Oral Hypoglycaemic Agents

Outline

1. What are the available OHG agents and how do they work?

2. Metformin – how much, and how safe?3. Can I still use TZDS (glitazones)?4. What is the place of acarbose?5. Suggested algorithm for initiating OHG6. My patient is on insulin, can I stop the orals?

Case 1

• Mike - 48 year old obese male, BMI 32• Routine annual check-up, fasting BGL 8.4 mmol/L,

otherwise asymptomatic.• Refer to diabetes educator and dietician,

commences diet and exercise program.• Home BGL monitoring, fasting BGL 6 - 9 mmol/L,

post-prandials up to 17 mmol/L• HbA1c 8.4%• What are your available treatment options?

Oral Hypoglycaemic Agents

• Biguanides (metformin)• Sulphonylureas (gliclazide, glimepiride, glipizide

glibenclamide)• Repaglinide• Thiazolidinediones (rosiglitazone, pioglitazone)• α-glucosidase inhibitors (acarbose)• DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin)

Metformin

• Decreases glucose output from liver

• Both fasting and postprandially

• Decreases GI absorption of glucose

• Increases peripheral insulin sensitivity

• Increases synthesis of GLP -1

Metformin

• Mild-mod weight loss• Improved lipids and fibrinolysis• As monotherapy, low risk of hypoglycaemia• Long term experience and safety• May reduce IHD and cancer

Metformin

• Used in combination with any of the other agents or insulin.

• Dosing bd or tds, or once daily long-acting.• Maximal dose 2.5g, little benefit over 2g.• Side-effects – metallic taste, nausea, bloating,

diarrhoea. • Start low dose and gradually increase, build up

tolerance to effects.

Case 2

• Mary, 75 y.o overweight female with Type 2 DM for 12 years

• Metformin 1g po bd• Gliclazide MR 120 mg po daily• HbA1c 7.3%• Known diabetic nephropathy with albuminuria.• Creatinine rising over years, now 140 mmol/L.

When to stop metformin?

• Metformin excreted by the kidneys• Renal failure may result in excess build up of

metformin.• Lactic acidosis is a rare complication• Clinically, can use cut-off of 130 mmol/L for men

and 120 mmol/L for women, or more accurately, creat clearance <60ml/min.

• Other predisposing factors – heart failure, liver disease, alcohol abuse, sepsis, decreased tissue perfusion or hypoxia.

When to stop metformin?

• Intravenous contrast

Low RiskNormal Renal Function

No increased risk of lactic acidosis post contrast

Multiple ComorbiditiesNormal Renal Function

Metformin witheld at the time of procedure for 48 hours.If no adverse events, no need to recheck creatinine before restarting

Known renal dysfunction

Metformin ceasedRestart only after renal function has returned to baseline.

Secretagogues

• Sulphonylureas– Stimulate the delayed second phase of insulin secretion– Major side-effect is late post-prandial hypoglycaemia– Risk is highest with long-acting sulphonylureas and in the

elderly– Often accompanied by weight gain, fluid retention,

especially if in combo with insulin/TZDs.– Most of beneficial effect occurs at submaximal doses. Eg

doubling dose of glicazide from 60 to 120mg has only minor increase in efficacy.

Secretagogues

• Repaglinide (Novonorm)– More rapid onset and shorter duration of action than

sulphonylureas– Less risk of late postprandial hypoglycaemia– Best administered before the meal– Only available on private script in Australia.

Thiazolidinediones

• PPAR-gamma agonists increase insulin sensitivity of muscle, fat, liver.

• Stimulate development of peripheral adipose tissue – shift bad fat and fatty acids into safe places.

• Improve both fasting and postprandial BGL.• Don’t cause hypoglycaemia on their own• Favourable lipid profile - decrease TG, increase HDL.

Thiazolidinediones

• Major side effect – fluid retention, weight gain, peripheral oedema

• Incidence of cardiac failure increased with both pioglitazone and rosiglitazone

• No increased mortality from heart failure.• Occurred in trials where subjects had no or minor

cardiac failure at baseline• Suggest caution with any significant form of CCF,

class III/IV NYHA is definite contraindication.

Thiazolidinediones

• 1.5 – 2.5 increase in fractures– Increased bone fat at expense of formation– Reductions in hip BMD, spine– Especially limb fractures – distal extremities.– Increased risk in postmenopausal women– Suggest BMD monitoring– No trials to show whether using bisphosphonates can

prevent these fractures.

Thiazolidinediones

• 2007, large but controversial meta-analysis suggested increased myocardial infarction (OR 1.43) with rosiglitazone.

• Supported by 1 other independent analysis.• Subsequent analyses didn’t show effect for

rosiglitazone or pioglitazone.• RECORD (prospective, open-label) study did not

confirm increase CV risk with Rosiglitazone.

Case 3

• John, 63 yo, overweight, Type 2 DM for 8 years• Currently well-controlled on

– Metformin 850mg bd– Pioglitazone 30mg daily

• Recent non-STEMI – aspirin, metoprolol 25mg bd• No episodes of CCF, normal myocardial contractility.

Thiazolidinediones

• ADS position statement on Rosiglitazone 2009

– Doctors should discuss study results with patients. OPTIONS

– 1. Continuation while awaiting further evidence in patients without heart failure.

