TREATMENT OF DIABETES MELLITUS

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Treatment of diabetes mellitus Nóra Hosszúfalusi 03.04.2017.

Treatment in diabetes • • • • •

Glycemic control Hypertension control Lipid control Lifestyle (diet, BW, physical activity) Cardiovascular prevention

Glycemic control • Life style (diet + physical exercise) • Insulin • Oral antidiabetic drugs & non-insulin injectibles

Good glycemic control (↓HbA1c) decreases the diabetic complications DCCT

Kumamoto

UKPDS

9 → 7%

9 → 7%

7,9 → 7%

Retinopathy

76% ↓

69%

17-21%

Nephropathy

54% ↓

70%

24-33%

Neuropathy

60% ↓

-

-

Macrovascular disease

41%* ↓

-

16%*

HbA1c

* not statistically significant DCCT Study Group. N Engl J Med 329:977-86, 1993 Ohkubo Y. Diabetes Res Clin Prac 28:103-17, 1995 UKPDS Study Group. Lancet 352:837-53, 1998

Hyperglycemia perglycemia

Postprandial hyperglycemia

Fasting hyperglycemia

HbA1c

Effect of fasting and postprandial blood glucoe on HbA1c level

Monnier L et al.: Diabetes Care 26:881-885, 2003

HbA1c targets for nonpregnant people with type 1 diabetes • • •



(ADA, 2014) Youth < 18 years: < 7.5% Adults: < 7.0% (< 6.5%) Older adults - healthy: < 7.5% - complex/intermediate: < 8.0% - very complex/poor health: < 8.5% Should be individualized!!!

Position Statement of ADA, Diab Care 06, 2014

Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM

Approach to the management of hyperglycemia HbA1c

more stringent

7%

less stringent

PATIENT / DISEASE FEATURES Risks potentially associated with hypoglycemia and other drug adverse effects Disease duration

Life expectancy

low

high

newly diagnosed

long-standing

Usually not modifiable long

short

Important comorbidities

Established vascular complications

Patient attitude and expected treatment efforts

Resources and support system

absent

few / mild

severe

absent

few / mild

severe

highly motivated, adherent, excellent self-care capacities

Readily available

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

Potentially modifiable

limited

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

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

3. ANTI-HYPERGLYCEMIC THERAPY

•Glycemic targets -

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

-

Pre-prandial PG <130 mg/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.

PG = plasma glucose

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

Insulin treatment

Discoverers of insulin

F.G. Banting

J.J.R. Macload

C.H. Best

Announcement: 12/30/1921 First application: 01/01/1922.

J.B. Collip

Physiologic insulin secretion and blood glucose • Glucose

dependent

• Follows the diurnal insulin sensitivity • Basal insulin secretion • Prandial insulin secretion • Into the portal vein

Type of insulin Human

Onset

Peak

Duration

Rapid acting (Regular) Intermediate acting (NPH) Analogs

30 min

1-3 h

4-8 h

1-2 h

4-6 h

8-12 h

Rapid acting (aspart, lispro, glulisine) Long acting (glargine, detemir, degludec)

5-15 min

1h

3-4 h

2h

flat

24 h (12-20)

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

3. ANTI-HYPERGLYCEMIC THERAPY

• Therapeutic options: Insulins

Insulin level

Rapid (Lispro, Aspart, Glulisine) Short (Regular)

Long (Detemir)

(Degludec)

Long (Glargine) 0

2

4

6

8

Hours

10 12 14 16 Hours after injection

18

20

22

24

Premix insulins used in conservative treatment twice a day • Human Humulin M3 30-70 % (R/N)

• Analogs NovoMix 30 Humalog Mix 25, 50

Human regular insulin

7:00 9:00 11:00 13:00 15:00 17:00 19:00 21:00 23:00 1:00 3:00 5:00 7:00

Time Blood glucose after meal

Multiple daily (insulin) injections MDI

Multiple Daily Injection (MDI) strategy Insulin time

6:00

12:00

18:00

22:00

Insulin dose

12E (R)

8E (R)

10E (R)

10 E (NPH)

Meal time Meal CH

6:30 9:00 12:15 15:00 18:30 21:0 0 30 g 20 g 50 g 20 g 40 g 20 g

insulin aspart glargin Gly

Pro

Asp

Tyr Arg

Phe

Phe

Gly

Arg Glu

Thr

Arg

Gly

B28

Cys

B29

detemir A1

A21

B30

Cys

Pro

Gly

Val Tyr Leu Asn

Lys

Tyr

Lys

Ile

Glu Leu

Pro

Val

Leu

insulin lispro

Glu

Ala Gln Glu

Gln

Tyr

Cys

Val

Leu Cys

Thr

Ser

Ile

Cys

Ser

Leu His Ser Gly

B1

Phe

Val

Asn

Gln

His

Leu

Cys

Absorption of rapid acting analogs and human regular insulin

Type of insulin

Onset

Peak

Duration

30 min

1-3 h

4-8 h

1-2 h

4-6 h

8-12 h

5-15 min

1h

3-4 h

2h

flat

24 h (12-20)

