Update on diabetes treatment strategies 2017

Update on Diabetes Update on Diabetes Treatment StrategiesTreatment Strategies

Dr P.Sudhakar,MDProf. of MedicineKurnool Medical College

The Ominous Octet of DM2The Ominous Octet of DM2Islet -cell

ImpairedInsulin Secretion

NeurotransmitterDysfunction

Decreased GlucoseUptake

Islet -cell

IncreasedGlucagon Secretion

IncreasedLipolysis

Increased GlucoseReabsorption

IncreasedHGP

DecreasedIncretin Effect

DM2 Is A Progressive DiseaseDM2 Is A Progressive Disease

M I C R O V A S C U L A R D I S E A S E M I C R O V A S C U L A R D I S E A S E ObesityObesity Pre-DMPre-DM DiabetesDiabetes Uncontrolled HyperglycemiaUncontrolled Hyperglycemia

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Post-meal GlucosePost-meal Glucose

Fasting GlucoseFasting Glucose

Insulin ResistanceInsulin Resistance

Insulin LevelInsulin Level

-cell Failure-cell Failure

M A C R O V A S C U L A R D I S E A S EM A C R O V A S C U L A R D I S E A S E

Years of DMYears of DM

Impact of Intensive Therapy For Impact of Intensive Therapy For Diabetes: Diabetes: Summary of Major Clinical Trials Summary of Major Clinical Trials

Study Micro Macro Mortality

UKPDSUKPDS

DCCT / EDIC DCCT / EDIC

ACCORDACCORD

ADVANCEADVANCE

VADTVADT

Initial Trial Initial Trial Long Term Follow-up Long Term Follow-up

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2016 Canadian Diabetes Association

GET TO TARGET WITHIN

3-6 MONTHS OF DIAGNOSIS


Initial Choice of Therapy Depends on Glycemia

Initial A1C ≥8.5%

Start metformin AND Consider combo therapy to achieve ≥1.5% A1C reduction

Initial A1C <8.5%

Start metformin OR Reassess in 2-3 months then decide on starting metformin


Initial Choice of Therapy Depends on Glycemia

Symptomatic Hyperglycemia

+ Metabolic

Decompensation

INSULIN +/- Metformin

• Polyuria• Polydipsia• Weight loss• Volume depletion

Concern about Insulin Deficiency


CHOICE OF AGENT AFTER INITIAL METFORMIN

NEEDS TO BE INDIVIDUALIZED


PRIORITY:Clinical Cardiovascular Disease

11/2016

Add another agent best suited to the individual by prioritizing patient characteristics:

Degree of hyperglycemiaRisk of hypoglycemiaOverweight or obesityCV disease or multiple risk factorsComorbidities (renal, CHF, hepatic)Preferences & access to treatment

Consider relative A1C loweringRare hypoglycemiaWeight loss or weight neutralEffect on cardiovascular outcomeSee therapeutic considerations; consider eGFR See cost column; consider access

PATIENT CHARACTERISTIC CHOICE OF AGENT

Antihyperglycemic agent withdemonstrated CV outcome benefit(empagliflozin, liraglutide)

PRIORITYClinical cardiovascular disease

Add another class of agent best suited to the individual (agents listed in alphabetical order):

Class RelativeA1C Lowering

Hypo-glycemia

Weight Effect in Cardiovascular Outcome Trial

Other therapeutic considerations Cost

-glucosidase inhibitor (acarbose)

Rare Neutral to Improved postprandial control, GI side-effects $$

DPP-4 Inhibitors Rare Neutral to alo, saxa, sita:

