime insulin 

– Short acting (human): regular 

– Rapid acting (analog): aspart, lispro, glulisine 

• Premixed insulins 

– Provide both basal and mealtime cover 

– Multiple combinations: Humalog75/25; Humalog50/50; 

Novolog70/30; Human 70/30 

• Concentrated Insulin: U500

Treat to Target in Type 2 Diabetes Trial 

• 708 patients not controlled 

with MF or SU 

• Duration – 3 years 

• Baseline A1c 8.3% 

• Treatment groups: 

– Basal insulin QD/BID (detemir) 

– Prandial insulin TID (aspart) 

– Biphasic insulin BID/TID 

(NovologMix 70/30) 

A1c 6.9% 

Holman et al, NEJM, 2009

Prandial Versus Basal Insulin: The HEART2D Trial 

. 

N=1115 patients post MI 

- 558 Basal Group 

(NPH or Glargine) 

- 557 Prandial Group 

(Lispro) 

- Mean age ~ 61yrs 

- Diabetes ~ 9 yrs 

Primary Outcome: Time to 

the first combined 

cardiovascular event 

Raz et al. Diabetes Care 2009

Prandial Versus Basal Insulin: The HEART2D Trial 

Raz et al. Diabetes Care, 2009

Insulin Initiation and Titration 

• Start with a Basal Insulin 

(Type 2 Diabetes) 

• Either NPH, Glargine or Detemir 

• Begin at 10 units or 0.2 units/Kg 

• Dose titration (2-3 units every 3 days) till fasting BG 

are in the “target range” (ADA, 70-130 mg/dl) 

– If hypoglycemia occurs reduce dose by 10-15% (min 4 

units) 

• If A1c is not at goal after achieving the target fasting 

level, add one dose of Rapid Insulin before the main 

meal (starting at 4-6 units) 

Adapted from Nathan et al, Diabetes Care, 2009

Colesevelam 

• Bile acid sequestrant with antidiabetic properties 

– A1c reduction ~ 0.5% 

– Dose: 3.75 g daily or 1.875 g PO BID 

– Used in combination with diet, oral agents or insulin 

• Lipid Effects: 

– Positive: reduction of the LDL levels ~ 15% 

– Negative: increase TG levels ~ 20% in combination with SU 

and insulin 

• Interfere with absorption of several drugs: OCPs, 

levothyroxine, cyclosporine, glyburide, warfarin, phenytoin

Colesevelam vs. Placebo in combination 

with metformin, sulfonylurea and insulin 

Study 

Characteristics 

Colesevelam 

A1c Effect 

Colesevelam 

A1c Effect 

Placebo 

N=461, 26 weeks, 


N=316, 26 weeks, 


N=287, 16 weeks, 

baseline A1c 8.3% 

vs. Placebo 

(add-on to SU) 

vs. Placebo 

(add-on to MF) 

vs. Placebo 

(add-on to Insulin) 

-0.3% +0.2% 

-0.39% +0.15% 

-0.4% +0.1% 

1. Fonseca et al, Diabetes Care, 2008 

2. Bays et al, Arch Intern Med, 2008 

3. Goldberg et al, Arch Intern Med, 2008

Bromocriptine 

• Ergot-derived dopamine agonist, unknown antidiabetic 

mechanism (presumably by increasing the hypotalamic 

dopamine levels and decreasing SNS activity) 

– A1c reduction ~0.4% 

– Dose 0.6-4.8 mg PO daily in AM within 2 hrs after waking 

– SE: nausea, dizziness, HA, syncope 

Bromocriptine 

N=80 

(1.6-4.8 mg/day) 

Placebo 

N=79 

HbA1c (%) 

•Baseline 9.0 8.8 

•Change from baseline -0.1 +0.3 

•Difference from placebo -0.4 

http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020866lbl.pdf, accessed 04/04/2012

Cycloset Safety Trial 

HR Bromocriptine QR vs. placebo: 0.60 (CI 0.37-0.96) 

Composite Cardiovascular Endpoint – time to first MI, stroke, CABG, 

hospitalization for unstable angina or CHF 

Gaziano et al, Diabetes Care, 2010

Pramlintide 

• Synthetic analogue of amylin witch is synthesized by 

beta-cells and released with insulin 

• Mechanism of action: decreases glucagon release, 

slows gastric emptying, and decreases food intake 

• Approved for use in patients who are taking mealtime 

insulin alone or in combination with MF and/or SU 

• Dose (DM2): Initiate at 60 mcg before meals and 

increase to 120 mcg if tolerated 

• Main SE: nausea and hypoglycemia (reduce mealtime 

dose by 50% when initiating PRA)

• N=656 

• DM2 for ~12 yrs 

• BMI ~ 34 

• Baseline A1c 9.0-9.3% 

N=161 

N=171 

N=166 

Hollander et al, Diabetes Care, 2003

Outline: 


2. Properties of Selected Therapeutic 

Agents 



So, we have 11 different classes of 

antihyperglycemic agents, 9 approved 

for use as monotherapy… 

• C (n, r) = n!/r!(n-r)! 

