Treatment of Diabetes Mellitus

Hasan Aydın, MD

Department of Endocrinology and Metabolism

Yeditepe University Medical Faculty

TURDEP-II

Total Europe World

TURDEP-II: Prediabetes

%30,4

Every 1$ of 7 $ of health expenditure is paid for diabetes

in USA

Rubin RJ, Altman WM et al: JCEM

Number One Cause of

• End Stage Renal Failure (% 35)

• Blindness in ages of 20- 74 years

• Nontraumatic lower extremity amputations

is DIABETES

Volume 24 Supplement 1 American Diabetes Association:Clinical Practice Recommendations 2001

DCCT

Relationship Between A1c and Microvascular Complicationsin Type 1 Diabetes

Skyler. Endocrinol Metab Clin. 1996;25:243-254, with permission.

Rel

ativ

e R

isk

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

HbA1c (%)

15

13

11

9

7

5

3

1

6 7 8 9 10 11 12

Glycemic Control and ComplicationsEffect of decreasing A1c from %8 to %7 on risk of complications

Study N

Folowup (years)

Retinop. Renal Neural CVD.

DCCT Primary

726 6.5 38 % 22 % 35 %

DCCT Secondary

751 6.5 27 % 28 % 29 % 40 %

Kumamoto Primary 55 6 38 % 50 %

Kumamoto Secondary 55 6 28 % 50 %

NCV increased

25 %

UKPDS 4209 9 19 % 26 % 18 % 18 %

Mortality in Diabetes

UKPDS 38. BMJ 1998;317:703-

years0

Mor

tali

ty (

%)

40

1 2 3 4 5 6 7 8 9

20

0

30

10

Conventional therapyIntensive therapy

Risk- decrease 32%P=0.019

normal target

FBG (mg/dl) <110 80-120

PPBG (mg/dl) <120 100-140

A1c (%) < 6 < 6.5

Target Glucose Levels in Diabetes Treatment

Depiction of the elements of decision making used to determine appropriate efforts to achieve glycemic targets.

Inzucchi S E et al. Dia Care 2012;35:1364-1379

DIABETES MELLITUSMetabolic Targets

Total cholesterol <200 mg/dL

LDL-C

Optimal <100 mg/dL

Treatment >130 mg/dL

HDL-C >45 mg/dL

Triglyceride < 150 mg/dL

Data from American Diabetes Association. Diabetes Care. 1999;22 (suppl 1):S32-S41; The National Cholesterol Education Program (NCEP) Expert Panel. JAMA. 1993;209:2015-3023.

•Systolic < 130 mmHg,

•Diastolic < 80 mmHg

Target Blood Pressure

TREATMENT

Collaborative Management

• Nutritional Therapy

• Activity

• Monitoring of Blood Glucose

• Medication - Insulin or Oral Agents

• Education

Nutrition Recommendations and Principles for People With

Diabetes Mellitus

Antihyperglycemic Therapy in Type 2 Diabetes: General Recommendations.

Inzucchi S E et al. Dia Care 2012;35:1364-1379

Nutritional Therapy

• Cornerstone of care for diabetics

• Use individualized approach

• Consider financial status and cultural and ethnic

influences

• Priority placed on amount of CHO, not source

of the CHO

Goals of Medical Nutrition Therapy

•Maintenance of as near-normal blood glucose levels

•Achievement of optimal serum lipid levels.

•Provision of adequate calories for maintaining or attaining reasonable weights for adults

•Prevention and treatment of the acute complications of insulin-treated diabetes

•Improvement of overall health through optimal nutrition

Medical Nutrition TherapyMedical Nutrition Therapy

• Meal plans should be individualized

– based on • nutrition assessment

• medical history

• psycho-social assessment

• treatment goals

Macronutrient CompositionMacronutrient Composition

• No absolute percentages

– 50-60 % CHO

– 15-20 % Protein

– 20-30 % Fat

Exchange ListsExchange Lists

Calories g CHO g Pro g Fat

Starch 80 15 3 0 -1

Fruit 60 15 0 0

Skim Milk 90 12 8 0 - 3

Low-fat Milk 120 12 8 5

Whole Milk 150 12 8 8

Vegetable 25 5 2 0

Very Lean Meat 35 0 7 0 - 1

Lean Meat 55 0 7 3

Medium Fat Meat 75 0 7 5

High Fat Meat 100 0 7 8

Fat 45 0 0 5

Drug Treatment

New Onset Type 2 Diabetes

A1C >%6.51

3 ayA1C ≥%8.5A1C <%8.5

A1C >%6.51

3-6 ay

MET + Antidiabetic combinations

MET + SU

MET + Glinid

MET + TZD4

MET + DPP-4 inh.

