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S Afr Fam Pract
ISSN 2078-6190 EISSN 2078-6204

GUIDELINES

About

This chapter summarises information for each of the non-insulin drug classes that are used for blood glucose control. Each summary
is accompanied by a table of recommendations to guide the clinical use of these medications. For the sake of completeness, and
for those that are interested, we have included a more detailed review of each drug as an appendix to each summary. These can be
found in the Appendix section of the guidelines. The treatment recommendations for each drug have been incorporated into the
treatment algorithm in Chapter 11. The following abbreviations are used in this chapter:

DPP-4: dipeptidyl peptidase-4

GLP-1: glucagon-like peptide-1

SGLT2- sodium-glucose linked transporter-2

South African Family Practice 2018; 60(1):4-14

Open Access article distributed under the terms of the
Creative Commons License [CC BY-NC-ND 4.0]
http://creativecommons.org/licenses/by-nc-nd/4.0

Glucose Control: non-insulin therapies*
The Society for Endocrinology, Metabolism and Diabetes of South Africa Type 2 Diabetes Guidelines Expert Committee.
*Chapter 9. Glucose Control: non-insulin therapies in 2017 SEMDSA Guideline for the Management of Type 2 Diabetes
Guideline Committee. JEMDSA 2017; 21(1)(Supplement 1): S39-48.

9.1: Drug Summary – Metformin
SEMDSA Type 2 Diabetes Guideline Expert Committee

(Refer to appendix 9.1 for full text and references)

Mechanism of Action
Metformin targets the liver, skeletal muscle and the gut to reduce hepatic glucose output, increase skeletal muscle
glucose uptake, increase GLP-1 levels and reduce glucose absorption.

Glycaemic efficacy and
indications

Mean HbA1C reductions
• As monotherapy vs. placebo: -1.1%
• As add-on therapy to other non-insulin agents: -0.9%
• Ass add-on to insulin: -0.6%

Cardiovascular outcome
trials

Proven superiority vs. diet alone in obese patients - reduced all-cause mortality, diabetes related mortality and
myocardial infarction, but not peripheral vascular disease or microvascular disease.
Proven superiority vs. SU and insulin in obese patients: reduced all cause mortality and stroke, but not myocardial
infarction, diabetes-related deaths, peripheral vascular disease or microvascular disease.
Safety when added to SU’s (glibenclamide and chlorpropamide) is unclear.

Hypoglycaemia No severe hypoglycaemia as monotherapy. Some patients may have symptoms of hypoglycaemia. Can potentiate the
hypoglycaemic effect of insulin or insulin secretagogues.

Weight Weight neutral or causes modest weight loss (-1.2kg). No weight loss in non-diabetic individuals.

Non-glycaemic benefits

Improves lipid profile.
Reduces cancer rates in population studies.
May improve outcomes in mild to moderate heart failure; Improves laboratory measures of inflammation,
coagulation, oxidative stress, endothelial function and tumour suppression; cancer rates are lower.

Glucose Control: non-insulin therapies 5

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Side Effects and
Precautions

Gastrointestinal (GI) side-effects are common, are not dose-dependent, and occur in 20-30% of patients (diarrhoea,
nausea, vomiting, cramping, bloating and flatulence). Up tp 10% will discontinue therapy due to GI side effects.
Switching to an extended release formulation improves GI tolerability and adherence.

Lactic Acidosis is rare with current usage (0.04 cases per 1000 patient years) and not different to non-metformin users.
Metformin should be discontinued at the time of, or before an iodinated contrast imaging procedure or general
anaesthesia in the following categories of patients: those with an eGFR < 60 mL/minute/1.73 m2; those with a history
of liver disease, alcoholism, or heart failure; those who will receive intra-arterial iodinated contrast. Re-evaluate eGFR
48 hours after the procedure and restart metformin if renal function is stable and the patient is eating normally.

Can cause low levels of serum vitamin B12 in 7-30% of long-term users, but is rarely associated with the clinical
features of vitamin B12 deficiency. The exact mechanism and significance is unknown. There is no recommendation
to screen for vitamin B12 deficiency routinely. Investigate and manage vitamin B12 deficiency according to standard
clinical practice, with a high index of suspicion in patients who are vegetarian or anaemic, or have peripheral
neuropathy.

