Type 2 Diabetes Mellitus

Medicine Treatment

Oral blood glucose lowering drugs

Insulin therapy in type 2 diabetes

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ICD-10 Code: E11.0-9/E12.0-9/E13.0-9/E14.0-9

MEDICINE TREATMENT

Management includes:

• Treatment of hyperglycaemia.
• Treatment of hypertension and dyslipidaemia after risk-assessment. See Hypertension.
• Prevention and treatment of microvascular complications.
• Prevention and treatment of macrovascular complications.

ORAL BLOOD GLUCOSE LOWERING DRUGS

• Metformin is the preferred initial medicine and is added to the combination of dietary modifications and physical activity/exercise. If metformin, in maximal dose, with diet and exercise fails to lower HbA1c to target, a second agent should be added. This second agent may be either a sulphonylurea, or basal insulin. The specific indication is dependent on individual circumstances.
• If a combination of two agents fails to lower HbA1c to target, a third agent is added. The preferential sequence of agents to use is metformin, followed by the addition of sulphonylurea, followed by the addition of basal insulin.
• If the combination of two oral agents and basal insulin fails to lower HbA1c to target, or if other reasons to adjust therapy exist (such as nocturnal hypoglycaemia), then intensified insulin therapy in consultation with a specialist is required (either twice daily pre-mix, or basal-bolus therapy) and sulphonylureas are discontinued. 

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Note
Secondary failure of oral agents occurs in about 5–10% of patients annually.

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Metformin

Metformin, oral, 500 mg twice daily with meals.

• Adjust dose based on fasting blood glucose levels and/or HbA1c to a maximum dose of 850 mg 8 hourly.
• Monitor renal function. 

LoE:I¹²

• Dose-adjust in renal impairment as follows:

eGFR	Metformin dose
eGFR >60 mL/min	Normal daily dose (see above).
eGFR 45-60 mL/min	Standard dose, measure eGFR 3-6 monthly.
eGFR 30-45 mL/min	Maximum dose 1 g per day; measure eGFR 3-6 monthly.
eGFR <30 mL/min	Stop metformin

• Contra-indicated in:

  LoE:III¹³

  • renal impairment i.e. eGFR < 30 mL/min,
  • uncontrolled congestive cardiac failure,
  • severe liver disease,
  • patients with significant respiratory compromise, or
  • peri-operative cases.

Sulphonylurea derivatives: glimepiride or glibenclamide.

• Glimepiride, oral, 1 mg daily.
  LoE:III¹⁴
  • Titrate the dose by 1 mg at weekly intervals up to 6 mg daily (according to blood glucose levels).
  • Usual dose: 4 mg daily.
  • Maximum dose: 8 mg daily.

OR

• Glibenclamide, oral, 2.5 mg daily 30 minutes before breakfast.
  • Titrate dose slowly depending on HbA1c and/or fasting blood glucose levels to 15 mg daily.
  • When >7.5 mg per day is needed, divide the total daily dose into 2, with the larger dose in the morning.
  • Avoid in the elderly and patients with renal impairment (i.e. eGFR <60 mL/minute).

LoE:III¹⁵

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Oral agents should not be used in type 1 diabetes and should be used with caution in liver and renal impairment.
Metformin should be dose adjusted in renal impairment.
Monitor patients on sulphonylurea derivatives and concomitant rifampicin and dose-adjust sulphonylurea as required. When rifampicin is discontinued, monitor for risk of hypoglycaemia and dose adjustment is required, particularly in the elderly.

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Monitor serum creatinine and estimated eGFR in patients with kidney disease. 

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INSULIN THERAPY IN TYPE 2 DIABETES

Indications for insulin therapy:

• Inability to control blood glucose pharmacologically, i.e. combination/substitution insulin therapy.
• Temporary use for major stress, e.g. surgery, medical illness.
• Severe kidney or liver disease.
• Pregnancy.

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Note
At initiation of insulin therapy, give appropriate advice on self-blood glucose monitoring (SBGM) and diet.
It is advisable to maintain all patients on metformin once therapy with insulin has been initiated.

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Insulin type - Add on therapy: Intermediate to long-acting insulin
Starting dose	Increment	Max. daily dose
10 units, (or 0.3 units/kg/day), in the evening before bedtime, but not after 22h00.	If the starting dose is not effective, increase by 2-4 units per dose every 3 to 7 days until fasting glucose is in the target range.	Refer if recurrent hypoglycaemia occurs and targets for control are not met.
Insulin type - Substitution therapy: Biphasic insulin (30/70 mix)
Starting dose	Increment	Max. daily dose
Total daily dose: 0.3 units/kg/day divided as follows: - 2/3 of total daily dose 30 minutes before breakfast. - 1/3 of total daily dose 30 minutes before supper. LoE:III16	4 units weekly. First increment is added to dose before breakfast. Second increment is added to dose before supper.	Refer if recurrent hypoglycaemia occurs and targets for control are not met.
Insulin type - Basal bolus insulin therapy
Starting dose	Increment	Max. daily dose
Start with 0.4 to 0.6 units/kg and divide this total daily dose to 50% basal and 50% bolus, using equal pre-meal doses.	Basal insulin is adjusted according to fasting glucose levels and bolus insulin is adjusted according to pre- and post-meal glucose, using the patient's home glucose record as a guide.	Refer if recurrent hypoglycaemia occurs and targets for control are not met.

Also see insulin protocols as in Type 1 diabetes mellitus.

LoE:III¹⁷

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Note
Insulin requirements decrease in patients with chronic renal impairment. In these situations, blood glucose monitoring must be done regularly (at least daily) in order to reduce the dose appropriately, reducing the risk of hypoglycaemia.

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To reduce cardiovascular risk

See Dyslipidaemia. 

Renal impairment

If urine ACR > 2.5 mg/mmoL (men) or > 3.5 mg/mmoL (women):

Start treatment with a low dose of ACE-inhibitor and titrate up to the maximum tolerated dose.

ADD

LoE:I¹⁸

• ACE-inhibitor, e.g.: 
  • Enalapril, oral.
    • Start with 5 mg 12 hourly and titrate to 20 mg 12 hourly, if tolerated (depending on BP and ACR). 

LoE:III¹⁹

See Chronic Kidney Disease (CKD).

If an ACE-inhibitor is not tolerated due to intractable cough, consider an angiotensin II receptor blocker. See Chronic Kidney Disease (CKD).

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Standard Treatment Guidelines and Essential Medicines List for South Africa, Hospital Level, Adults 2024 Edition