INSULIN TREATMENT IN DIABETES

• Dr Ahsan Rauf Sheikh

• FCPS(Medicine)
 INDICATION OF INSULIN IN DIABETES

• All patients with type 1 within 24 hrs

• 50% of type 2 patients within 6 years of diagnosis
 INDICATIONS OF INSULIN IN TYPE 2 DM
• Failure of glycemic control with diet and oral hypoglycemics
• Hyperglycemia with polyuria nocturia and weight loss
• Failure to tolerate oral hypoglycemic agents
• Gestational diabetes
• Post MI diabetes control
• Diabetes control in patients on steroids
• Treatment of acute neuropathy in diabetics
 WHAT!?
Did you say
INSULIN?!

Barriers to
the Use of
Insulin
 PATIENT CONCERNS ABOUT INSULIN

• Fear of injections
• Worries that insulin could worsen diabetes
• Hypoglycemia
• Occupation
• Complexity of regimens
• Concerns about potential weight gain •
 DECREASING FEARS OF INSULIN

• In T2DM important to discuss possible progression to insulin soon after diagnosis

• Disussion to start insulin is sensitive
• The benefits of insulin must be discussed with the individual
• Patient’s clinical needs and preferences
• Combination of non insulin therapies and insulin.
• Lifestyle changes and diet
• Usually commenced on Metformin as monotherapy unless there is contraindication
or there are other management or clinical issues.
• If glycaemic control is not optimised then various options are given for consideration
Introduction of insulin recommended usually as third line treatment unless the
individual has osmotic symptoms
• Usual meal times
• Does the patient work shifts?
• Is travel involved in their daily work?
• • Do they drive a taxi or hold an HGV license? (consider driving restrictions)
• • Is the number of injections per day an issue?
• Are they at risk of hypoglycaemia?
• Will dexterity be a problem?
• Is weight an issue?
• Type 1 patients a basal bolus regimen is usually commenced in the majority of individuals.
• Begin with human NPH insulin injected at bed-time or twice daily Insuman Basal, Humulin N
or Insulatard
• Consider, long-acting insulin analogue such as Insulin Detemir, Insulin Glargine :
• this reduce the frequency of injections from twice to once daily, and recurrent symptomatic
hypoglycaemic episodes.
• Consider twice daily pre - mixed human insulin (particularly if HbA1c ≥ 9%
• pre-mixed include short-acting insulin analogues, if: A person prefers injecting insulin
immediately before a meal, Hypoglycaemia is a problem. Blood glucose rise markedly after
meals
• Rapid acting NovoRapid (Aspart) and Humalog (Lispro) and Apidra (Glulisine) injected
with food , or indeed, post prandial. Better at controlling post prandial glucose with less
need for snacks and have a lower risk of hypoglycaemia.

• Short acting The disadvantages are to be injected 20 - 30 minutes before a meal. Patients
may need to snack between meals and there is a risk of hypoglycaemia.

• Intermediate actingHumulin N , Insuman Basal and Human Insulatard addresses basal

hyperglycaemia. Intermediate- acting insulin has a longer life span than rapid or short-
acting insulin but is slower to reach a peak. Cloudy insulin always contai
• Long acting
• Intermediate acting insulin: A traditional
 Natural History of DM 2

Years from -10 -5 0 5 10 15

diagnosis Onset Diagnosis

Insulin resistance
Insulin secretion

Postprandial glucose
Fasting glucose
Microvascular complications
Macrovascular complications
Pre-diabetes Type 2 diabetes
Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789;
Nathan DM. N Engl J Med. 2002;347:1342-1349
BEGINNING INSULIN THERAPY

6-36
WHEN ORAL MEDICATIONS ARE NOT
ENOUGH
• Watch for the following signs
– Increasing BG levels
– Elevated A1C
– Unexplained weight loss
– Traces of ketonuria
– Poor energy level
– Sleep disturbances
– Polydipsia
• Next steps
– Make a decision to start insulin
– Offer patient encouragement, not blame

Remind the patient of disease progression…

 NATURAL HISTORY OF TYPE 2
DIABETES
Severity of Glucose Intolerance
NGT IGT Frank
Diabetes
Insulin
Resistance