Dosing and prescribing

Metformin (standard release): Dose range is 500 mg/day to 3 000 mg/day in two or three divided doses with meals.
Optimum glycaemic efficacy is achieved with 2 000 mg/day; few patients have additional glycaemic benefit with
higher doses. The optimum dose for cardiovascular benefit in obese patients is 2 550mg/day.

Metformin extended-release: Dose range is 500 mg/day to 2 000 mg/day as a single dose with the evening meal. The
2 000mg dose can be split to 1000mg twice daily without losing efficacy.

Start with 500 mg/day of standard metformin tablets, and increase the dose by 500 mg every one to two weeks
to minimise side effects. If GI side effects occur reduce the dose and re-titrate slowly. If GI disturbances persist try
switching to the extended-release formulation.

Renal dosing

eGFR ≥60 ml/min 45-60 ml/min 30-45 ml/min < 30 ml/min

Standard dosing.
Monitor eGFR annually

Standard dosing.
Monitor eGFR
3 to 6 monthly

Maximum dose:
1000 mg/day

Monitor eGFR 3 to 6
monthly

Metformin is
contraindicated

SEMDSA 2017 Recommendations for metformin
Initiate standard-release metformin therapy in all newly diagnosed obese patients with type 2 diabetes. A

Initiate standard-release metformin therapy in all newly diagnosed non-obese patients with type 2 diabetes. C

Dosing: Start with 500 mg once daily and up-titrate the dose slowly every 10 to 14 days until glycaemic targets are met or side
effects occur. Few patients will achieve and maintain glycaemic targets with 500 mg once daily. Most patients will require1000
– 2550 mg per day in two or three divided doses. The optimum dose for cardiovascular benefit in obese patients is 2550 mg/day
(850 mg TDS).

If gastrointestinal (GI) adverse events are limiting, try temporarily reducing or discontinuing the drug, and re-titrate when the GI
disturbances resolve. The GI side-effects with metformin extended-release is not different to the standard release when used
as initial therapy; however patients who switch due to the extended release may have improved tolerability. If GI disturbances
remain intolerable with standard metformin tablets, try switching to a metformin extended release (XR) formulation and titrate
the dose every 10-14 days again.

The extended release formulation should be dosed once daily with the evening meal at a dose not exceeding 2000 mg/day. The
2000 mg dose can be taken as 1000 mg twice a day without disadvantages if the patient so prefers. Patients not achieving their
glycaemic target with 2000 mg of the extended release may benefit from switching to a higher dose of the standard release
metformin.

Monitor renal function (eGFR) in all patients at least annually. Do not exceed 1000 mg/day if the eGFR is
30-45 ml/min/1.73m2. Stop metformin therapy if the eGFR is < 30 ml/min/1.73m2.

The significance of low serum vitamin B12 levels associated with long-term metformin use is not known. Measure and treat
whenever clinically appropriate.

Profile of the patient in whom metformin may not be a preferred option:
Patients with irritable bowel syndrome or other chronic gastrointestinal disorders
Normal weight individuals who do not wish to lose weight
Patients at high risk for lactic acidosis (severe heart, lung, liver, renal or peripheral vascular disease)
There is a history of metformin intolerance.

Do not persist with any chosen treatment if the HbA1C has not decreased by > 0.5% after six months

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9.2: Drug Summary – Gliclazide modified-release

SEMDSA Type 2 Diabetes Guideline Expert Committee

(Refer to appendix 9.2 for full text and references)

Mode of action Gliclazide modified-release is a sulphonylurea (SU) and insulin secretagogue that binds selectively to the
sulphonylurea receptor-1A (SUR1A) binding-site of KATP channels on pancreatic beta cells resulting in membrane
depolarization, calcium influx and exocytosis of stored insulin.

Glycaemic efficacy and
indications

When used as monotherapy or as add-on to other non-insulin glucose lowering drugs the mean HbA1C
reduction is -1% with sustained efficacy beyond 2 years.