NeutralCaution with saxagliptin in heart failure $$$

GLP-1R agonists to Rare lira: Superiorityin T2DM patientswith clinical CVD

lixi: Neutral

GI side-effects $$$$

Insulin Yes Neutral (glar) No dose ceiling, flexible regimens $-$$$$

Insulin secretagogue: Meglitinide Sulfonylurea

Yes

Yes

Less hypoglycemia in context of missed meals but usually requires TID to QID dosingGliclazide and glimepiride associated with less hypoglycemia than glyburide

$$

$

SGLT2 inhibitors to Rare empa:Superiority in

T2DM patientswith clinical CVD

Genital infections, UTI, hypotension, dose-related changes in LDL-C, caution with renal dysfunction and loop diuretics, dapagliflozin not to be used if bladder cancer, rare diabetic ketoacidosis (may occur with no hyperglycemia)

$$$

Thiazolidinediones Rare Neutral CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect

$$

Weight loss agent (orlistat)

None GI side effects $$$

alo=alogliptin; glar=glargine; saxa=saxagliptin; sita=sitagliptin; lira=liraglutide; lixi=lixisenatide; empa=empagliflozin

Start metformin immediately

Consider initial combination with another antihyperglycemic agent

Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin

A1C <8.5% Symptomatic hyperglycemia with metabolic decompensationA1C 8.5%

Initiate insulin +/-metformin

If not at glycemic target (2-3 mos)

Start / Increase metformin

If not at glycemic targets

LIFESTYLE

Add another agent best suited to the individual by prioritizing patient characteristics :

Degree of hyperglycemiaRisk of hypoglycemiaOverweight or obesityCardiovascular disease or multiple risk factorsComorbidities (renal, CHF, hepatic)Preferences & access to treatment

See next page…

AT DIAGNOSIS OF TYPE 2 DIABETES

Consider relative A1C loweringRare hypoglycemiaWeight loss or weight neutralEffect on cardiovascular outcomeSee therapeutic considerations, consider eGFRSee cost column; consider access

PATIENT CHARACTERISTIC CHOICE OF AGENT

PRIORITY: Clinical Cardiovascular Disease

Antihyperglycemic agent withdemonstrated CV outcome benefit(empagliflozin, liraglutide)

If not at glycemic target

From prior page…

• Add another agent from a different class• Add/Intensify insulin regimen

Make timely adjustments to attain target A1C within 3-6 months

LIFESTYLE

Empagliflozin 45

eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90CKD Stage: 5 4 3 2 1

Acarbose Not recommended 25

Dapagliflozin 60

Thiazolidinediones 30Contraindicated SafeCaution and/or reduce dose

Canagliflozin 25 60*100 mg45

Adapted from: Product Monographs as of March 2016 Harper W et al. Can J Diabetes 2015;39:440.

* = do not initiate if eGFR <60 ml/min Not recommended

Metformin 30 60

15Linagliptin

Sitagliptin 5030 50 mg25 mg

Saxagliptin 5015 2.5 mg

Alogliptin Not recommended 506.25 mg 12.5 mg30

Exenatide (BID/QW) 30 50Liraglutide 50

Albiglutide 50

30

Repaglinide

Gliclazide/Glimepiride 15 30Glyburide 30 50

Insulin Secreta-gogues

SGLT2 inhibitors

GLP-1R agonists

Alpha-glucosidase

InhibitorBiguanid

e

DPP-4 inhibitors

Dulaglutide 50

Antihyperglycemic agents and Renal Function

60*45

No dose adjustment but close monitoring of renal function


Types of Insulin

Types of Insulin (continued)

Seru

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Analogue BolusHuman Basal

Analogue BasalHuman Bolus


Time

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Human PremixedAnalogue Premixed


INSULIN ANALOGUES• FAST ACTING LisproAspartGlulisine• LONG ACTINGDetemir insulinDegludec insulinGlargine insulin• Premixed analogue insulins: Humalog Mix 25, Humalog Mix 50, NovoMix 30

