Implementing Diabetes Guidelines in the “Real World”

Martin J. Abrahamson, MD FACPAssociate Professor of Medicine, Harvard Medical

SchoolSenior Vice President for Medical Affairs, Joslin

Diabetes Center

What I will cover

• Pathophysiology of type 2 diabetes• The guidelines – do they help us?• How should we choose drugs to add on

metformin• Is there an alternative “approach” to treating

diabetes?

Pathophysiology of Type 2 DM:From the Triumvirate…

From DeFronzo Diabetes 2009; 58:773-795

To the Ominous Octet

From DeFronzo Diabetes 2009; 58:773-795

Non Insulin Medications to Treat Type 2 DM

TZDMetformin

MetforminTZD

TZDMetformin

α glucosidase inhibitorsIncretinsPramlintideColesevelam

Dopamine receptor agonistsSerotonin receptor agonistsIncretins

SGLT2 Inhibitors

β cells

SulfonylureasMeglitinidesIncretins

α cells

IncretinsPramlintide

© M.J. Abrahamson, MD FACP

Type 2 Diabetes Management 2014

• Lowering A1c to around 7% especially early after diagnosis can reduce the risk for the development or progression of the long term complications of diabetes

• There are many medications available today to treat type 2 diabetes – if used appropriately this could translate to improved control and less risk for complications

• The challenge for the practicing physician is to know which medications to use and when best to use them

Type 2 Diabetes Management 2014

• There IS consenus that metformin should be first line therapy

• There is NO clear consensus what to add to metformin when A1c goals are not met– Few head to head comparator trials– Even fewer long term studies evaluating durability

of medications on glycemic control, especially when added to metformin

T2DM Antihyperglycemic Therapy: General Recommendations

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

T2DM Antihyperglycemic Therapy: General Recommendations

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

Fig. 2. T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

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

Choice of drug depends on

• Safety• Efficacy• Tolerability/acceptability• Durability• Cost

• Phenotypic and genotypic approaches to determine most effective therapy are lacking

Safety

• Hypoglycemia

• Cardiac safety

Hypoglycemia

• Insulin• Sulfonylureas (SUs)• NOT (when used alone/without insulin or SUs)

– Metformin– DPP-IV Inhibitors– GLP-1 agonists– TZD– SGLT-2 inhbitors

Hypoglycemia• Glyburide is associated with more hypoglycemia than

other sulfonylureas1

• Hypoglycemia in ADOPT2

– Minor: about 28% had symptoms– Major: about 0.6% during the 5 years of the study

• UKPDS - rates of major hypoglycemia3

Conventional Chlorpropamide Glibenclamide Insulin

Hypoglycemia rate (per year)

0.7 1.0 1.4 1.8

Gangji AS et al. Diabetes Care 2007; 30:389-394Kahn S et al. New Engl J Med 2006;355:2427-2443 UKPDS 33. Lancet 1998; 352:837-853

UKPDS Long Term Follow Up:Outcomes (Relative Risk Reduction)

SU – Insulin Metformin

Any diabetes related end point 9% (p = 0.04) 21% (p = 0. 01)

Death from any cause 13% (p = 0.007) 27% (p = 0.002)

Microvascular disease 24% (p = 0.001)

Myocardial infarction 15% (p = 0.01) 33% (p = 0.005)

Holman RR et al. New Engl J Med 2008; 359:1577-1589

Improved outcomes despite no difference in A1c betweentreatment groups which occurred within a year of study end

“Legacy effect”

Comparison of Medications that Could be Added to Metformin

SU TZD DPP-IV GLP-1

Efficacy High High Moderate High

Tolerability High Moderate High Moderate

Side effects HypoglycemiaWeight gain

Edema/CHF/Fractures /Weight gain

Rare pancreatitis

GIRare pancreatitis

Risk of hypoglycemia

Moderate Low Low Low

CV Safety Neutral Neutral Unknown Unknown

Durability ? ? ? ?