Cardiovascular outcome trials

The ADVANCE study, using a gliclazide modified-release intensive treatment strategy achieved an HbA1C target
of 6.5% (vs. 7.3% for conventional treatment) and demonstrated a significant reduction in microvascular
outcomes (and therefore also the combined microvascular and macrovascular outcomes), driven mainly by the
reduction in the incidence of nephropathy.
There have been no dedicated cardiovascular safety studies with any sulphonylurea. Meta-analyses of
observational and randomized controlled trials consistently demonstrate that gliclazide has a better
cardiovascular safety profile than glibenclamide and glimepiride.

Hypoglycaemia
Gliclazide modified-release increases the risk of hypoglycaemia when used as monotherapy or combination
therapy, but this is significantly lower when compared to glibenclamide and glimepiride. The rates of
hypoglycaemia increase with lower glycaemic targets.

Weight Weight change ranges from 0 to +1.5 kg. Mean weight gain in a meta-analysis of RCTs was 0.5kg.

Non-glycaemic benefits
Gliclazide modified-release increases peripheral insulin sensitivity, decreases hepatic glucose production,
inhibits platelet aggregation and adhesion, increases t-PA activity and has antioxidant effects. There are also
reports of possibly a lower cancer risk compared to other SUs and insulin.

Side Effects and Precautions
Side-effects apart from hypoglycaemia and weight gain are rare. Cross-reactivity with sulphonamide antibiotic
allergy is uncommon and is not a contra-indication.
Do not use with advanced liver disease because of hepatic metabolism.

Dosing and prescribing

• The usual starting dose for gliclazide modified-release is 30 to 60 mg administered once daily with the
morning meal.

• Consider starting with the higher (60 mg) dose when the HbA1C target is more than 0.5% from the prevailing
HbA1C level, or if the patient is has symptomatic hyperglycaemia.

• The dose can be escalated by 30 to 60mg every one to four weeks, guided by fasting glucose levels.
• The maximum dose is 120 mg administered once daily with the morning meal.
• If mild hypoglycaemia occurs unexpectedly reduce the dose by 30 to 60 mg.
• A single episode of severe hypoglycaemia or recurrent episodes of mild hypoglycaemia would be a strong

indication to switch to an alternative glucose lowering drug.
• The 60 mg tablets are scored and can be broken to improve cost effectiveness.

Renal dosing

Current guidelines recommend that gliclazide modified-release can be used at all stages of chronic kidney
disease using standard dosing guidelines. Caution is advised however, when the eGFR is
< 30 ml/min/1.73m2, and these patients with CKD stage 3 or worse should be managed with specialist
supervision.

Cost of cheapest formulation at
maximum dose

R93.00 for 120 mg (Single exit price as at March 2017).

SEMDSA 2017 Recommendations for sulphonylureas

The sulphonylurea of choice should be gliclazide modified-release because:
• It has equivalent efficacy compared to other sulphonylureas.
• It is consistently associated with lower rates of hypoglycaemia and better cardiovascular and renal safety relative to other

sulphonylureas.
• It has proven benefits for long-term microvascular disease outcomes.

Glibenclamide must not be used at primary care level. A

Consider gliclazide modified-release as initial monotherapy when metformin is not tolerated or is contraindicated. B

Consider gliclazide modified-release as add-on (dual therapy) to metformin (or other initial drug therapy) in most patients not
achieving or maintaining their glycaemic targets.

If not already in use, consider gliclazide modified-release as a third glucose lowering drug. A

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To convert treatment from another sulphonylurea to gliclazide modified-release, use the following dose conversion:
• Glibenclamide 5 mg ≈ Gliclazide modified-release 30 mg
• Glimepiride 1-2 mg ≈ Gliclazide modified-release 30 mg

Only continue gliclazide modified-release beyond stage 3 chronic kidney disease (when the eGFR is less 30 ml/min/m2) with
specialist supervision.

Circumstances where gliclazide MR may be preferred to other treatment options:
• Gliclazide MR should be the preferred second drug for the majority of patients with type 2 diabetes.
• At diagnosis when rapid control of hyperglycaemic symptoms is required.

Circumstances where gliclazide MR may not be the preferred option:
• The individualised glycaemic target is ≤ 6.5% (as the risk of hypoglycaemia may be unacceptably high with this target).
• There is a history of severe hypoglycaemia or hypoglycaemia unawareness.
• There is a history of recurrent hypoglycaemia (any degree) despite dose adjustments.
• The risk of hypoglycaemia is high and/or its consequences are severe.
• The patient has advanced liver disease.