Anti-hyperglycemic Therapy:Anti-hyperglycemic Therapy:Glycemia TargetsGlycemia Targets• HbA1c < 7.0% (MPG HbA1c < 7.0% (MPG 150 mg/dL)150 mg/dL)• Pre-prandial PG 80-130 mg/dL Pre-prandial PG 80-130 mg/dL • Post-prandial PG <180 mg/dL Post-prandial PG <180 mg/dL • Avoidance of hypoglycemiaAvoidance of hypoglycemia• Individualization is key:Individualization is key:

– More stringent (More stringent (HbA1cHbA1c 6.0-6.5%) - short disease 6.0-6.5%) - short disease duration, healthier, no CVDduration, healthier, no CVD

– Less stringent (Less stringent (HbA1cHbA1c 7.5-8.0%+) – comorbidities, 7.5-8.0%+) – comorbidities, complications, hypoglycemias, short life expectancy, complications, hypoglycemias, short life expectancy, limited resources, support or motivation limited resources, support or motivation

Antihyperglycemic Therapy in Antihyperglycemic Therapy in DM2DM2

Approach to Starting and Adjusting Approach to Starting and Adjusting Injectable Therapy in DM2Injectable Therapy in DM2

Anti-hyperglycemic Therapy:Anti-hyperglycemic Therapy:Oral agents & non-insulin injectablesOral agents & non-insulin injectables

– Biguanides Biguanides – SulfonylureasSulfonylureas

– ThiazolidinedionesThiazolidinediones– MeglitinidesMeglitinides– Alpha-glucosidase Alpha-glucosidase

inhibitorsinhibitors– DPP-4 inhibitorsDPP-4 inhibitors

– SGLT-2 inhibitorsSGLT-2 inhibitors

– Dopamine-2 agonistsDopamine-2 agonists

– Bile acid sequestrantsBile acid sequestrants

– GLP-1 receptor GLP-1 receptor agonistsagonists

– AmylinomimeticsAmylinomimetics

Efficacy of Non-insulin Anti-diabetes Efficacy of Non-insulin Anti-diabetes Agents*Agents*Drug A1c Reduction (%)Drug A1c Reduction (%)MetforminMetformin 1.5–2.01.5–2.0Secretagogue (SFU/Glinide)Secretagogue (SFU/Glinide) 1.5–2.01.5–2.0GLP1RAGLP1RA 1.0-1.51.0-1.5TZDTZD 1.0–1.51.0–1.5SGLT2iSGLT2i11 0.8-1.50.8-1.5DPP4iDPP4i11 0.5–1.50.5–1.5GIGI 0.5–1.00.5–1.0Bromocriptine IRBromocriptine IR22 0.6-0.90.6-0.9AmylinAmylin22 0.4-0.70.4-0.7ColesevelamColesevelam22 0.3-0.50.3-0.5

*Not head to head. Baselines and background therapies differ. Information derived from multiple studies.

BIGUANIDESBIGUANIDES

MetforminMetformin• Weight neutralWeight neutral• Low costLow cost• GI side effects common (~30%/5%)GI side effects common (~30%/5%)

– Slow titration and administration with Slow titration and administration with mealsmeals

– Consider extended releaseConsider extended release• Vitamin B12 malabsorptionVitamin B12 malabsorption• Cardioprotective?Cardioprotective?

Updated Guidelines For Use in CKD Updated Guidelines For Use in CKD PatientsPatients

• Contraindicated eGFR < 30Contraindicated eGFR < 30• Starting with eGFR 30-45 is not recommendedStarting with eGFR 30-45 is not recommended• Obtain eGFR at least annuallyObtain eGFR at least annually

– More often if at risk to develop of renal impairmentMore often if at risk to develop of renal impairment• If eGFR later falls below 45 assess risks vs benefits If eGFR later falls below 45 assess risks vs benefits • Discontinue if eGFR later falls below 30Discontinue if eGFR later falls below 30• The National Kidney Foundation recommends using The National Kidney Foundation recommends using

the CKD-EPI Creatinine Equation to estimate GFRthe CKD-EPI Creatinine Equation to estimate GFR