Worsens
Insulin Secretion with Time
Postprandial Glucose

Normal Blood
Glucose
Risk of Microvascular Complications

Risk of Macrovascular Complications

Years to
Decades Typical Diagnosis of Diabetes
INITIATING INSULIN THERAPY IN TYPE 2
DIABETES
• Let blood glucose levels guide choice of insulins
– Select type(s) of insulin and timing of injection(s) based on pattern of
patient’s sugar (fasting, lunch, dinner, bedtime)
• Choose from currently available insulin preparations
– Rapid-acting (mealtime): lispro, aspart
– Short-acting (mealtime): regular insulin
– Intermediate-acting (background): NPH, lente
– Long-acting (background): ultralente, glargine
– Insulin mixtures
• Provide long-acting or intermediate-acting as basal
and rapid-acting as bolus
• Titrate every week

Goal: to approximate endogenous insulin secretion…

STARTING WITH BASAL INSULIN: ADVANTAGES

• 1 injection with no mixing

• Slow, safe, and simple titration
• Low dosage
• Limited weight gain
• Effective improvement in glycemic control

6-37
GLARGINE AT HS + ORAL AGENTS OR MEALTIME LISPRO
TZD lispro
Metformin Glargine
Glargine
Insulin Effect

Insulin Effect
B L S HS B B L S HS B

6-56
 STARTING WITH BASAL INSULIN
• Continue oral agent(s) at same dosage (eventually stop secretegogue)
• Add single, evening insulin dose (around 10 U)
• Glargine (bedtime or anytime?)
• NPH (bedtime)
• 70/30 (evening meal) or 75/25

• Adjust dose by fasting BG

• Increase insulin dose weekly as needed
• Increase 4 U if FBG >140 mg/dL
• Increase 2 U if FBG = 120 to 140 mg/dL
• Treat to target (usually <120 mg/dL)

6-59
ADVANCING BOLUS/ ADDING BOLUS INSULIN
• Indicated when FBG acceptable but
• HbA1c not at goal and/or
• Postprandial BG not at goal (<140mg/dl)
• Insulin options
• To Glargine, add mealtime Regular or Lispro
• To bedtime NPH, add morning NPH and
mealtime Regular or Lispro
• To suppertime 70/30 or 75/25, add morning 70/30 or 75/25
• Oral agent considerations
• Usually stop secretagogue (it is redundant to be on insulin and secretagogue)
• Continue metformin and TZD for additional glycemic and other benefits

6-60
CHANGING FROM OTHER REGIMENS TO
BASAL/BOLUS INSULIN
Total Daily Dose
(~70-75% of prior insulin regimen TDD)

~50% ~50%
Basal* Bolus*

Usually divided into 3 premeal

*Range: 40 to 60% doses
 AN EXAMPLE:

• Mr. M: 58 yo with history type 2 diabetes for 8 years

• In addition to oral meds, he is on 70/30 insulin: 30 u AM and 15 u PM
• Current Total Daily Dose = 45 u of 70/30
• However, he has been having difficulty with wide glycemic excursions

• After discussing his options in detail, he is willing to begin basal/bolus regimen:

• New TDD= 45 u x .75 = 33.75 = 34 u

• Basal = 17 u Lantus at bedtime
• Bolus = 17 u total / 3 = 5.6 u = 5 u Humalog with meals
 ANOTHER METHOD

• Same patient: Mr. M on 70/30 insulin: 30 u AM and 15 u PM

• Current Total Daily Dose = 45 u of 70/30

• Instead, some clinicians prefer to instead calculate the new basal/bolus doses independently of each other
• Current Basal= 0.70 x 45 u TDD = 31.5 u N
• Current Bolus= 0.30 x 45 u TDD = 13.5 u R

• Then, use 70 to 75% of prior NPH, but divide prior short acting into 3 premeal doses
• New Basal= 0.75 x 31.5 u N = 24 u Lantus
• New Bolus= 13.5 u R / 3 = 4.5 u (round up or down) premeal Humalog
 SO WHICH METHOD IS BEST?
• This is where the “Art of Medicine” comes in:

• If patient has been having difficulty with hypoglycemia, then

start any new insulin regimen with conservative doses

• If patient, on the other hand, has been having hyperglycemia,

then one can be more aggressive

Remember: every patient is an individual!