9.3: Drug Summary – Pioglitazone

SEMDSA Type 2 Diabetes Guideline Expert Committee

(Refer to appendix 9.3 for optional full text and references)

Mode of action
Agonist of nuclear receptors called peroxisome proliferator-activated receptor-gamma (PPARγ). Leads to increased
transcription of proteins that augment the post-receptor actions of insulin resulting in improved insulin sensitivity
and ß-cell function.

Glycaemic efficacy and
indications

Good efficacy as monotherapy, dual therapy and triple therapy (± 1% HbA1C reduction); similar efficacy to
metformin, SU or GLP-1RA.

Cardiovascular outcome
trials

PROactive study (secondary prevention) showed reductions in secondary endpoints (composite of all-cause
mortality, non-fatal myocardial infarction, and stroke) by 16%. Meta-analysis of RCTs also reported a significant
18% relative risk reduction in the composite outcome (death, myocardial infarction, or stroke). Increases heart
failure hospitalisations because of fluid retention, but not mortality.

Hypoglycaemia Does not cause hypoglycaemia except when combined with insulin or insulin secretagogues.

Weight
Causes dose-dependent weight gain (~2-4 kg) due to fluid retention and adipocyte differentiation. Weight gain
correlates with therapeutic response.

Non-glycaemic benefits

Increases HDL-C; reduces triglycerides, reduces LDL atherogenicity, CRP and microalbuminuria; increases PAI-1
and adiponectin; reduces carotid intima media thickness and atheroma volume. Reduces hepatic fibrosis in
non-alcoholic steatohepatitis (NASH); improves ovulation and metabolic abnormalities in polycystic ovary
syndrome.

Side Effects and
Precautions

Can cause fluid retention, oedema, and may worsen or precipitate congestive heart failure.
Associated with an increase in distal long-bone fractures in women and men.
Possible small increase in bladder cancer.

Dosing and prescribing
Start with 15 once daily in the morning; increase to 30 mg after one to three months if necessary. Most patients will
derive optimum benefit at this dose; do not exceed 30 mg in the primary care setting. Maximum registered dose is
45 mg daily.

Renal dosing
No dose adjustment is necessary, but do not use if renal disease is causing fluid retention, or when the eGFR is <30
ml/min/1.73m2.

Cost of cheapest
formulation

R117.00 for 30 mg.

Do not persist with any chosen treatment if the HbA1C has not decreased by > 0.5% after six months

Glucose Control: non-insulin therapies 9

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SEMDSA 2017 Recommendations for pioglitazone

Consider pioglitazone as initial monotherapy when metformin is contraindicated or not tolerated. A

Consider pioglitazone as add-on to metformin or other initial drug therapy, in selected patients not achieving or maintaining their
glycaemic targets.

Consider pioglitazone as a third non-insulin glucose lowering drug in selected patients not achieving or maintaining their
glycaemic targets on an existing oral two-drug regimen.

Circumstances where pioglitazone may be preferred to other treatment options:
• Gliclazide MR is contraindicated or not tolerated.
• Non-alcoholic steatohepatitis is present.
• The patient has features of severe insulin resistance.
• There is a history of previous myocardial infarction, previous stroke or chronic kidney disease stage-3 (pioglitazone offers

probable benefit for secondary prevention)

Circumstances where pioglitazone may not be the preferred option:
• Age > 75 years old (risk of congestive heart failure (CHF), fracture and bladder cancer)
• History of congestive heart failure.
• History of osteoporosis.
• History of bladder cancer, or haematuria that has not been investigated.
• Stage-4 or worse chronic kidney disease (risk of fluid retention).
• Patients on insulin therapy (higher risk of fluid retention and CHF).
• Elevated liver enzymes (>2x ULN), which is not due to NASH.

Do not persist with any chosen treatment if the HbA1C has not decreased by > 0.5% after six months

9.4: Drug summary - DPP-4-inhibitors

SEMDSA Type 2 Diabetes Guideline Expert Committee

(Refer to Appendix 9.4 for review and references)

Mode of action and
pharmacology

DPP-4 inhibitors (gliptins) are capable of inhibiting the degradation of endogenous GLP-1, thereby therapeutically
raising circulating GLP-1 levels.

