The criteria for the diagnosis of diabetes are now:

• HbA1c ≥6.5% (48 mmol/mol)
• Fasting glucose ≥7.0 mmol/L
• Random glucose ≥11.1 mmol/L
• On a 75 g oral glucose tolerance test: fasting glucose ≥7.0 mmol/L or 2 hr glucose ≥11.1 mmol/L

https://www.diabetessociety.com.au/guideline/hba1c-for-diagnosis-of-diabetes-mellitus-may-2023

In an asymptomatic patient the test should be repeated for confirmation of the result and diagnosis. An abnormal result on 2 different diagnostic tests is also acceptable

Treatment Algorithm Overview

https://www.diabetessociety.com.au/wp-content/uploads/2023/03/ADS_POSITION-STATEMENT_v2.4.pdf

All patients should receive education on lifestyle measures, including:

• Healthy diet
• Physical activity
• Weight management

Rationale for Treatment:

• Prompt management of symptoms related to hyperglycaemia is essential, including acute or chronic symptoms such as fatigue, polyuria, vision disturbances, muscle cramps, and urinary incontinence in cognitively impaired patients.
• In severe cases, hyperglycaemia can lead to coma, requiring emergency treatment.
• Insulin therapy is highly effective for rapid reduction of high blood glucose levels, especially in symptomatic hyperglycaemia.

HbA1c Target:

• Determine the individual’s HbA1c target, commonly ≤53 mmol/mol (7.0%).
• Regularly review the target based on individual circumstances.

Therapy Review Timeline:

• Review the effects of any changes in therapy within 3 months.

Algorithm for Suboptimal HbA1c:

• If HbA1c is not at target, proceed with the following steps:
  1. Review Current Therapies: Assess the current treatment regimen.
  2. Assess Medication Adherence: Evaluate how consistently the patient is taking their medications.
  3. Monitor for Side Effects: Check if any side effects from medications are impacting adherence or effectiveness.
  4. Consider Comorbidities: Exclude other comorbidities or therapies that may affect glycaemic control.
  5. Evaluate Patient Understanding: Ensure the patient understands their treatment plan and is capable of self-managing their condition.

First-Line Treatment:

1. Lifestyle Modification:
   • Diet and exercise are fundamental to managing type 2 diabetes and should be reinforced at all stages.
   • Focus on weight loss and prevention of weight gain.
   • Consider insulin early if blood glucose levels are very high or persistently high overnight.
2. Metformin:
   • Recommended as the first pharmacotherapeutic step in the absence of contraindications.
   • Effective and widely accepted as initial therapy.
3. Sulfonylureas:
   • Consider if metformin is contraindicated or not tolerated.
4. Other Medications:
   • Acarbose and insulin are available options, although not PBS-subsidised for initial monotherapy.
   • Other therapies exist but are not generally subsidised for use as first-line treatments.

Second-Line Treatment for Type 2 Diabetes

General Considerations:

• Second-line treatment is recommended when glycaemic control is not achieved with a single agent.
• Individualisation of therapy is crucial, considering factors like potency, weight effects, hypoglycaemia risk, comorbidities, patient preference, PBS subsidy, and cost.

Options for Second-Line Treatment:

1. Sulfonylureas:
   • Effective as second-line agents.
   • Provide similar HbA1c reduction as other second-line oral agents.
   • Cost-effective at approximately 25% of the daily cost of other second-line options.
2. DPP-4 Inhibitors:
   • Commonly used alternative second-line agents.
   • Available in combination with metformin, enhancing patient compliance.
   • Suitable for patients with problematic hypoglycaemia, weight gain, or other side effects associated with sulfonylureas.
3. SGLT2 Inhibitors:
   • PBS-subsidised for use with metformin or sulfonylurea.
   • Can be considered if control is not achieved with a DPP-4 inhibitor.
   • Beneficial in managing blood glucose and additional weight management benefits.
4. Acarbose:
   • Useful in managing post-prandial hyperglycaemia, particularly in obese patients.
   • A non-injectable option that can be trialled if injections are to be avoided.
5. Thiazolidinediones (TZDs):
   • Can be used in carefully selected insulin-resistant individuals.
   • Preferred in combination with metformin.
6. GLP-1 Receptor Agonists (GLP-1RA):
   • Highly effective in reducing blood glucose, facilitating weight and blood pressure reduction.
   • Can be used in combination with metformin or sulfonylurea.
   • No current data on combination use with DPP-4 or SGLT2 inhibitors.
7. Insulin:
   • Considered for patients with HbA1c > 75 mmol/mol (9.0%) on oral therapy.
   • Provides robust glycaemic control and should not be delayed if needed.

Key Points for Second-Line Choice:

• Selection Criteria: Weigh factors such as side effect profile, patient’s weight concerns, hypoglycaemia risk, comorbidities, and patient acceptance of injection therapy.
• Cost and Subsidy Considerations: Ensure therapy is feasible for the patient within the PBS framework, with private costs evaluated when necessary.

Third-Line Treatment for Type 2 Diabetes

General Considerations:

• Third-line treatment is considered when dual oral therapy fails.
• Metformin should be continued for its insulin-sensitising effects unless contraindications arise.
• Ineffective therapies should be discontinued and replaced.
• Options include triple oral therapy or the addition of injectable GLP-1 receptor agonists (GLP-1RA) or insulin.
• Comparative evidence from RCTs for guiding treatment is limited.

Triple Oral Therapy Options:

1. Metformin, Sulfonylurea, and DPP-4 Inhibitors:
   • Adding sitagliptin or linagliptin to metformin and sulfonylurea can reduce HbA1c by 7-10 mmol/mol (0.6-0.9%).
   • Associated with slight weight gain (0.4-0.8 kg).
   • Increased hypoglycaemia rate (approx. 10%), though mostly non-severe.
   • PBS-subsidised in Australia.
2. Metformin, Sulfonylurea, and Thiazolidinediones (TZDs):
   • Reduces HbA1c by approximately 11 mmol/mol (1.0%).
   • Associated with significant weight gain (3-5 kg) and higher hypoglycaemia rates (>20% in some studies).
   • Consider lowering the sulfonylurea dose initially, with potential up-titration.
   • Only pioglitazone is PBS-subsidised for this combination.
3. Metformin, Sulfonylurea, and SGLT2 Inhibitors:
   • Effective for glycaemic control improvement.
   • Canagliflozin or dapagliflozin added to metformin and sulfonylurea reduces HbA1c by 11 mmol/mol (1.0%).
   • Greater reduction in blood glucose, weight, and systolic BP compared to DPP-4 inhibitors.
   • Similar adverse event rates with high hypoglycaemia rates.
   • PBS-subsidised for dapagliflozin or empagliflozin combinations.
4. Metformin, Sulfonylurea, and Acarbose:
   • Acarbose is approved for use in triple therapy with metformin and sulfonylurea.
   • Reduces HbA1c by 15 mmol/mol (1.4%) and may decrease weight by 1.9 kg.
   • Commonly decreases HbA1c by 6-9 mmol/mol (0.5-0.9%) in other studies.

Additional Considerations:

• Injectable options such as GLP-1RAs or insulin should be considered if triple oral therapy does not achieve target glycaemic control.
• Self-Monitoring of Blood Glucose: Tailor to individual needs, especially for those on complex oral or injectable therapies.