FINE TUNING OF BOLUS
DOSES
 BOLUS DOSE INSULIN
• Premeal boluses:
• Taken before meals
• Covers mealtime carbohydrate intake
• Prevents postprandial hyperglycemia

• Correction or supplementation boluses:

• Used to Correct and treat hyperglycemia
• May be given alone between meals for hyperglycemia
• May be given to supplement already scheduled insulin to cover
premeal hyperglycemia
 CALCULATION OF PREMEAL BOLUS DOSES

Methods

1. Estimate patient’s individual insulin-to carb ratio

2. Formula: 500 Rule

3. Weight based Method

* Bode et al: Diabetes Care 1994: 19: 324-7

DETERMINATION OF INSULIN TO CARB RATIO:
METHOD 1

EXAMPLE: Estimate 1 unit of insulin: 15 gm carb

Note: 1 unit: 15 gm is often a “safe” starting point

for most patients . . .
DETERMINATION OF INSULIN TO CARB RATIO:
METHOD 2

Use the 500 Rule:

Divide 500 by TDD= 1 unit insulin to ___ gm CHO as bolus

EXAMPLE: 500 ÷ 34 u= 15

Bolus ratio is 1 u insulin : 15 gm CHO

Determination of Insulin to Carb Ratio:
Method 3

Weight (lb) Insulin u: CHO gm *

100-109 1: 16
110-129 1: 15
130-139 1: 14
140-149 1: 13
150-169 1: 12
170-179 1: 11
180-189 1: 10
190-199 1: 9
200+ 1: 8

Weight Based Method

*Walsh, Pumping Insulin, 2nd ed.
PREMEAL INSULIN AND CARB
COUNTING
MACRONUTRIENT CONVERSION
TO BLOOD GLUCOSE
 CARBOHYDRATE COUNTING

Benefits
Allows for variation in appetite
and preferences

Increases variety of food

choices

Can be used to match insulin

bolus doses to food intake
 CARB COUNTING AND INSULIN
BOLUSING
Insulin-to-Carb Ratio

EXAMPLE: 1 unit insulin: 15

grams CHOSample Meal Sample Meal
1 c. orange juice 30 g 2 slices wheat bread 30 g
2 slices toast 30 g 2 oz. turkey breast
½ c. oatmeal 15 g Lettuce leaf, tomato slice
1 soft-cooked egg 1 tsp mayonnaise
1 tsp margarine 6-8 3-ring pretzels 15 g
Coffee & 1 T cream 2 small choc cookies 15 g
_____________________ Diet soda, 16 oz__________
Total CHO: 75 g Total CHO: 60 g
Insulin bolus: 5 units Insulin bolus: 4 units
 FINE TUNING: MEAL BOLUS DOSES

• Adjust bolus based on post-meal BGs

• Carbohydrate counting or pre-determined meal portion

• Individualize insulin to carbohydrate dose or insulin to

premeal dose
CORRECTION BOLUSES
FOR HYPERGLYCEMIA
 CORRECTION BOLUS INSULIN

• To be taken to correct for hyperglycemia

• Based on insulin sensitivity factor

• Goal is for correction bolus to lower blood glucose to within 30 to

50 mg/dl of target value
 INSULIN SENSITIVITY FACTOR

Use to  high blood glucose

1 unit of insulin will  blood glucose by: mg/dl

Regular: 1500 Rule

Humalog: 1800 Rule

1500 or 1800 divided by TDD= amount of blood glucose

lowered by 1 unit insulin
 INSULIN SENSITIVITY FACTOR
EXAMPLE
TDD is 34 units

1500 Rule: 1500 ÷ 34 = 44

1 unit of Regular  bg 44 mg/dl

1800 Rule: 1800 ÷ 34 = 53

1 unit of Humalog  bg 53 mg/dl
COMBINING CORRECTION AND PREMEAL
BOLUSES
If a patient’s insulin to carb ratio is 1:15gm and the insulin
correction factor is 1: 50 mg/dl and their premeal BG
goal is < 110 mg/dl…..

What dose of Humalog would you give premeal if their

actual premeal BG = 210 mg/dl and they are about to
eat a turkey sandwich (30 gms carbs)?
•210 mg/dl –110 mg/dl = 100/50 = 2 u for correction
•30 gms carbs/15 = 2 u for mealtime carb coverage

Premeal total insulin bolus dose = 4 u

A QUICK WORD ON USING
SLIDING SCALE INSULIN….