Metformin and Iodinated Metformin and Iodinated ContrastContrast• Discontinue at the time of or before an Discontinue at the time of or before an

iodinated contrast imaging procedure if iodinated contrast imaging procedure if eGFR between 30 and 60; in patients with a eGFR between 30 and 60; in patients with a history of liver disease, alcoholism, or heart history of liver disease, alcoholism, or heart failure; or in patients who will be failure; or in patients who will be administered intra-arterial iodinated administered intra-arterial iodinated contrast contrast

• Re-evaluate eGFR 48 hours after procedure; Re-evaluate eGFR 48 hours after procedure; restart metformin if renal function is stablerestart metformin if renal function is stable

SULFONYLUREASSULFONYLUREAS

SulfonylureasSulfonylureas• 11st st GenerationGeneration

– Chlorpropamide, tolazamide, acetohexamide or Chlorpropamide, tolazamide, acetohexamide or tolbutamidetolbutamide

• 22ndnd Generation Generation– Glyburide, glipizide or glimepirideGlyburide, glipizide or glimepiride

• Can target fasting Can target fasting hyperglycemia/postprandialhyperglycemia/postprandial– Enhance insulin secretionEnhance insulin secretion

SulfonylureasSulfonylureas• Secondary failure rate Secondary failure rate • HypoglycemiaHypoglycemia

– ElderlyElderly– Impaired renal functionImpaired renal function– Irregular meal scheduleIrregular meal schedule

• Weight gainWeight gain• Low costLow cost• Increase cardiovascular events?Increase cardiovascular events?

THIAZOLIDINEDIONESTHIAZOLIDINEDIONES

ThiazolidinedionesThiazolidinediones• Directly reduce insulin resistanceDirectly reduce insulin resistance

– Targets fasting and postprandial hyperglycemiaTargets fasting and postprandial hyperglycemia

• No hypoglycemiaNo hypoglycemia• No renal metabolism No renal metabolism • Indirect markers of CVDIndirect markers of CVD• -cell preservation-cell preservation

ThiazolidinedionesThiazolidinediones• Weight gainWeight gain• Edema Edema • AnemiaAnemia• Bone fractures Bone fractures • Bladder cancerBladder cancer• Cardiovascular affects Cardiovascular affects

MEGLITINIDESMEGLITINIDES

Repaglinide and NateglinideRepaglinide and Nateglinide• Targets postprandial hyperglycemiaTargets postprandial hyperglycemia

– Stimulates insulin secretionStimulates insulin secretion– Rapid onset; short actingRapid onset; short acting

• No dose adjustment in renal insufficiencyNo dose adjustment in renal insufficiency• Less hypoglycemia than sulfonylureasLess hypoglycemia than sulfonylureas• No sulfa moiety No sulfa moiety

-GLUCOSIDASE INHIBITORS-GLUCOSIDASE INHIBITORS

Acarbose and MiglitolAcarbose and Miglitol• Target postprandial hyperglycemiaTarget postprandial hyperglycemia• Inhibit saccharidases of small intestineInhibit saccharidases of small intestine

– Delay glucose entry into the circulationDelay glucose entry into the circulation• Flatulence (80%), diarrhea (27%), n/v (8%)Flatulence (80%), diarrhea (27%), n/v (8%)• No hypoglycemia or weight gainNo hypoglycemia or weight gain

– Treatment of hypoglycemia in combination Treatment of hypoglycemia in combination treated patients may be affected. Use treated patients may be affected. Use simple sugarssimple sugars

DIPEPTIDYL PEPTIDASE-4 DIPEPTIDYL PEPTIDASE-4 INHIBITORSINHIBITORS

GLP-1 and GIP Are Degraded GLP-1 and GIP Are Degraded by the DPP-4 Enzymeby the DPP-4 Enzyme