Parenteral Therapy for Type 2 Diabetes

Options for Parenteral Therapy:

1. Metformin, Sulfonylurea, and GLP-1 Receptor Agonists (GLP-1RA):
   • Triple therapy with metformin, sulfonylurea, and GLP-1RA is effective in patients with poor glycaemic control despite maximal dual oral therapy.
   • Average HbA1c reduction: 11 mmol/mol (1.0%).
   • Associated with weight loss of 1-2 kg over 6-12 months.
   • To reduce hypoglycaemia risk, sulfonylurea dose should be initially reduced with gradual up-titration if needed.
   • GLP-1RA agents available in Australia have TGA approval for use with metformin and sulfonylurea; however, only exenatide is PBS-subsidised.
2. Insulin Therapy:
   • Insulin can be introduced at any stage but is generally reserved for when other treatments fail to achieve glycaemic targets.
   • Commonly initiated as once-daily basal insulin in combination with oral agents, particularly metformin.
   • Alternatively, premixed insulin (once- or twice-daily) can be used, often alongside metformin.
   • Insulin therapy can be intensified by increasing injection frequency, combining long-acting insulin with short-acting insulin, or using continuous subcutaneous insulin infusion (rarely used in type 2 diabetes).
   • Recent studies show beneficial effects when insulin is combined with DPP-4 inhibitors, SGLT2 inhibitors, or GLP-1RA:
     • DPP-4 Inhibitors: Linagliptin and sitagliptin are PBS-subsidised for use with insulin.
     • SGLT2 Inhibitors: Dapagliflozin and empagliflozin are PBS-subsidised for use with insulin.
     • GLP-1RA: Only exenatide is PBS-subsidised for use with insulin.

Key Considerations for Insulin Therapy:

• Self-Monitoring of Blood Glucose: Essential for safe insulin titration and minimising hypoglycaemia risk.
• Individualisation of Therapy: Adjust insulin regimen according to patient response, comorbidities, and treatment goals.

Glucose-Lowering Therapy in the Setting of Renal or Liver Impairment

Considerations in Chronic Kidney Disease (CKD):

• Metabolic and pharmacokinetic changes occur with renal impairment, particularly in CKD stages 4 and 5, increasing the risk of hypoglycaemia and drug-related side effects.
• Changes include:
  • Reduced renal gluconeogenesis.
  • Increased insulin resistance with elevated counter-regulatory hormones.
  • Reduced insulin degradation and clearance.
  • Altered lipid metabolism, electrolyte abnormalities, acidosis, and uraemic toxins.
• Drug adjustments may be necessary:
  • Sulfonylureas: Glipizide and gliclazide can be used at reduced doses up to CKD stage 4.
  • DPP-4 Inhibitors: Linagliptin can be used without dose adjustment in dialysis patients.
  • Insulin: Consider if glycaemic targets are unmet with oral agents.
• Close monitoring of drug efficacy, side effects, and interactions is essential.

Considerations in Liver Disease:

• Metabolic and pharmacokinetic changes affect drug prescribing decisions in hepatic impairment.
• Most drugs do not need to be discontinued in mild to moderate hepatic impairment, including:
  • Metformin, Sulfonylureas, Acarbose, DPP-4 Inhibitors, TZDs, and Insulin.
• Important considerations:
  • Adjust dosing and monitor for potential adverse effects such as lactic acidosis and hypoglycaemia.
  • Drug-specific liver toxicity risks should also be taken into account.
• Limited clinical experience exists with newer glucose-lowering agents in advanced hepatic impairment.
• Regular monitoring for hypoglycaemia and adverse effects is critical.

Glucose-Lowering Therapy in the Elderly

Key Considerations:

• Glycaemic targets should be individualised, taking into account life expectancy and frailty.
  • Symptom control or less stringent targets (e.g., HbA1c ≤ 64 mmol/mol or 8.0%) may be appropriate.
• Estimation of renal function using eGFR is crucial as serum creatinine may not reliably indicate renal status.
• Cardiac Dysfunction:
  • Significant cardiac dysfunction, including severe congestive heart failure, is more common and is a contraindication to metformin.
• Polypharmacy:
  • Minimise use of multiple medications, regularly review drug regimens.
  • Use the lowest effective doses to achieve safe glycaemic targets.
• Avoid Hypoglycaemia:
  • Prioritise agents and dosages that reduce hypoglycaemia risk.