MET + AGİ

MET + GLP-1A5

MET + Insulin combinations

MET + Basal insulin

MET + Mixed insulin

MET + Bolus insulin

A1C >%6.5

3-6 ay

Intensive insulin therapy

Basal-bolus insulin therapy + MET

Insulin pump therapy

Clinical assessment + Life Style Modification

A1C ≥%10 or Metabolic decompansation/Symptomatic hyperglycemia A1C <%10

MET

Insulin ± MET

SU 1. Step Theray

2. Step Therapy

3. Step Therapy

TEMD(2009)

Treatment Algorithm fo Type 2 Diabetic Patients

Drugs Stimulating Insulin Secretion

(Insulin Secretegogues)

Sulfonylurea

Meglitinides

Sulfonylurea

•Decrease blood sugar by stimulating insulin secretion from pancreatic β-cells

•Metabolized in liver and excerted in urine as active and inactive metabolites

Sulfonylurea

• Decreases A1c 0.8 - 1.7 % and fasting blood sugar 50 - 70 mg/dl

• 20-25 % of patients using a sulfonylurea for the first time does not achieve enough blood sugar control (Primary Failure).

• Annually 5-10 % of patients started on sulfonylurea treatment fails to control blood sugars (Secondary Failure).

Relative Potency Dosing Range

(mg/d) Duration of Action (h)

Relative Cost

First Generation SU

Chlorpropamide 6 100-750 24-72 ($$)

Second Generation SU

Glimeperide 450 1-8 24 ($$)

Glipizide (GITS) 100 2.5-40/(5-20) 16-24 ($)/($$)

Gliclazide (MR) 40–320/(30-120) 12-14/(24) ($$)

Glyburide 150 1.25-20 18-24 ($$)

Non-SU Secretagogues

Nateglinide 120 - 360 0.5 – 4 ($$$$)

Repaglinide NA 1-16 0.5-4 ($$$$)

SU = Sulfonylurea.Feinglos MN, Bethel F: Treatment of type 2 DM. Med Clin North Am 82:757-791, 1998

Insulin Secretegogues

Sulfonylurea; Side Effects

• Hypoglycemia

• Weight gain

• SIADH (Chlorpropamide)

• Hematological abnormalities (Hemolytic anemia, Thrombocytopenia, Agranulocytosis)

• GI side effects

• Abnormal LFT

Meglitinides

• Benzoic acid derivatives.

• Short effect insulinotrophic (insulin secretion

stimulating) drugs.

• Bind same reseptor for sulfonylurea at different

position.

Repaglinide and Nateglinide

• Indicated in type 2 diabetic patients not responding diet, excercise and life style modifications

• Taken before meals

• Dose: Repaglinide 3 X 0.5-2mg, Nateglinide 3 X 60-120mg

• 0.5 – 2% decrease in A1c and 50-70 mg/dl in postprandial blood glucose

• Side effect: Hypoglycemia (less than SU)

• Contrandications: Pregnancy, lactation, hypersensitivity

• Avoid in end stage liver and renal failure

• Safer than SU in advanced ages

Alpha-Glucosidase Inhibitors

AcarboseMiglitol

Voglibose

Alpha-Glucosidase Inhibitors

• Effect by blocking alpha glucosidase which converts

disaccharides into monosaccharides in intestinal lumen

• Decrease A1c 0.9 %, FBG 20 mg/dl.

• Postprandial glucose levels decrease 50 mg/dl.