Glycaemic efficacy and
indications

Can be used as monotherapy in selected patients when there is intolerance to metformin (where there is a high risk
for hypoglycaemia).
Can be used as dual or triple therapy when added to metformin / sulphonylurea / SGLT 2 inhibitor / insulin.
HbA1C reduction when used as monotherapy is between 0.5 and 1.1 %.

Macrovascular and
Mortality Outcomes

Cardiovascular outcome safety trials for all 3 DPP-4 inhibitors have been neutral for major adverse cardiovascular
events. Saxagliptin was associated with increased rates of hospitalisation for heart failure.

Hypoglycaemia Hypoglycaemia rates are not different to placebo except when DPP 4 inhibitors are combined with insulin or insulin
secretagogues.

Non-glycaemic benefits Weight-neutral.

Side Effects and
Precautions

Small absolute risk for pancreatitis.

Increased risk of hospitalisation for heart failure with saxagliptin.

Contraindications

Acute, chronic or recurrent pancreatitis or high risk for pancreatitis.
Pancreatic cancer.
All are contraindicated in severe liver disease. Use saxagliptin and vildagliptin with caution in moderate liver
disease.
Heart failure (saxagliptin).

Dosing

eGFR Saxagliptin Sitagliptin Vildagliptin

≥50 ml/min 5 mg daily 100 mg daily 50 mg twice a day

30-50 ml/min 2.5 mg daily 50 mg daily 50 mg daily

<30 ml/min 2.5 mg daily 25 mg daily 50 mg daily

Cost at maximum dose Moderate (R260 – 340 per month - single exit pricing as at March 2017)

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Do not persist with any chosen treatment if the HbA1C has not decreased by > 0.5% after six months

SEMDSA 2017 Recommendations for DPP-4 inhibitors
Consider a DPP-4 inhibitor as initial monotherapy when metformin is contraindicated or not tolerated. C

Consider a DPP-4 inhibitor as add-on to metformin or other initial drug therapy, in selected patients not achieving or maintaining
their glycaemic targets.

Consider a DPP-4 inhibitor as the third glucose lowering drug in selected patients not achieving or maintaining their glycaemic
targets on an existing oral two-drug regimen.

Combination DPP-4 inhibitor and insulin therapy should be initiated at specialist level. C

Be aware of dose adjustments for chronic kidney disease. C

Circumstances where a DPP-4 inhibitor may be preferred to other treatment options:
• As the 2nd add-on drug when gliclazide MR is contraindicated or not tolerated.
• As the 3rd add on drug for most patients if HbA1C targets are potentially achievable.
• Older patients with multiple comorbidities.
• Patients with stage-4 chronic kidney disease (can be used without risk of hypoglycaemia).
• If a fixed-dose combination tablet will improve adherence, compliance and/or cost-effectiveness.

Circumstances where a DPP-4 inhibitor may not be the preferred option:
• Very high HbA1C and the glycemic target is not likely to be achieved with a DPP-4 inhibitor.
• History of pancreatitis or pancreatic tumour.
• History of heart failure or high risk of heart failure (saxagliptin).
• Liver disease: moderate (do not use saxagliptin or vildagliptin) or severe (do not any DPP-4 inhibitor).

9.5: Drug summary - GLP-1 receptor agonists

SEMDSA Type 2 Diabetes Guideline Expert Committee

(Refer to Appendix 9.5 for drug review and references)
Mode of action and
pharmacology

GLP-1 receptor agonists are modified GLP-1 molecules that have structural homology with endogenous GLP-1 but
are resistant to the enzymatic cleavage by DPP-4.

Glycaemic efficacy and
indications

Reduces HbA1C by 0.9 to 1.2 %.
Monotherapy: registered (liraglutide) but not recommended for primary healthcare.
Dual therapy: registered but not recommended for primary healthcare.
Triple therapy: Can be combined with any 2 of metformin / sulphonylurea / TZD.
Do not combine with DPP-4 inhibitor or SGLT2 inhibitor.
Exenatide can be as added to basal insulin with or without oral agents.

Macrovascular and
Mortality Outcomes

Lixisenatide was neutral in the ELIXA trial.
Liraglutide and semaglutide have each demonstrated reductions in a composite endpoint of major adverse
cardiovascular events by 13% and 26% in the LEADER and SUSTAIN-6 trials respectively (vs. placebo), when used in
patients with established cardiovascular disease.
There are no cardiovascular outcomes trials with exenatide.