MEDICATIONS

Metformin

• Indications:
  • Preferred first-line therapy for overweight individuals with Type 2 Diabetes Mellitus (T2DM).
  • Recommended for improving glycemic control and reducing cardiovascular risk.
• Efficacy:
  • Lowers HbA1c by 15-22 mmol/mol (1.5-2.0%).
• Benefits:
  • Safety: Long-term safety data (>50 years
  • Cardiovascular Outcomes: Reduces risk of myocardial infarction and improves overall cardiovascular outcomes in T2DM.
  • Weight Neutral
  • Hypoglycemia: Low risk when used alone, as it does not directly increase insulin secretion.
• Mechanism of Action:
  • Reduces Hepatic Glucose Production: Inhibits gluconeogenesis in the liver, decreasing overall glucose output.
  • Improves Insulin Sensitivity: Increases peripheral glucose uptake and utilization, particularly in muscles.
  • Modest Reduction in Intestinal Glucose Absorption: Slightly reduces the absorption of glucose from the gastrointestinal tract.
• Side Effects:
  • Gastrointestinal Symptoms: Common, including nausea, vomiting, anorexia, diarrhea, and abdominal cramps. Often dose-dependent and can be minimized by gradual dose titration.
  • Lactic Acidosis: A rare but serious complication, especially in patients with renal impairment, liver disease, or conditions associated with hypoxia. Requires discontinuation 48 hours before surgery or radiographic studies with contrast dye to prevent this risk.

Sulfonylureas

• Action: Stimulate insulin release in a glucose-independent manner.
• Efficacy: Lowers HbA1c by 7-16 mmol/mol (0.6-1.5%) when combined with metformin.
• Safety: Good long-term safety, but risk of hypoglycemia and weight gain.
• Studies: UKPDS and ADVANCE trials report cardiovascular safety and reduced microvascular complications.

Here is a table summarizing the sulfonylureas available in Australia, their doses, and usage:

Medication	Brand Name	Available Doses	Starting Dose	Usual Maintenance Dose	Maximum Dose
Glimepiride	Amaryl	1 mg, 2 mg, 3 mg, 4 mg	1 mg once daily	1–4 mg once daily	8 mg daily
Gliclazide (Immediate-release)	Diamicron	80 mg	40–80 mg once or twice daily	40–320 mg daily in divided doses	320 mg daily
Gliclazide (Modified-release)	Diamicron MR	30 mg, 60 mg, 120 mg	30 mg once daily	30–120 mg once daily	120 mg daily
Glipizide	Minidiab	2.5 mg, 5 mg	2.5–5 mg once daily	2.5–20 mg daily in single or divided doses	40 mg daily
Glibenclamide (Glyburide)	Daonil	2.5 mg, 5 mg	2.5–5 mg daily	2.5–15 mg daily in divided doses	20 mg daily

GLP-1 Agonists and DPP-4 Inhibitors

GLP-1 (Glucagon-like Peptide-1) is an incretin hormone, also known as a gut hormone, that is released from intestinal cells in response to nutrient intake, especially glucose.

In individuals with type 2 diabetes (T2D), levels of endogenous GLP-1 are reduced, leading to several metabolic issues:

• Increased gastric emptying, which can affect blood glucose levels.
• Reduced glucagon suppression, resulting in increased gluconeogenesis in the liver.
• Impaired glucose-mediated insulin secretion, affecting overall glucose control.
• Decreased satiety, causing patients to feel hungry more often and struggle with feeling full after meals.

To address this deficiency, there are currently two main strategies to enhance GLP-1 levels:

1. DPP-4 Inhibitors: These medications prevent the breakdown of endogenous GLP-1, increasing its levels naturally.
2. GLP-1 Receptor Agonists: These provide a direct, exogenous source of GLP-1, boosting its effects significantly.