Don’t!
 INSTEAD OF SLIDING SCALE....
Think Supplementation or Correction Scale…

• Basal insulin is necessary even in the fasting state

• Sliding scales do not provide physiologic insulin needs
• Sliding scales often result in “chasing” of blood sugars
• There can be wide glycemic excursions
Remember: Just because a diabetic’s FBG is <150
does not mean that they need no insulin!
 THE SOLUTION:

• In acutely ill hospitalized diabetics: use continuous IV insulin

•If one must use an insulin scale in an outpatient or stable

inpatient setting:
• Insulin scale should only supplement a routine scheduled
regimen of basal and premeal insulin
•May use to correct for hyperglycemia between scheduled
doses of insulin
•It should NEVER be ordered such that the scale is the only
source of insulin for the patient
 The Future
of
Insulin Therapy

6-53
 THE FUTURE OF INSULIN
• Inhaled Insulin: Exubra, others

• Oral / Buccal Insulin: Oralin

• New basal insulin: Insulin Detemir

• New Rapid Acting Insulin Analogue

• Other: Closed Loop Systems (Artificial pancreas)

6-54
ORAL AGENTS + MEALTIME INHALED INSULIN: EFFECT ON
HBA1C

Oral Agents +
Oral Agents Alone Inhaled Insulin
10

2.3%
HbA1c (%)

8
*

5
Baseline Follow-up Baseline Follow-up
(0) (12) (0) (12)
Weeks
*P < .001
Weiss, et al. Diabetes. 1999;48(suppl 1):A12.

6-55
 SUMMARY: INSULIN THERAPY
• Replaces complete lack of insulin in type 1 diabetes

• Supplements progressive deficiency in type 2 diabetes

• Basal insulin added to oral agents can be used to start

• Full replacement requires basal-bolus regimen

• Hypoglycemia and weight gain are main medical risks

• New insulin analogues and injection devices facilitate use

INSULIN AND GLUCOSE PATTERNS: NORMAL AND TYPE
2 DIABETES

Normal
Type 2 Diabetes
Glucose Insulin
400 120
100
300
80

U/mL
mg/dL

200 60

40
100
20

0600 1000 1400 1800 2200 0200 0600 0600 1000 1400 1800 2200 0200 0600
B L S B L S
Time of Day Time of Day

Polonsky, et al. N Engl J Med. 1988;318:1231-1239.

6-17
 THE GOAL OF INSULIN THERAPY:
ATTEMPT TO MIMIC NORMAL PANCREATIC FUNCTION
B L S HS
160
140
PLASMA 120
GLUCOSE
100
m g/dl
80
60
75
60
PLASMA FREE 40
INSULIN
30
u/m l
15
0
330 1130 1530 1930 2330 0330 0730
HOURS
Schade, Skyler, Santiago, Rizza, “Intensive Insulin Therapy,” 1993, p. 131.
RAPID-ACTING INSULIN ANALOGUES: LISPRO AND ASPART

400 500 Aspart

Lispro 450
350
Plasma Insulin (pmol/L)

Plasma Insulin (pmol/L)

400
300 350
250 300
200 250
Regular 200
150 Human
150
100 Regular
100 Human
50 50
0 0
0 30 60 90 120 150 180 210 240 0 50 100 150 200 250 300
Time (min) Time (min)
Meal Meal
SC injection SC injection

Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care.

1999;22:1501-1506.

6-28
COMPARISON OF HUMAN INSULINS AND ANALOGUES
Insulin Onset of Duration of
Preparations Action Peak Action
Lispro/Aspart 5-15 minutes 1-2 hours 3-5 hours
Human
Regular 30-60 minutes 2-4 hours 4-8 hours
Human
NPH/Lente 1-4 hours 4-12 hours 10-20 hours
Human
Ultralente 6-8 hours Unpredictable 16-20 hours
Glargine 2-3 hours Flat ~24 hours

The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because
of this variation, time periods indicated here should be considered general guidelines only.

6-
 IMPACT OF DIABETES MELLITUS

Diabetes

The leading The leading A 2- to 4- The leading

cause of cause of fold cause of
nontraumatic new cases increase in new cases
lower of end cardio- of blindness
extremity stage renal vascular in working-
amputations disease mortality aged adults
www.hypertensiononline.org
 INSULIN SENSITIVITY IN GLUCOSE CLAMP STUDIES:
IMPROVED BY INSULIN TREATMENT

Baseline
After Insulin
100
87
% of Matched Control Values 80
80
67
Glucose Disposal

60 57
53
40
40

20

0
Scarlett Andrews Garvey

Scarlett, et al. Diabetes Care. 1982;5:353-363; Andrews, et al. Diabetes. 1984;33:634-642; Garvey, et al. Diabetes.
1985;34:222-234.