Intestinal Intestinal GLP-1 and GLP-1 and GIP releaseGIP release

DPP-4DPP-4enzymeenzyme

Active GLP-1 Active GLP-1 and GIPand GIP

Inactive Inactive metabolitesmetabolitesRapid inactivationRapid inactivation

MealMeal

xx

DPP4 InhibitorsDPP4 Inhibitors• No significant hypoglycemia or weight No significant hypoglycemia or weight

gaingain• Most common ADRs: URI, Most common ADRs: URI,

nasopharyngitis, headache nasopharyngitis, headache • No head-to-head trialsNo head-to-head trials• No clear concern regarding CV No clear concern regarding CV

outcomes/outcomes/CHF (saxagliptin)CHF (saxagliptin)• Can be used in CKD/ESRDCan be used in CKD/ESRD

DPP4 InhibitorsDPP4 Inhibitors• Pancreatitis reports, although no causal Pancreatitis reports, although no causal

relationship has been establishedrelationship has been established– ““FDA has not concluded these drugs may FDA has not concluded these drugs may

cause or contribute to the development of cause or contribute to the development of pancreatic cancer.” pancreatic cancer.”

• Extensive review by FDA (>80,000 Extensive review by FDA (>80,000 patients) has not uncovered reliable patients) has not uncovered reliable evidence of increased pancreatic risk evidence of increased pancreatic risk with incretins vs other agents.with incretins vs other agents.

Sodium-glucose co-transporter 2 Sodium-glucose co-transporter 2 (SGLT-2) inhibitor(SGLT-2) inhibitor

Glucose RegulationGlucose Regulation

SGLT-2 InhibitorsSGLT-2 Inhibitors

Valentine V. Clin Diabetes 2015;33:5-13.

SGLT-2 InhibitorsSGLT-2 Inhibitors• Mechanism is not insulin-dependentMechanism is not insulin-dependent• Reduction of weight and BPReduction of weight and BP• Increased genital mycotic infectionsIncreased genital mycotic infections• Cannot be used with reduced eGFRCannot be used with reduced eGFR • Hyperkalemia, renal insufficiency, Hyperkalemia, renal insufficiency,

hypotension and LDL elevation hypotension and LDL elevation

SGLT-2 InhibitorsSGLT-2 Inhibitors• Euglycemic diabetic ketoacidosisEuglycemic diabetic ketoacidosis• Bladder cancer incidence higher with Bladder cancer incidence higher with

dapagliflozin dapagliflozin • Amputations higher with canagliflozinAmputations higher with canagliflozin• Non significant incidence of bone fxNon significant incidence of bone fx• CV benefits with empagliflozin in CV benefits with empagliflozin in

patients with established CV diseasepatients with established CV disease

Centrally Acting Dopamine AgonistCentrally Acting Dopamine Agonist

Bromocriptine IRBromocriptine IR• Increases CNS dopaminergic activityIncreases CNS dopaminergic activity

– Diabetes patients may have low morning levels of Diabetes patients may have low morning levels of hypothalamic dopamine, which is thought to lead to hypothalamic dopamine, which is thought to lead to hyperglycemia and dyslipidemiahyperglycemia and dyslipidemia

• PPG reductions, without increasing PPG reductions, without increasing plasma insulin concentrationsplasma insulin concentrations– Not prone to hypoglycemia or weight gainNot prone to hypoglycemia or weight gain

• Side effects-nausea, dizziness, fatigue, HA Side effects-nausea, dizziness, fatigue, HA

Bile Acid SequestrantBile Acid Sequestrant

ColesevelamColesevelam• Lowers LDL cholesterol Lowers LDL cholesterol • Mechanism to improve glycemic Mechanism to improve glycemic

control is uncertaincontrol is uncertain– May act in the gastrointestinal tract to May act in the gastrointestinal tract to

reduce glucose absorptionreduce glucose absorption• Side effects constipation, nausea, Side effects constipation, nausea,

dyspepsia and increase TG ~20% dyspepsia and increase TG ~20%

Incretins and AmylinomimeticIncretins and Amylinomimetic

PostprandialPostprandialGlucagonGlucagon

PancreasPancreas

InsulinInsulin

Multihormonal Regulation of Multihormonal Regulation of Glucose:Glucose:Insulin, Glucagon, GLP1 and Amylin Insulin, Glucagon, GLP1 and Amylin