Safety: General cardiovascular safety, except increased heart failure risk with saxagliptin (SAVOR-TIMI trial).

DPP-4 Inhibitors (e.g., Sitagliptin, Saxagliptin, Vildagliptin, Linagliptin )

• Mechanism of Action:
  • Inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), which degrades endogenous GLP-1, thus prolonging the action of GLP-1.
  • Helps increase postprandial insulin secretion and decrease glucagon levels.
• Efficacy:
  • Lowers HbA1c by 7-11 mmol/mol (0.6-0.7%).
• Side Effects:
  • Generally well tolerated.
  • Common: Nasopharyngitis, headache, upper respiratory infections.
  • Weight-neutral, making it suitable for overweight and obese patients with T2DM.
• Glucose Control:
  • Primarily targets postprandial glucose levels with moderate reductions in HbA1c (typically around 0.5-0.8%).
• Cardiovascular Effects:
  • Low risk of hypoglycemia when used alone or with other non-secretagogue medications.
  • Some studies suggest beneficial effects on systolic blood pressure and triglyceride levels.

GLP-1 Receptor Agonists ( eg: Exenatide (Byetta), Liraglutide (Victoza), Dulaglutide (Trulicity), Semaglutide (Ozempic))

• Mechanism of Action:
  • Mimic the action of GLP-1 by binding to the GLP-1 receptor, enhancing insulin secretion, reducing glucagon, slowing gastric emptying, and increasing satiety at supraphysiological levels.
• Side Effects:
  • Common: Nausea, vomiting, especially with higher doses or rapid titration.
  • Gastrointestinal symptoms often improve over time or with slow titration of doses.
  • Weight loss commonly observed, beneficial for overweight or obese patients.
• Glucose Control:
  • Efficacy: Superior glycemic control compared to oral agents
  • Targets both fasting and postprandial plasma glucose, leading to a more significant reduction in HbA1c (often >1%).
• Cardiovascular Effects:
  • Studies have shown benefits in reducing cardiovascular events, including heart attacks and strokes.

Oral GLP-1

• Semaglutide (Brand name: Rybelsus)
  • Available in 3 mg, 7 mg, and 14 mg tablets.
  • Starting dose is 3 mg once daily for 30 days, followed by 7 mg once daily.
  • If additional glycemic control is required, it can be increased to 14 mg once daily.

Injectable GLP-1 receptor agonists

provide an external source of GLP-1 at much higher levels than naturally occurring hormone levels, enhancing its effects. These medications:

• Deliver GLP-1 in supraphysiologic concentrations, significantly higher than the body’s endogenous levels.
• Slow gastric emptying and increase feelings of fullness, which can help with appetite control.
• Common side effects include nausea and sometimes vomiting, especially if patients do not adjust their food intake appropriately. These side effects can be minimized by gradually increasing the dose from the initial to the therapeutic level.
• Often promote weight loss, which is an added benefit for many patients with type 2 diabetes.

Under PBS

1. Exenatide (Byetta®, Bydureon®):
   • Forms: Byetta (twice daily injection), Bydureon (once weekly injection).
   • Indication: For adults with T2DM as an adjunct to diet and exercise, particularly for patients with inadequate control on metformin, sulfonylurea, or both.
2. Liraglutide (Victoza®):
   • Forms: Once-daily injection.
   • Indication: For adults with T2DM, used as monotherapy when metformin is inappropriate or in combination with other oral antidiabetics or basal insulin.
3. Dulaglutide (Trulicity®):
   • Forms: Once-weekly injection.
   • Indication: For adults with T2DM as monotherapy when metformin is not tolerated or in combination with other glucose-lowering therapies.
4. Semaglutide (Ozempic®):
   • Forms: Once-weekly injection.
   • Indication: For adults with T2DM as monotherapy or in combination with other antidiabetic agents when other drugs are insufficient.

