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
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