Hypoglycaemia Hypoglycaemia rates are not different to placebo except when GLP-1 receptor agonist are combined with insulin or
insulin secretagogues.

Non-glycaemia benefits
Weight reduction of between 1 and 3 kg for exenatide and liraglutide.
Both exenatide and liraglutide reduce SBP and DBP by 1 to 5 mmHg.
Reduction in liver fat content (liraglutide).

Side Effects and
Precautions

Nausea and vomiting in up to 25%; Discontinuation rate 5-20%.
Pancreatitis.
Skin reactions.

Contraindications

History of pancreatitis, or at high risk for pancreatitis (e.g. untreated gallstone disease, recent or planned ERCP,
excessive alcohol use).
History of pancreatic tumour.
History of medullary thyroid cancer (MTC) or multiple endocrine neoplasia (MEN) syndrome type 2

Dosing

eGFR Exenetide
Initial dose is 5 ug BD for the 1st

month; then 10 ug BD

Liraglutide

≥30 ml/min
Initiate 0.6 mg daily Maximum dose

of
1.8 mg daily

<35 ml/min Contraindicated No adjustment

Cost High (R620.00 to R2145.00 - single exit price March 2017)

6 mg/ml

GLP-1 receptor
agonists

DPP-IV
inhibitors

SU
SGLT-2

inhibitors

HbA1c - lowering
effect

High Intermediate High Intermediate

Weight Loss Neutral Gain Loss

Risk of
hypoglycaemia

Low Low Moderate Low

Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. 150 Rivonia Road, 10 Marion Street Office Park, Building C1 Sandton, Johannesburg, 2196, South Africa. Tel: (011) 202 0500.

Fax: (011) 807 7989.

Z A/ V T/0218/0094

References: 1. lnzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.
2. The Society for Endocrinology, Metabolism and Diabetes of South Africa Type 2 Diabetes Guidelines Expert Committee. The 2017 SEMDSA Guideline for the Management of Type 2 Diabetes Guideline Committee. JEMDSA 2017;21(1)(Supplement 1): S1-S192 / 196. 3. AACE Comprehensive Diabetes
Management Algorithm. Endor Pract. 2013;19(No. 2) 327-335.

ADA/EASD = American Diabetes Association/European Association for the Study of Diabetes.
DPP-4 inhibitor = Dipeptidyl Peptidase-4 inhibitor;
SU = Sulphonylurea.
AACE = American Association of Clinical Endocrinologists.

Victoza® – your force for
change in type 2 diabetes
Victoza® efficacy is consistent across multiple guidelines:
SEMDSA/ADA/EASD1,2