– 2. Discontinuation AND maintenance of glycaemic control by• The use of alternative oral hypoglycaemic agents from

either the same or another class OR• The commencement or adjustment of insulin

Thiazolidinediones

• ADS position statement on Rosiglitazone

– While ADS do not consider the current evidence allows a definitive recommendation on the use of rosiglitazone except in the setting of known heart failure, it is prudent practice to advise alternative management if a patient has ongoing concern after discussion.

– PBS guidelines now do not allow for initiating new patients on Rosiglitazone as triple therapy.

– Pioglitazone still available.

Thiazolidinediones

• Rosiglitazone vs Pioglitazone

– No head to head randomised trials comparing the two– Pioglitazone has a more favourable lipid profile– Observational data reached different conclusions about

relative safety of rosiglitazone vs pioglitazone.

Thiazolidinediones

• Pioglitazone and bladder cancer– Possible increase in bladder cancer in patients on pioglitazone for >2

years. (US study)– Risk was 1.4 times that of diabetic patients not on it.– Preliminary results from French trial – increased risk if treatment for

>1 year.– Normal bladder cancer incidence – 2500 new cases in 2010, 75%

males.– Do not use in patients with bladder cancer or history of it.– Report any lower urinary tract symptoms.

Alpha-glucosidase Inhibitors

• Acarbose inhibits conversion of oligosaccharides to monosaccharides at the intestinal brush border.

• Decrease the postprandial rise in glucose after eating complex carbs.

• Also slight effect on fasting BGL.• Used alone or in combination

Alpha-glucosidase Inhibitors

• Especially if diet is high in carbs (>50%), good for Asian diet, moderate effect in Western diet.

• Side-effects – bloating, flatulence, diarrhoea• STOP-NIDDM: Reduces incident diabetes in pre-

diabetic states.

Case 1

• Mike - 48 year old obese male, BMI 32• Routine annual check-up, fasting BGL 8.4 mmol/L,

otherwise asymptomatic.• Refer to diabetes educator and dietician,

commences diet and exercise program.• Home BGL monitoring, fasting BGL 6 - 9 mmol/L,

post-prandials up to 17 mmol/L• HbA1c 8.4%• What are your available treatment options?

Treatment algorithm for Type 2

• AACE/ACE Algorithm for Glycaemic Control 2009• Not completely applicable to Australians due to PBS

guidelines.• Principles– Lifestyle modification along with diabetes education,

dietary advice, home BGL monitoring are the mainstay, can be initiated ALONG with medical therapy.

– Minimise risk and severity of hypoglycaemia– Minimise risk and magnitude of weight gain

Treatment algorithm for Type 2

• Principles– Use drugs that have complementary actions– Select therapy based on HbA1c stratification and known

HbA1c-lowering potential– Target HbA1c 6.5% early in the diagnosis– Use fasting and post-prandial BGL as endpoints– Long-term safety, efficacy and cost are other

considerations

Treatment algorithm for Type 2

• HbA1c 6.5-7.5%– May achieve target with monotherapy. – If not, progress to dual, then triple therapy.

• HbA1c 7.6 – 9%– Commence with dual therapy from start– Then progress to triple or insulin.

• HbA1c >9%– Commence triple therapy from start– Insulin +/- oral therapies

Treatment algorithm for Type 2

• Metformin is the mainstay of therapy for all diabetic patients.

• Safe, long-term efficacy and experience• Before 2008 in Australia under PBS

metformin + sulphonylurea + either glitazone

+ insulin metformin + glitazone sulphonylurea + glitazone

If intolerance to one or other

Treatment algorithm for Type 2

• 55-70% of pts who initially achieve target HbA1c with metformin monotherapy have progressive deterioration in next 2 – 3 years.

• Adding sulphonylurea to metformin is commonly used – effective, available, cheap.

• Effect of sulphonylurea may not be long term, control could deteriorate in as little as 6 months.

• Sulphonylurea have 4-5 times increased risk of hypoglycaemia compared to metformin alone, or metformin plus TZD.

Treatment algorithm for Type 2

• In 2011

Metformin

Sulphonylurea

Pioglitazone

InsulinGliptin

PioglitazoneExenatide

Where does Acarbose fit?

Treatment algorithm for Type 2

• Meta-analysis examining third-line agents• Equivalent reductions in HbA1c with TZDs,

Acarbose, Gliptins (ranging from mean of 0.7% to 1.08%)

Case 4 - Len

• Len 68 yo male, Type 2 DM 20 years– Metformin 1g bd– Gliclazide MR 120mg daily– Lantus 24 units nocte

• HbA1c 7.8%• Home BGL monitoring– Fasting BGL 5 – 8 mmol/L– Postprandial BGL up to 15 mmol/L

• Decision to switch to bd pre-mixed regime.

Use of OHG in patients on insulin

• Long-acting insulin is often added as third agent in patients on maximal oral hypoglycaemic therapy.

• Once patients commenced on basal-bolus or bd premixed insulin, little benefit of sulphonylurea.

• Continue metformin, complementary effect to insulin.

• Sulphonylureas may be having little effect, can be replaced with short-acting insulin.

Summary

• Lifestyle modification and pharmacotherapy can begin simultaneously.

• Metformin still the mainstay of oral hypoglycaemic therapy – safety, efficacy, durability of effect.

• Beware metformin use in renal impairment• Traditionally, sulphonylureas are 2nd line agent.• Consideration of newer agents with less

hypoglycaemia and weight gain.• Side-effect profile vs benefits of TZDS needs

clarification.