Privately (Non-PBS)

1. Semaglutide (Wegovy®):
   • Forms: Higher dose formulation than Ozempic®, specifically designed for weight management in overweight or obese individuals.
   • Indication: Approved for weight management but not listed under PBS; available privately.
2. Liraglutide (Saxenda®):
   • Forms: Once-daily injection.
   • Indication: Specifically for weight management in patients with obesity or overweight with weight-related comorbidities; not listed under PBS for diabetes.

SGLT2 Inhibitors (e.g., Dapagliflozin, Empagliflozin, Ertugliflozin)

• Mechanism of Action:
  • Inhibit sodium-glucose co-transporter 2 (SGLT2) in the proximal renal tubules, reducing glucose reabsorption and promoting glucose excretion (glycosuria).
  • Lowers plasma glucose independently of insulin, making it effective at various stages of diabetes.
• Efficacy:
  • Reduces HbA1c by 0.5% to 1.5%.
  • Promotes weight loss (average weight reduction of 2-3 kg).
  • Low incidence of hypoglycemia, as the action is independent of insulin.
  • Efficacy is Diminished with renal impairment.
• Side Effects:
  • Increased risk of
    • genital infections (3-13%) and
    • urinary tract infections (1-12.9%).
  • Potential for increased hematocrit and decreased blood pressure, requiring careful patient selection and monitoring.
  • Generally well tolerated, but close monitoring is needed, especially in patients prone to dehydration or hypotension.
• Special Considerations in CKD:
  • Studies have shown a significant reduction in the risk of kidney disease progression, acute kidney injury, and cardiovascular death or hospitalization for heart failure in CKD patients, particularly those with diabetes.
  • a review (13 trials; n=90,409; 82.7% with diabetes) found SGLT2 inhibitors reduced risk of kidney disease progression (RR 0.63; 95% CI 0.58-0.69), acute kidney injury (0.77, 0.70-0.84) and cardiovascular death or hospitalisation for heart failure (0.77, 0.74-0.81) vs placebo (3) 
• Cardiovascular Benefits:
  • Significant reduction in cardiovascular events, particularly heart failure hospitalizations and cardiovascular death, making it a valuable option in patients with T2DM and high cardiovascular risk.