6-9
REASSURANCE ABOUT COMMON CONCERNS
Insulin Therapy in Type 2 DM

• Improves Insulin Sensitivity by Reducing Glucotoxicity

• Reduces Cardiovascular Risk

• Causes Modest Weight Gain

• Rarely Causes Severe Hypoglycemia

• Patients fears and concerns can be addressed by education

6-15
TWICE-DAILY SPLIT-MIXED REGIMENS
Regular
NPH

Insulin Effect

B L S HS B

6-23
 MULTIPLE DAILY INJECTIONS (MDI)
NPH + REGULAR

NPH at AM and HS + Regular AC NPH at HS + Regular AC

Regular Regular
NPH NPH
Insulin Effect

Insulin Effect
B L S HS B B L S HS B

6-24
 THE BASAL/BOLUS INSULIN CONCEPT
• Basal Insulin
• Suppresses glucose production between meals and overnight
• Nearly constant levels
• 50% of daily needs
• Bolus Insulin (Mealtime or Prandial)
• Limits hyperglycemia after meals
• Immediate rise and sharp peak at 1 hour
• 10% to 20% of total daily insulin requirement at each meal

Ideally, for insulin replacement therapy, each

component should come from a different
insulin with a specific profile
6-
LIMITATIONS OF HUMAN REGULAR INSULIN
• Slow onset of action

• Requires inconvenient administration: 20 to 40 minutes prior

to meal
• Risk of hypoglycemia if meal is further delayed
• Mismatch with postprandial hyperglycemic peak
• Long duration of activity

• Up to 12 hours’ duration
• Increased at higher dosages
• Potential for late postprandial hypoglycemia

6-26
RAPID-ACTING ANALOGUES: CLINICAL FEATURES
• Insulin profile more closely mimics normal physiology
• Convenient administration immediately prior to meals
• Faster onset of action
• Limit postprandial hyperglycemic peaks
• Shorter duration of activity
• Reduced late postprandial hypoglycemia
• But more frequent late postprandial hyperglycemia

• Need for basal insulin replacement revealed

6-27
 MULTIPLE DAILY INJECTIONS (MDI)
NPH + MEALTIME LISPRO
NPH at AM and HS + Lispro AC NPH at HS + Lispro AC
Lispro Lispro
NPH NPH
Insulin Effect

Insulin Effect
B L S HS B B L S HS B

6-29
LIMITATIONS OF HUMAN NPH, LENTE, AND ULTRALENTE
• Do not mimic basal insulin profile
• Variable absorption
• Pronounced peaks
• Less than 24-hour duration of action

• Cause unpredictable hypoglycemia

• Major factor limiting insulin adjustments
• More weight gain

6-30
THE QUEST FOR BASAL INSULIN REPLACEMENT
Mealtime Lispro + NPH and NPH at HS

Lispro
NPH
Insulin Effect

B L S HS B

Bolli, et al. Diabetologia. 1999; 42:1151-1167.

6-31
 THE IDEAL BASAL INSULIN . . .
• Mimics normal pancreatic basal insulin secretion
• Long-lasting effect around 24 hours
• Smooth, peakless profile
• Reproducible and predictable effects
• Reduced risk of nocturnal hypoglycemia
• Once-daily administration for convenience

6-32
 PROFILES OF VARIOUS BASAL INSULINS

SC insulin n = 20 T1DM
Mean ± SEM
4.0 24
NPH
20

µmol/kg/min
mg/kg/min
3.0 Ultralente
16

2.0 CSII 12

8
1.0
Glargine 4

0 0
0 4 8 12 16 20 24
Time (h)
SC=subcutaneous; CSII=continuous subcutaneous insulin infusion
Lepore M et al. Diabetes. 2000;49:2142-2148.
 LONG-ACTING INSULINS:
ULTRALENTE AND GLARGINE
Ultralente
• Injected once or twice daily
• Onset within 6–8 hours
• Peak effect within 10–20 hours

Glargine
• 24-hour, long-acting recombinant human insulin analogue
has no peak
• Cannot be diluted or mixed with other insulins or solutions
• Administered once daily
– In combination therapy, glargine given at bedtime; rapid- or
short-acting given during the day
GLARGINE VS NPH INSULIN IN TYPE 1 DIABETES
ACTION PROFILES BY GLUCOSE CLAMP

5
Glucose Utilization Rate
(mg/kg/h) 4 NPH
3

2
Glargine
1

0
0 10 20 30
Time (h) After SC Injection
End of observation period
Lepore, et al. Diabetes. 1999;48(suppl 1):A97.