• Side effects: Flatulence, bloating (less in stepwise increase in

doses)

• Only 1-2 % absorbed but should be careful because seldomly

causes LFT increase

Biguanides

(Metformin)

Biguanides (Metformin)

•Decreases endogenous insulin production. ( Gluconeogenesis and Glycogenolysis).

•Increases insulin stimulated glucose uptake in peripheral tissues ( insulin resistance)

•FBG decrease 35 - 50 mg/dl, A1c 1%.

•Can cause weight loss.

•100% of absorbed drug is excreted in urine.

Side Effects:• Gastrointestinal complaints.

• Lactic acidosis

Contrendications:*Renal failure *Liver failure

*Vitamin B12 deficiency

*Alcoholism *Severe trauma and shock

*Heart failure *Systemic infection

*Severe pulmonary disease

Biguanides (Metformin)

Thiazolidinediones

Rosiglitazone

Pioglitazone

(Troglitazone)

Thiazolidinediones

•Effect by binding Peroxisome Proliferator Activated Receptors (PPAR) in nucleus

• Increases insulin sensitive gene transcription ( Lipoprotein lipase, fatty acid binding protein, GLUT-4, acyl-CoA synthase…)

•Increases fatty acid and glucose uptake and use in cells

•Metabolised with P-450 system in liver excreted in bile.

•Decreaes FBG 45 mg/dl, A1c 1%.

Troglitazone Rosiglitazone Pioglitazone

Dosage (mg/dl) 200–600 2–8 15–30Frequency ofadministration

od od, bd od

Elimination half-life (h) 20 3–4 5–6Decrease of FPG (mg/dl) 25–40 30–50 30–50Decrease of HbA1c (%) 0.7 1.0 1.0Decrease of insulin(µU/ml)

2–5 3

Effect on serum lipids TG, Chol nc, HDL,LDL()

FFA, TG nc,Chol nc, HDL,LDL

FFA nc, TG, Chol nc,HDL, LDL nc

Adverse effectsHepatotoxicity Yes No1 NoCK elevation nd No YesCardiac hypertrophy No No NoInteraction with CPY 3A4 Yes No Yes

Thiazolidinedione

Thiazolidinedione – Side Effects:

• Edema and water retention (Contrendicated in NYHA Class III ve IV heart failure)

• Weight gain (not different than insülin and sulfonylurea)

• Increase in CPK (mechanism?)

• Increase in LFT (not different than placebo with Rosiglitazone and Pioglitazone)

The family of incretin-based therapies

Human GLP-1 analogues, e.g.

liraglutide

Exendin-basedtherapies, e.g.

exenatide

GLP-1 receptor agonists

DPP-4 inhibitors, e.g.

sitagliptin, vildagliptin

Incretin-basedtherapies

DPP-IV Inhibitors

• Improves glucose tolerance and insulin response to oral glucose in patients with T2DM

• Available as oral formulation• Will provide a once-daily treatment option for

patients with T2DM• Reduce A1c 1% and fasting BG 30-50 mg/dl, PPBG

30-50 mg/dl• Lower risk of hypoglycemia• Weight neutral• Sitagliptin, Vildagliptin, Saxagliptin

GLP-1 has multiple desirable effects

• Efficacious glucose lowering• increased insulin secretion (glucose-dependent),

increased insulin biosynthesis, increased beta-cell glucose sensitivity

• decreased glucagon secretion (glucose-dependent)• delayed gastric emptying• increased beta-cell mass (shown in animal models)

• Body weight lowering• delayed gastric emptying• increased fullness and satiety• decreased food intake

• Potential to halt disease progression• increased beta-cell glucose sensitivity• Increased beta-cell mass (shown in animal models)

LEAD covers the continuum of T2D care, compared with standard treatments

Diet/exercise

Start an oral agent

Add another oral agent

Add a third oralor start insulin

Liraglutide monotherapy vs. SULEAD-3

Liraglutide+MET vs. SU+MET LEAD-2

Liraglutide+SU vs. TZD+ SU LEAD-1

Liraglutide+MET+TZDvs. MET+TZDLEAD-4

Liraglutide+MET+SUvs. glargine+MET+SULEAD-5

Liraglutide+MET and/or SU vs. exenatide+MET and/or SULEAD-6

LEAD: Liraglutide Effect and Action in Diabetes. All studies 26 weeks’ duration (LEAD 3=52 weeks); all RCT; Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009; DOI:10.2337/dc08-2124 (LEAD-4); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD-5); Buse et al. Lancet 2009; DOI:10.1016/S0140-6736(09)60659-0 (LEAD-6)