Class			HbA1c reduction	Benefits	Adverse effects	Contraindications /Precautions
Biguanides – 🡫 hepatic glucose output – 🡫 insulin resistance	Active ingredients	Brand name(s)a	1-2%		GIT symptoms (N/V, anorexia, diar, abdo cramps) Lactic Acidosis (cease 48hrs before surgery or contrast radiography)	Avoid if eGFR<30. Caution if eGFR<45, or variable and therefore at risk of decompensation. Advise all patients to stop metformin temporarily if vomiting/diarrhoea, or other risk of acute renal impairment
	Metformin	Diaformin Formet Glucobete Diabex
	Metformin XR	Diaformin XR Metex XR Diabex XR
Sulfonylureas – Improves microvascular complications – 🡩 insulin secretion – max 120mg daily	Glibenclamide	Daonil	0.5–1.3%	Nil	Hypoglycaemia weight gain	Can use at any level of renal function. But use cautiously in CKD as there is increased risk of accumulation and hypoglycaemia. Prefer gliclazide (predominantly hepatic excretion). Start gliclazide 40mg daily if eGFR<30, then adjust to response.
	Gliclazide	Glyade Nidem
	Gliclazide MR	Glyade MR Diamicron MR
	Glimepiride	Dimirel Amaryl
	Glipizide	Minidiab, Melizide
DPP4 – Dipeptidyl peptidase-4 inhibitors inhibit DDP4 which prolongs action of GLP-1 which enhances insulin secretion + inhibits glucagon secretion Mainly improve post-prandial BGLs	Alogliptin	Nesina	0.7–1%	Minimal hypoglycaemic risk	Pancreatitis	Pancreatic disease kidney impairment (dose reduction may be required)
	Linagliptin	Trajenta
	Saxagliptin	Onglyza
	Sitagliptin	Januvia
	Vildagliptin	Galvus
GLP1 – Glucagon-like peptide-1 analogues increase GLP-1 action which enhances insulin secretion + inhibits glucagon secretion Decrease fasting + post prandial BSL	Dulaglutide	Trulicity	0.8–0.9%	Weight loss	Nausea and vomiting RIsk of pancreatitis	contraindicated if CrCl <30  Trulicity – avoid if eGFR<15. Byetta – avoid if eGFR<30 if eGFR 30-50, be cautious when increasing from 5mcg to 10mcg dose. Bydureon  – avoid if eGFR<50. contraception is the recommendation with GLP-1 agonists in women should avoid in patients with severe gastrointestinal diseases (gastroparesis and (BD) caution with pancreatic disease, gallbladder disease, family or personal history of thyroid cancer
	Exenatide	Byetta (SR)Bydureon (ER)
	Liraglutide	Victoza
	Semaglutide	Ozempic
SGLT2 inhibitors – Sodium-glucose co-transporter 2 inhibitor slower blood sugar by causing the kidneys to remove sugar from the body through the urine effective in delaying the progression of CKD in people with and without type 2 diabetes	Dapagliflozin	Forxiga	0.5–0.7%	Lowering of blood pressure cardioprotection weight loss	Genitourinary infections Euglycaemic ketoacidosis Avoid use with loop diuretics.	contraindicated if CrCl <30 approved for – Type 2 DM – HFrEF : Dapagliflozin, Empagliflozin – CKD (stage 2, 3 or 4 and urine ACR≥ 30 mg/g) : Dapagliflozin
	Empagliflozin	Jardiance
	Ertugliflozin	Steglatro
Insulin	Superior to other  diabetes drugs			Nil	Hypoglycaemia weight gain	Inability to safely administer insulin or monitor glucose
Alpha glucosidase inhibitor	Acarbose	Glybosay	0.8%	Nil	weight neutral Gastrointestinal symptoms – bloating – flatulence	contraindicated if – CrCl <25 mL/min  – Gastrointestinal disease note: glucose (not sucrose) must be administered to treat hypoglycaemia
Thiazolidinediones	Pioglitazone	Acpio, Actaze, Actos, Vexazone	0.7–0.8%	Nil	Fluid retention Increased risk of non-axial fractures in women, Weight gain Worsening of heart failure Macular oedema Cardiac ischaemia Bladder cancer	Patient must have a contraindication or intolerance to metformin- sulfonylurea combination

COMBINATION:

• Example: Janumet (Metformin / sitagliptin)
  • Short acting MF + sitagliptin 500/50; 850/50; 1000/50 daily or BD
  • MAX: 2000/100 daily

DRUG	MONO	DUAL w MF or sulphonylurea	TRIPLE w MF & sulphonylurea	W INSULIN
Metformin	Yes			Yes
Sulphonylurea	Yes			Yes
Insulin	Yes	Yes	Yes
DPP-4 Inhibitors	No	Yes *	No	– **
Pioglitazone	No	Yes *	Yes	Yes
Acarbose	Yes	Yes	Yes	Yes
Exenatide	No	Yes *	Yes	– **

* Only where either MF or sulphonylurea is contraindicated (using obesity + risk of hypoglycaemia) or not tolerated

** No restriction, but data are lacking to support use w insulin

Key points 

• Metformin is the drug of first choice for glucose lowering in patients with type 2 diabetes. 
• A sulphonylurea is an appropriate second option. 
• GLP-1 agonists and SGLT-2 inhibitors provide some benefits for weight loss. 
• DPP-4 inhibitors are reasonable substitutes when metformin and/or a sulphonylurea is contraindicated or apparently ineffective. 
• Patients with symptoms of insulin deficiency require insulin. 
• The effectiveness of any new treatment should be reviewed at an appropriate time before continuing indefinitely.