Plasma GlucosePlasma Glucose

TissuesTissues

Rate ofRate ofglucoseglucose

appearanceappearance

Rate ofRate ofglucoseglucose

disappearancedisappearance

StomachStomach

BrainBrainFoodFoodIntakeIntake——

GastricGastricEmptyingEmptying

——LiverLiver

GLP-1GLP-1

GutGutAmylinAmylin

Edelman S et al. Diabetes Technol Ther 2002; 4:175-189.

Safety ConcernsSafety Concerns• Most common ADRs: nausea, vomiting, Most common ADRs: nausea, vomiting,

diarrhea, headache, injection site reactiondiarrhea, headache, injection site reaction• Renal impairmentRenal impairment• Severe gastrointestinal disease (gastroparesis)Severe gastrointestinal disease (gastroparesis)• Hypoglycemia risk increased when used with Hypoglycemia risk increased when used with

insulin or sulfonylureainsulin or sulfonylurea• Hypersensitivity reactionsHypersensitivity reactions

– angioedema, anaphylaxis, rash, pruritisangioedema, anaphylaxis, rash, pruritis• Acute pancreatitisAcute pancreatitis

GLP-1 Agonists and Thyroid GLP-1 Agonists and Thyroid CarcinomaCarcinoma• GLP-1 agonists except exenatide IR/lixisenatide GLP-1 agonists except exenatide IR/lixisenatide

have black box warning for thyroid carcinomahave black box warning for thyroid carcinoma• Contraindicated with a personal or family history Contraindicated with a personal or family history

of medullary thyroid cancer or multiple of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2endocrine neoplasia syndrome type 2

• Thyroid C-cell tumors observed in animal studiesThyroid C-cell tumors observed in animal studies• Cases of MTC in humans treated with liraglutide Cases of MTC in humans treated with liraglutide

have been reported in post marketing periodhave been reported in post marketing period

Incretins and Amylin:Incretins and Amylin:The Diabetes Treatment ContinuumThe Diabetes Treatment Continuum

Time - YearsTime - Years

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IGTIGTDiet +Diet +ExerciseExercise

OralsOrals InsulinsInsulins

BasalBasal

IncretinIncretinIndicationIndication

AmylinAmylinIndicationIndication

MealMealTimeTime

PramlintidePramlintide• Synthetic amylinSynthetic amylin• Inhibits post prandial glucagon secretionInhibits post prandial glucagon secretion• Slows gastric emptyingSlows gastric emptying• Promotes satietyPromotes satiety• Contraindicated with high A1c, Contraindicated with high A1c,

gastroparesis, hypoglycemia unawarenessgastroparesis, hypoglycemia unawareness• Dosed qAC tidDosed qAC tid• ADR: hypoglycemia, n/v, ha, dizziness ADR: hypoglycemia, n/v, ha, dizziness

Diabetes Care. 2016; 32(S1): S1-S112.

Key PointsKey Points• Glucose goals & therapies must be Glucose goals & therapies must be

individualized individualized • Diet, exercise & education = foundationDiet, exercise & education = foundation• Unless contraindicated, metformin 1Unless contraindicated, metformin 1stst-line -line

drugdrug• After metformin, data are limitedAfter metformin, data are limited

– Combination therapy with oral and/or injectables is Combination therapy with oral and/or injectables is reasonablereasonable

– Minimize side effects and address patient specific Minimize side effects and address patient specific characteristics characteristics

• Many patients will require insulin therapy Many patients will require insulin therapy

Update on diabetes treatment strategies 2017

Health & Medicine

Transcript of Update on diabetes treatment strategies 2017