LEAD programme: reductions in HbA1c with liraglutide

#C

hange in H

bA

1c

(%)

0.0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

-1.4

SU combination

LEAD-1

Metformin combination

LEAD-2

Met + TZD combination

LEAD-4

Met + SU combination

LEAD-5

-1.6

-1.3*

-1.5*-1.5*

MonotherapyLEAD-3

51% 43%

-1.4*-1.3

-1.1

-1.6*

-1.2*

-1.5*

-0.9

-1.3

-0.8

-1.1

-0.5

Baseline A1c % 8.3 8.18.68.58.38.68.58.2 8.28.6 8.6 8.48.4 8.4

Liraglutide 1.8 mgLiraglutide 1.2 mg Glimepiride 8 mg Rosiglitazone 4 mg Glargine

Significant *vs. comparator; #Change in HbA1c from baseline for overall population (LEAD-4,-5) add-on to diet and exercise failure (LEAD-3); or add-on to previous OAD monotherapy (LEAD-2,-1). Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009; DOI:10.2337/dc08-2124 (LEAD-4); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD-5)

Liraglutide in combination with met presents a low risk of hypoglycaemia

***p<0.0001 for treatment differences in changes versus glimepiride

******

***

• Minor hypoglycaemic events are at the placebo level (LEAD-2, above)

• There is a small but increased risk of minor hypoglycaemia when combined with SUs (1.0 events per subject every second year; LEAD-1)

Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009; 32; 84–90 (LEAD-2)

A quarter of patients lose an average of 7.7 kg with liraglutide

-9-8-7-6-5-4-3-2-1012

≤Q1 Q1-Q2 Q2-Q3 >Q3

Weig

ht

chan

ge (

kg)

Liraglutide 1.8 mg + met + SU

Q3-Q4

0–Q1: mean weight change for the 25% of subjects who had the largest weight loss Q1–Q2: mean weight change for the 25–50% weight loss quartile Q2–Q3: mean weight change for the 50–75% weight loss quartile Q3–Q4: mean weight change for the 75–100% weight loss quartile, that is, the 25% who had the smallest weight loss

Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2)

New Drugs

Success rate of monotherapy in is limited type 2 diabetes. (UKPDS)

Turner RC et al. JAMA 1999;281:2005–12

HbA1c <8%

HbA1c <7%

3 years 48–55% 41–46%

6 years 35–38% 25–27%

9 years 16–21% 10–18%

Target

Treatment period

Start with basal insulin

(NPH at night; once daily long-acting analog insulin)

If FPG >120 mg/dl

increase insulin dose

If hypoglycemia or FPG <70 mg/dl decrease the night dose

A1C >%6.5 3 months later

No Yes

Keep thearpy, A1C at 3-6 months

If premeal PG >120 mg/dl at lunch add fast acting insulin before morning

If premeal PG >120 mg/dl at dinne add fast acting insulin before lunch

If premeal PG >120 mg/dl at night add fast acting insulin befor dinner

Basal-bolus (intensive) insulin therapy

A1C >%6.5 at month 3

FPG <120 mg/dl

Increase injection number

Yes

No

TEMD(2009) Insulin Therapy in Type 2 Diabetes

Start with biphasic insulin

( Twice daily human/analog insulin)

EvetIf morning or evening PG >120 mg/dl increase dose

• Only treatment option for type 1 DM

• Uncontrolled hyperglycemia

• Decompansating factors eg: infections, acute trauma or

other stressful events

• Ketonemia and ketonuria

• Uncontrolled weight loss

Indications for Insulin Treatment

•Perioperative period

•Pregnancy

•Renal and liver failure

•Allergic reactions to oral antidiabetic patients

•LADA (Latent autoimmune diabetes in adults)