Human Rapid acting (Regular) Intermediate acting (NPH) Analogs Rapid acting (aspart, lispro, glulisine) Long acting (glargine, U300, detemir, degludec)

Analog rapid acting

7:00 9:00 11:00 13:00 15:00 17:00 19:00 21:00 23:00 1:00 3:00 5:00 7:00

Time

Blood glucose after meal

MDI • Total daily dose: T1DM: 0.5-0.7 U/BWkg T2DM: ≥ 1.0 U/BWkg • Basal-bolus ratio: 50-50 % T1DM: 30/40-70/60 % T2DM: 60-40 % • Type of insulin • Meal pattern (# of meals)

Insulin syringes

Insulin “pens”

Insulin pumps

Basal insulin profile in insulin pump therapy

Gluco-sensor (CGM) Open loop

Future? Closed loop!

Insulin treatment in T2DM • Once daily (1x): BOT (21 h, BS) • Twice daily (2x): Premix (human) • 3x daily: PPT prandial premix (analog)



Aims of diet • In T1DM: match the carbohydrate intake and action of the insulin absorbed from the injection site (the latter is not physiologic, as it is not given into the portal vein). Maintain the ideal body weight. • In T2DM: regain and maintain the ideal body weight (this will decrease the insulin resistance). Match the absorption of carbohydrates to the abnormal insulin secretion.

HbA1c ↓in 3-6 months 0.25-2.9 %

T2DM and obesity vs. CHO • • • • •

Risk Refined grains or white bread Ready-to eat cereals Sugar sweetened beverages Potatoes or French fries Sweets or sweet bakery products

• • • • •

Protective effect Fruits Vegetables Legumes Whole-meal or wholegrain bread High-fibre breakfast cereals

Adequate composition of diet • Carbohydrate • Protein • Fat

50-60% 10-20% < 30%

• Encourage complex, high fiber carbohydrates (dried beans, lentils, peas, oats, barley, whole-grain cereals, green leafy and root vegetables) and limit sucrose (<25 g added, <50 g total • Fiber 14g/1000 kcal • Saturated fats <7 % of total energy intake; encourage MUFA (olive oil, rapeseed oil) and PUFA (fish); cholesterol <200 mg/day (less if dyslipidaemia) • Avoid trans fatty acids and „diabetic foods” • Limit salt intake; limit alcohol intake;

Frequency of meals • Depends on the form of treatment • If diet only - 3-5 meals/day if diet + SU - 5 meals/day if insulin - 3-6 meals/day • 3 main meals + 2-3 snacks • Breakfast 30-45g carbohydrate • Lunch 50-90g carbohydrate • Dinner 40-80 g carbohydrate • Snacks 2–3 x 10-20 g • Sum: 170-300 g carbohydrate (600-1200 kcal)

Checking the blood sugar Self-monitoring blood glucose (SMBG)

Aims of physical exercise • In T1DM: maintenance of the patient’s fitness.

• In T2DM: regain of ideal body weight. Decrease of insulin resistance. Transformation of T2DM to IGT/IFG; transformation of IGT/IFG to normal glucose tolerance.

The effect of one-hour exercise on blood glucose in children n=50 J Pediatr 147:528, 2005

(Drug) therapy in T2DM

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

3. ANTI-HYPERGLYCEMIC THERAPY

• Therapeutic options: Lifestyle - Weight optimization - Healthy diet

- Increased activity level Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

Multiple, Complex Pathophysiological Abnormalities in T2DM pancreatic insulin secretion

incretin effect

_ gut carbohydrate delivery & absorption

pancreatic glucagon secretion

?

HYPERGLYCEMIA _

+ hepatic glucose production

renal glucose excretion

peripheral glucose uptake

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Drug therapy in T2DM • Enhance insulin secretion - sulfonylureas - meglitinides - GLP-1 system - insulin

• Enhance insulin sensitivity - metformin („insulinsparing” drug - pioglitazone (thiazolidinediones)

• Decrease glucagon secretion - GLP-1 system

• Enhance glucosuria

- SGLT2-I • Delay CH absorption from the gut - acarbose

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

3. ANTI-HYPERGLYCEMIC THERAPY

• Therapeutic options: Oral agents & non-insulin injectables

- Metformin - Sulfonylureas - Thiazolidinediones - DPP-4 inhibitors - SGLT-2 inhibitors - GLP-1 receptor agonists

- Meglitinides - α-glucosidase inhibitors - Colesevelam - Dopamine-2 agonists - Amylin mimetics

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

Current Therapies for Type 2 Diabetes Biguanides (Metformin): Overview Mechanism of action

Primary: Decreased hepatic glucose production Secondary: Increased peripheral glucose uptake

Efficacy depends on

Presence of insulin

Power

Decreased HbA1c by 1.0–2.0%

Dosing

Once or twice daily

Side effects

Nausea, anorexia, diarrhea

Main risk

Lactic acidosis

Adapted from Kirpichnikov D et al Ann Intern Med 2002;137(1):25–33; DeFronzo RA Ann Intern Med 1999;131:281–303; Glucophage/ Glucophage XR prescribing information, Bristol-Myers Squibb, April 2003; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004.