Cost Low Low - Mod High High

Adapted from Goldfine, Phua and Abrahamson, 2014 in press

Comparison of Medications that Could be Added to Metformin

SGLT 2 Inhibitor

Bromocriptine Colesevalam Insulin

Efficacy High Moderate Moderate Highest

Tolerability High Moderate High High

Side effects UTIVag yeast infnOrthostasis

Nausea/Vomiting

Nil HypoglycemiaWeight gain

Risk of hypoglycemia

Low Low Low High

CV Safety ? Neutral Neutral Neutral

Durability ? ? ? Yes

Cost High Mod Mod Variable

Adapted from Goldfine, Phua and Abrahamson, 2014 in press

So what would you add on to metformin if glycemic goals are not being met?

Choose One Only!

1. Sulfonylurea2. DPP-IV inhibitor3. GLP-1 receptor agonist4. TZD5. SGLT 2 inhibitor6. Basal Insulin

We need more data!

Glycemia Reduction Approaches in Diabetes (GRADE) Study: Comparative Effectiveness

Nathan DM et al. Diabetes Care epub May 20, 2013

• Canagliflozin (Invokana)• Dapagliflozin (Farxiga)

– Once daily dosing before 1st meal of the day

• Mechanism of action– Inhibition of SGLT2 reduces reabsorption of glucose in

the kidney, resulting in increased urinary glucose excretion, with a consequent lowering of plasma glucose levels as well as weight loss.

– Blocks approximately 50-80 grams of glucose per day from being reabsorbed

– New finding – increased glucose production

SGLT-2 Inhibitors

• Positive effects– Reduction in body weight and systolic blood pressure

• Side effects– Vaginal yeast infection, urinary tract infection and increased

urination– Hypoglycemia (<5%), dehydration, dizziness or fainting,

hyperkalemia

• Contraindications– Type 1 diabetes, patients with type 2 diabetes and ketonuria or

ketosis– Severe renal impairment, end-stage renal disease or patients

receiving dialysis

SGLT-2 Inhibitors

Can we simplify the guidelines/treatment approach?

Is there evidence to support this approach?

A1c Change with Liraglutide followed by Detemir

60% of subjects achieved A1c < 7% with liraglutide alone43% of the remainder achieved A1c < 7% with additional detemirAlmost 75% of subjects achieved A1c < 7% with GLP-1 RA and detemir

Cost notwithstanding, is there an alternate approach to treating type 2 diabetes?

Lifestyle+

Metformin+

GLP-1 analogue/DPP-IV inhibitor/

SGLT 2 Inh+

Insulin

Lifestyle

Lifestyle+

Metformin

Lifestyle+

Metformin+

GLP-1 analogueor

DPP-IV inhibitorOr

? SGLT 2 Inh

Bariatric surgery?

List A

Diabetes Medications and Body Weight

Weight Gain Weight Neutral Weight Loss

Significant Modest

Pioglitazone

Sulfonylureas Glyburide Glipizide

Insulin NPH Glargine Regular Aspart Lispro Glulisine

Sulfonylureas Glimepiride Glipizide XL

Glinides Repaglinide Nateglinide

Insulin Detemir Glulisine (PP)

Metformin

DPP-4 Inhibitors Sitagliptin Saxaglipitin Linagliptin Alogliptin

α-glucosidase Inhibitors Acarbose Miglitol

Colesevelam

Bromocriptine

GLP-1 Analogs Exenatide Exenatide ER Liraglutide

Pramlintide

SGLT-2 inhibitors

Stop, reduce, or switch Continue Add

Mitri J, Hamdy O. Expert Opin Drug Saf. 2009;8(5):573-84.

List B

Summary

• Type 2 diabetes is a progressive disease• While more people are reaching therapeutic goals, many

more need to get there• We have many tools available to help patients achieve

optimal metabolic control• The challenge is which ones to use, and when to use

them• We need to treat all cardiovascular risk factors

aggressively• Lifestyle modification remains the cornerstone of therapy

Summary

• Don’t be afraid to add medications or even start combination therapy simultaneously

• Start insulin earlier if control not possible with oral medications and incretins