•Patient or doctor choice

Indications for Insulin Treatment

Insulin Treatment Types

•Intravenous continuous infusion

•Conventional insulin therapy

•Intensive insulin therapy

Insulin Delivery• Insulin devices (pens)

– Durable (replace insulin cartridge)

– Disposable (no need to replace cartridge)

• Insulin vials and syringes

Front Back

Insulin Application Sites

Insulin Types

Insulin Start ofPreparations Effect Peak Max Effect

Lispro/Aspart/Glulysin 5-15 min 1-2 hrs 4-6 hrs

Human Regular 30-60 min 2-4 hrs 6-10 hrs

Human NPH 1-2 hrs 4-8 hrs 10-20 hrs

Glargine 1-2 hrs Flat ~24 hrs

AIM; Mimic physiologic insulin profile

130

120

110

0

7 8 9 10 11 12 1 2 3 4 5 6 7 8 9

Breakfast

LunchDinner

75

50

25

0 Basal Insulin

Basal Glucose

Insulin (µU/ml)

Glucose (mg/dl)

Insulin Treatment Regimens

• Once daily injection

• Twice daily injection

• Three times daily injection

• Intensive insulin therapy

– Basal-bolus insulin therapy

– Continuous subcutaneous insulin injection (insulin pump)

Breakfast Lunch Dinner

Endogenous

NPH

Sabah GeceÖğle Akşam

Insulin Tactics

Breakfast Lunch Dinner

Sabah GeceÖğle Akşam

İnsulin Tactics

Breakfast Dinner

R

Lunch

NPH NPH

R

Breakfast

İnsulin Tactics

Night

Breakfast Lunch DinnerEndogenous

NPH

Short analog

Breakfast NightLunch Dinner

İnsulin Tactics

Breakfast Lunch Dinner

Endogenous

Long Acting Analog

Short analog

Breakfast NightLunch Dinner

Insulin Tactics

1. Mild Type 2 Diabetics FBG< 140mg/dl

Insulin not indicated

2. Moderate Type 2 DiabeticsFBG 140 -220 mg/dl

Basal Insuin 0.3 - 0.4 IU/kg/day

3. Severe Diabetics FBG> 220 mg/dl

0.3- 1.0 IU/kg/dayPremix Insulin

4. Very Severe Type 2DiabeticsFBG>280 mg/dl

Treat likeTyp 1 Diabetics

Insulin Programs in Type 2 Diabetics

Insulin Therapy

Moderate DM(FBG 140-200 mg/dL)

(0.3-0.5 U/kg/day)

Basal Insulin(Glargine/Detemir/NPH)

Premix insulins

Mix 25 or Mix 30(Humalog Mix 25/ Humulin M

70/30/Novomix 30)

Mix 50 insulin(Humalog Mix 50 )

2/3 breakfast 1/3 dinner 1/3 Breakfast 1/3 dinner1/3 Lunch

Insulin Therapy

Basal-Bolus İnsülin

Severe DM (FBG >200 mg/dL)(0.5-0.1 U/kg/day)

Premix insulin

Mix 25/75 or Mix 30(Humalog Mix 25/75/ Humulin M

70/30/Novomix 30)

2/3 breakfast 1/3 dinner 1/3 breakfast

1/3 dinner

1/3 lunch

Mix 50 insulin(Humalog Mix 50 )

Breakfast 15-25% fast

Lunch 15% fast

Dinner 15-20% fast

Night 40-50% basal

FOLLOW-UP ?

At least 3 day/week glucose profile shold be done

Glycemia in a meal is controlled by previous insulin dose

If exist, hypoglycemia should be corrected first

If hyperglycemia persists all day long, begin titration from the highest

Insulin Dose Titration

Bad Glycemic Profile

• General assessment

• Control diet–excercise plan

• Control insulin effectivity

• Focal infection or anything increasing insulin need

• Control application site and style

Most Common Type of Insulin Resistance

EDUCATION

Insulin Pump Therapy

Continuous Glucose Monitoring System (CGMS)

Islet Cell Transplantation in Type 1 Diabetes Mellitus

Donor ?

Immunosupression ?

Success?

Edmonton protocol

•Insulin free pts rate 70% at 2 year