Putative mechanism of action of metformin Molecular mechanism of action of metformin: old or new insights?

G Rena Diabetologia 56:1898, 2013

Current Therapies for Type 2 Diabetes PPARs: Overview

Mechanism of action

Enhance tissue response to insulin

Efficacy depends on

Presence of insulin and resistance to its action

Power

Decreased HbA1c by up to 1.0%

Dosing

Once or twice daily

Side effects

Weight gain, edema, anemia

Main risk

Congestive heart failure

Adapted from Actos prescribing information, Takeda Pharmaceuticals, December 2003; Avandia prescribing information, GlaxoSmithKline, May 2004; DeFronzo RA Ann Intern Med 1999;131:281–303; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004.

Current Therapies for Type 2 Diabetes PPARs: Mechanism of Action Modify gene expression in adipocytes

Modify fatty acid uptake and lipolysis

PPARgamma ligand

Modify free fatty acids

Skeletal muscle

Modify insulin-sensitizing factor(s) (e.g., adiponectin) Adipose Tissue

Modify expression/action of insulin-resistance factor(s) (e.g., resistin/TNF)

Small, insulinsensitive adipocytes modify visceral adiposity

Adapted from Moller DE Nature 2001;414:821–828.

Modify insulin action Liver

GLP1 GLP1 receptor

Adenyl cyclase CAMP PKA

Florez J.C.: Diabetologia, 2008, 51, 1100-1110.

Physiological insulin secretion n the beta cell Ca++

Voltage dependent Ca chanel

ATP-sensitive potassium chanel K+ Glucose GLUT-2

Glikolízis ATP

Insulincontaning Granule

Insulin

AAz depolarizáció hatására intracelluláris kalciuma A glukóz a GLUT2 ATP hatására záródnak azsorán ATP A béta-sejtben feszültségfüggő a glikolízis feszaporodás azkalcium inzulin Atranszporteren sejtmembrán depolarizálódik keresztül jut a szenzitív kálium csatornák csatonák a kalcium ATPnyílnak, keletkezik szekréciós granulomok béta-sejtbe. beáramlik a sejtbe exocytosisához vezet The Physiology of Glucagon-like Peptide 1. Jens Juul Holst Physiol Rev 87: 1409–1439, 2007;

A szulfonilureák hatásmechanizmusa Feszültségfüggő Ca++ csatorna Ca++

Sulfanylurea

ATP-szenzitív K+ csatorna K+

GLUT-2

Inzulin Szekréciós Granulum

Inzulin

A szulfonilureák okozta hypoglycaemia oka,hatására hogy hatásuk intracelluláris kalcium AAz depolarizáció a A szulfanilureák az ATPkialakulásához szükség feszaporodásnincs azkalcium inzulin feszültségfüggő Aszenzitív sejtmembrán depolarizálódik kálium csatornához glükózra, illetve glukóz-szenzorra: szekréciós granulomok csatonák nyílnak, a kalcium kötődnek és zárják a csatornát folyamatos inzulinszekréciót exocytosisához vezet beáramlik a sejtbe okoznak. The Physiology of Glucagon-like Peptide 1. Jens Juul Holst Physiol Rev 87: 1409–1439, 2007;

A szulfanilureák okozta hypoglycaemia oka, hogy hatásuk kialakulásához nincs szükség glükózra, illetve

At fasting plasma glucose >6.4 mmol/l first phase insulin response is absent FBG: 6.4 mmo/l 115 mg/dl

Brunzell JD, J Clin. Endoc Metab 42:22, 1976

Current Therapies for Type 2 Diabetes Sulfonylureas: Overview Mechanism of action

Increased insulin release

Efficacy depends on

Functioning beta cells

Power

Decreased HbA1c by 1.5–2.0%

Dosing Side effects

Once or twice daily Weight gain Hypoglycemia

Main risk

HbA1c=glycosylated hemoglobin Adapted from Siconolfi-Baez L et al Diabetes Care 1990;13(suppl 3):2–8; Riddle MC Am Fam Physician 1999;60(9):2613–2620; DeFronzo RA Ann Intern Med 1999;131:281–303; Glynase prescribing information, Pharmacia Corporation, April 2002; Glucotrol prescribing information, Pfizer, 2000; Glucotrol XL prescribing information, Pfizer, 2003.