6-34
BEDTIME GLARGINE VS NPH, WITH MEALTIME REGULAR

4 48
NPH Glargine

Patients (%)
3 ** 36
2 24
1 Baseline Baseline 12
8.5 ± 1 8.8 ± 1 11.1± 4 10.6± 4
0 0
1 * *
*
2
*
HbA1c FPG Nocturnal
(%) (mmol/L) Hypoglycemia

*P < .01 (change from baseline to endpoint within each group)

**P < .02 (compared to NPH)

Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100.

6-51
BEDTIME GLARGINE VS NPH, WITH MEALTIME
REGULAR

4 48
NPH Glargine

3 36

Patients (%)
Weight (kg)
**
2 24

1 12
*
0 0
Weight Gain Nocturnal
Hypoglycemia
*P < .0007
**P < .02 (compared to NPH)

Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100.

6-52
 INSULIN GLARGINE
SUMMARY OF COMPLETED TRIALS
• Glucose-insulin clamp studies of Glargine vs NPH
• Smooth, continuous release from injection site
• Longer duration of action with effect for about 24 hours
• Peakless profile

• Equivalent absorption rates at various injection sites

• Clinical efficacy equivalent to NPH, with significantly less nocturnal
hypoglycemia

6-35
 INTERMEDIATE-ACTING INSULIN

• Cloudy longer lifespan than short-acting insulin starts working within 2 - 4 hours
after injection, peaks between 4 and 8 hours and remains working for approximately
16 hours. Occasionally this insulin is given twice daily.
• ! Re-suspension is critical.
 LONG ACTING INSULIN GLARGINE
(LANTUS), DETEMIR (LEVEMIR)
• Starts working within 2 hours and provides
• · Reinforce advice on diet, lifestyle and adherence to drug treatment. ·
• Individualised HbA1c target. Measure HbA1c levels at 3/6 monthly intervals .
• Base choice of drug treatment on: effectiveness, safety (see MHRA guidance), tolerability,
the person’s individual clinical circumstances, preferences ,needs, and cost (if 2 drugs in
the same class are appropriate, choose the option with the lowest acquisition cost).
• Do not routinely offer self-monitoring of blood glucose levels unless the person is on
insulin, on oral medication that may increase their risk of hypoglycaemia while driving or
operating machinery, is pregnant or planning to become pregnant or if there is evidence
of hypoglycaemic episodes.
• Person hyperglycemic & symptomtic consider SU or Insulin
• Metformin tolerated A1c >6.5 :start metformin if lifestyle measures fail to bring A1c
to <6.5
• If A1c >7.5 add second agentSU or DPP IV or Pioglitazone or SGLT 2 inhibitors aim
A1c <7
• If A1c >7.5 add third agent or insulin based regimen
• If standard-release metformin is not tolerated, consider modified–release metformin
If triple therapy is not effective, not tolerated or contraindicated, consider
combination therapy with metformin, an SU and a GLP-1 agonist for adults with type 2
diabetes with BMI of 35 kg/m2 or higher and specific psychological or other medical
problems associated with obesity or - have a BMI lower than 35 kg/m2 but who
benefits from wt loss
• If metformin not tolerated and A1c >6.5 after lifestyle intervention start with DPP IV I
• Or SU or Pioglitazone . If SU and Pioglitazone not tolerated start with SGLT 2 inhibitors

• FIRST INTENSIFICATION If HbA1c rises to 58 mmol/mol (7.5%): · Consider dual therapye

with: - a DPP-4i and pioglitazonea - a DPP-4i and an SU - pioglitazonea and an SU · Support
the person to aim for an HbA1c level of 53 mmol/mol (7.0%)
• SECOND INTENSIFICATION If HbA1c rises to 58 mmol/mol (7.5%): · Consider insulin-
based treatment · Support the person to aim for an HbA1c level of 53 mmol/mol (7.0%)