• Monotherapy – 9 possible options 

• Dual Therapy – 45 possible combinations 

• Triple Therapy – 240 possible combinations

Treatment Guidelines for Type 2 DM 

• 2008 AACE/ACE Road Map 

• 2008 Canadian Diabetes Association Clinical Practice 

Recommendations 

• 2009 AACE/ACE Treatment Algorithm 

• 2009 American Diabetes Association (ADA)/ 

European Association for the Study of Diabetes 

(EASD) 

• 2012 Position Statement of the ADA and EASD

Comparative Effectiveness and Safety of Medications for Type 2 

Diabetes: An Update Including New Drugs and 2-Drug Combinations 

Bennett W L et al. Ann Intern Med 

doi:10.1059/0003-4819-154-9-201105030-00336 

©2011 by American College of Physicians

Strength of Evidence for the Comparative Effectiveness and Safety of Diabetes 

Medications as Monotherapy and Combination Therapy on Long-Term Clinical Outcomes 


doi:10.1059/0003-4819-154-9-201105030-00336 


Pooled between-group differences in HbA1c level with 

monotherapy and combination therapies 


doi:10.1059/0003-4819-154-9-201105030-00336 


Effect of Antihyperglycemic Agents Added to Metformin 

and a Sulfonylurea on Glycemic Control and Weight 

Gain in Type 2Diabetes: A Network Meta-analysis 

• To evaluate the effect of the THIRD antihyperglycemic 

agents in the reduction of HbA1c level, change in body 

weight, and the frequency of severe hypoglycemic events 

• Meta-analysis of 18 trials, 4535 participants 

• Mean duration of follow-up 31 weeks (26 -52 weeks) 

• Duration of diabetes 7.5 – 13.1 years 

• Baseline A1c 7.5 – 10.6% 

Gross et al, Ann Intern Med, 2011

Effect of Antihyperglycemic Agents Added to Metformin 

and a Sulfonylurea on Glycemic Control and Weight 

Gain in Type 2Diabetes: A Network Meta-analysis 

Gross et al, Ann Intern Med, 2011

Type 2 Diabetes: Assessing the Relative 

Risks and Benefits of Glucose-lowering 

Medications 

Richard M. Bergenstal, MD, Clifford J. Bailey, PhD David 

M. Kendall, MD 

International Diabetes Center, Minneapolis, Minn; Diabetes 

Research, Life and Health Sciences, Aston University, 

Birmingham, UK. 

The American Journal of Medicine (2010) 123, 374. 

Figure 4 Events per 1000 patient-years for representative endpoints. Black bars indicate excess risk of events in diabetes patients relative 

to nondiabetic subjects;19,75,85,86 gray bars indicate excess risk of events in patients treated with specific glucose- lowering medications 

relative to diabetic patients on other agents;2,25,41,54,60,61,74 and white bars indicate the decreased risk of events in patients undergoing 

intensive glucose control policies. Foley RN et al. J Am Soc Nephrol. 2005;16(2):489-495; b = 19Haffner SM et al. N Engl J 

Med.1998;339(4)229-234; c = 75Noel RA et al. Diabetes Care. 2009;32(5):834-838;d = 86Trautner C et al. Diabetes Care. 1997;20(7):1147-1153; e = 

60,61HamptonT. JAMA. 2007;297(15):1645 and Meier C et al. Arch Intern Med. 2008;168(8):820-825; f = 41Lago RM et al. Lancet. 

2007;370(9593):1129-1136; g = 25Patel A et al. N Engl J Med. 2008;358(24):2560-2572; h = 2Nissen SE, Wolski K. N Engl J Med. 

2007;356(24)2457-2471; i = 54Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2006; j = 74Dore DD et al.

Yearly Cost for Different Antihyperglycemic 

Agents Adjusted for 1% Reduction in A1c 

AGENT 

COST (approximate) 

Metformin* $ 50 

Glimepiride* $ 50 

Pioglitazone $ 3700 

Glargine $ 1400 

Sitagliptin $ 2800 

Linagliptin $ 4800 

Exenetide $ 3600 

Liraglutide $ 5000 

Acarbose $ 2100 

Pricing information from drugstore.com, *target.com, accessed 3/10/2012

Standards of Medical Care in Diabetes 2012 

• At the time of type 2 DM diagnosis, initiate metformin 

along with lifestyle interventions, unless MF is 

contraindicated 

• If MF monotherapy at maximal tolerated dose does not 

achieve or maintain the A1C target over 3–6 months, add 

a second oral agent, a GLP-1 receptor agonist, or insulin 

• In newly diagnosed type 2 DM patients markedly 

symptomatic and/or elevated glucose levels or A1C, 

consider insulin therapy, with or without additional agents 

DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2012

2012 Position Statement of the ADA and EASD 

Inzucchi et al, www.care.diabetesjournals.org, accessed April 23, 2012

Treatment Options – Patient Preferences 

Low Cost 

Low 

Hypoglycemia 

Low Weight 

Metformin Metformin Metformin 

Glimepiride Sitagliptin Exenetide LAR 

NPH Pioglitazone Acarbose 

$ ~ 900/yr $ ~ 6400/yr $ ~ 6000/yr 

Pricing information from www.drugstore.com

Thank You !

Clinical Approach to Medical Management of Type 2 Diabetes

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