Current Therapies for Type 2 Diabetes Meglitinides: Overview Mechanism of action Increased insulin release Efficacy depends on Functioning beta cells Decreased HbA1c by 1.0–2.0% Power Dosing Side effects

Two, three, or four times daily Weight gain Hypoglycemia (rarely)

Main risk Very short acting drugs: repaglinide, nateglinide, Postprandial blood glucose regulators. To be taken at the start of the meal. Adapted from Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004; Riddle MC Am Fam Physician 1999;60(9):2613–2620; Del Prato S et al Diabetes Care 2003;26(7):2075–2080; Starlix prescribing information, Novartis Pharmaceuticals, December 2000; DeFronzo RA Ann Intern Med 1999;131:281–303.

Effects of GLP-1 (glucagon-like peptid-1) • Enhance the After meal…

glucose-dependent insulin secretion • Inhibit glucagon secretion • Delay gastric emptying

GLP-1 is secretad in ileum (L-cells)l

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412 Drucker DJ. Mol Endocrinol 2003; 17:161-171

• Decrease the appetite

GLP-1 system

Holst: International Journal of Obesity (2013) 1161 – 1168; Holst: Physiological Reviews Published 1 October 2007 Vol, 87 no, 4, 1409-1439 DOI: 10,1152

GLP-1 system

• Insulin secretion ↑ • Glucagon secretion ↓ • Appetite ↓ • Gastric emptying ↓

Holst: Physiological Reviews Published 1 October 2007 Vol, 87 no, 4, 1409-1439 DOI: 10,1152/physrev,00034,2006; Kevin: Nature 444, 854-859(14 December 2006)

Prolonged effect of GLP-1 • DPP-4 resistant molecules: - GLP-1 analogs liraglutide - GLP-1 receptor agonist exenatide

• DPP-4 (dipeptidyl peptidase) inhibitors: vildagliptin, sitagliptin, saxagliptin etc.

SGLT2-inhibitors

• Sodium-glucose co-transporter 2 (SGLT2) inhibitors • 70 g glucose in the urine/day • Weight loss, no hypoglycemia

Figure 1 Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Cherney DZ; Perkins BA; Soleymanlou N; Maione M; Lai V; Lee A; Fagan NM; Woerle HJ; Johansen OE; Broedl UC; von Eynatten M Circulation. 129(5):587-97, 2014 Feb 4. DOI: 10.1161/CIRCULATIONAHA.113.005081

Figure 1 . Postulated tubuloglomerular feedback (TGF) mechanisms in normal physiology, early stages of diabetic nephropathy, and after sodium-glucose cotransporter (SGLT) 2 inhibition. A, Under physiological conditions, TGF signaling maintains stable glomerular filtration rate (GFR) by modulation of preglomerular arteriole tone. In cases of conditional increases in GFR, the macula densa within the juxta-glomerular apparatus senses an increase in distal tubular sodium delivery and adjusts GFR via TGF accordingly. B, Under chronic hyperglycemic conditions (diabetes mellitus), increased proximal SGLT2-mediated reabsorption of sodium (Na+) and glucose impairs this feedback mechanism. Thus, despite increased GFR the macula densa is exposed to lowered sodium concentrations. This impairment of TGF signaling likely leads to inadequate arteriole tone and increased renal perfusion. C, SGLT2 inhibition with empagliflozin treatment blocks proximal tubule glucose and sodium reabsorption, which leads to increased sodium delivery to the macula densa. This condition restores TGF via appropriate modulation of arteriolar tone (eg, afferent vasoconstriction), which in turn reduces renal plasma flow and hyperfiltration.

© 2014 by the American College of Cardiology Foundation and the American Heart Association, Inc. .

2

Multiple, Complex Pathophysiological Abnormalities in T2DM GLP-1R GLPagonists

Insulin Glinides S U s

incretin effect DPP-4 DPPinhibitors

Amylin mimetics

_

pancreatic insulin secretion

pancreatic glucagon secretion DA

agonists

AGIs

gut carbohydrate delivery & absorption

?

HYPERGLYCEMIA

Metformin

_

Bile acid sequestrants

+ hepatic glucose production

renal glucose excretion

TZDs

peripheral glucose uptake

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

ADA 2017 Consider initiating combination injectable therapy (Fig. 8.2) when blood glucose is >300 mg/dL (16.7 mmol/L) or A1C is > 10% (86 mmol/mol) or if the patient has symptoms of hyperglycemia (i.e., polyuria or polydipsia). As the patient’s glucose toxicity resolves, the regimen may, potentially, be simplified.

ADA 2017

Thanks!