Non-insulin therapy options recommended as an add-on to metformin 1

AACE Guidelines also support the use of GLP-1 receptor
agonists after metformin3

Scheduling Status: S4 Proprietary Name: Victoza®. Composition: Liraglutide 6 mg/ml. Indications: Adjunct to diet & exercise to achieve glycaemic control in type 2 diabetes mellitus, as monotherapy or combination therapy with one or more oral antidiabetic medicines when inadequate
control with previous therapy. Contra-indications: Hypersensitivity to liraglutide or any of its excipients, a history of previous pancreatitis, Type 1 diabetes mellitus, pregnancy and lactation. Warnings and Special precautions: Not to be used for the treatment of DKA and Type 1 Diabetic
patients. Not for IM/IV administration. Limited experience in CHF Class I-II NYHA & no experience in classes III-IV, not recommended in patients with inflammatory bowel disease/ diabetic gastroparesis. Blood glucose self-monitoring is advised when initiating therapy with concomitant
of sulphonylurea, possible development of anti-liraglutide antibody, warning of signs and symptoms of acute pancreatitis, discontinue therapy if suspected, reduce concomitant sulphonylurea dosage to reduce hypoglycaemia risk, limited experience in patients with hepatic impairment,
pre-existing thyroid disease. Safety and efficacy of Victoza® in patients below 18 years of age and in patients with any degree of hepatic impairment has not been established. Victoza® is not recommended for use in patients with severe renal impairment including patients with end stage
renal disease. The use of Victoza® has been associated with a risk of developing acute pancreatitis. Once acute pancreatitis is confirmed, Victoza® or any other GLP-1 receptor agonist should never again be restarted. Victoza® is not recommended for use in patients with severe renal impairment
including patients with end stage renal disease. Victoza® is not a substitute for insulin. Interactions: Increased hypoglycaemia risk with concomitant sulphonylurea. Upon initiation of Victoza® treatment in patients on warfarin or other coumarin derivatives, more frequent monitoring of
INR is recommended. Pregnancy & Lactation: Victoza® is contraindicated during pregnancy and lactation. Treatment to be discontinued if a woman wishes to become pregnant/pregnancy occurs. Crossed the placental barrier in rabbits, reproductive toxicity in animals, excreted in milk
of lactating rabbits. Dosage & Directions for use: Monotherapy: Administration SC once daily at any time. Initiate 0,6 mg for at least one week, thereafter increase to 1,2 mg based on clinical response and after at least one week, may be increased to 1,8 mg to achieve maximum efficacy.
Daily doses higher than 1,8 mg are not recommended. Combination therapy: May be added to existing metformin or combined metformin & thiazolidinedione combination therapy. Current dose of these meds may be continued unchanged. No dose adjustment is required for patients
with mild or moderate renal impairment (creatinine clearance between 60 - 90 ml/min and 30 – 59 ml/min respectively). There is no therapeutic experience in patients with severe renal impairment (creatinine clearance below 30 ml/min). Side-effects: Malaise, anaphylactic reaction,
urticaria, pruritus, renal failure, increased heart rate, dehydration, GI disturbances including eructation, headache, URTI, Hypoglycaemia especially in combination with sulphonylurea, bronchitis, osteomyelitis, prostate/ breast cancer, thrombocytopenia, decreased appetite, CVA, syncope,
cataract, cardiac disorders including MI/CCF/ supraventricular tachycardia, pulmonary embolism, appendicitis with perforation, inguinal hernia, pancreatitis, intervertebral disc protrusion, osteoarthritis, chest pain, fall, injection site reactions, thyroid adverse events including neoplasms,
antibody formation. Known symptoms of overdosage and particulars of its treatment: With overdose, the patients reported severe nausea, vomiting and diarrhoea, but recovered without complications. None of the patients reported severe hypoglycaemia. Reg. No.: 43/21.13/0781.

For full prescribing information refer to package insert approved by the medicines regulatory authority.

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SEMDSA 2017 Recommendations for GLP-1 receptor agonists (GLP-1RA)
Consider a GLP-1RA injectable as the third glucose lowering drug (triple therapy) in overweight and obese patients when
glycaemic targets are not being achieved or maintained.

Consider adding a GLP-1RA to existing basal insulin therapy (with oral therapies) as an alternative to intensifying the insulin
regimen, especially when weight gain and/or hypoglycaemia is a limiting factor.

Escalate the dose of GLP-1RA slowly to minimise side-effects. C

Circumstances where a GLP-1RA may be preferred to other treatment options:
• Overweight and obese patients
• Weight gain or hypoglycaemia has been, or is likely to be problematic with other treatment options.
• HbA1C is very high (GLP-1RA and insulin are the most effective glucose lowering drugs for most patients).
• Patients with established cardiovascular disease (liraglutide benefit); to be managed at specialist care level.

Circumstances where a GLP-1RA may not be the preferred option:
• Patients with chronic gastrointestinal disorders.
• Patients with a history of pancreatitis or pancreatic tumour.

Do not persist with any chosen treatment if the HbA1C has not decreased by > 0.5% after six months

9.6: Drug Summary - SGLT2 inhibitors

SEMDSA Type 2 Diabetes Guideline Expert Committee

(Refer to Appendix 9.6 for review and references)

MOA
By inhibiting SGLT2, gliflozins reduces renal glucose reabsorption, leading to increased urinary excretion of excess
glucose and a reduction in plasma glucose concentrations in a non-insulin dependent manner.

Glycaemic efficacy and
indications

As monotherapy: 0.6% to -1.2%; non-inferior to metformin.
As add on to metformin: -0.5% to -1.0%; non-inferior to other classes
As add on to metformin + SU: -0.7% to -0.9%; non-inferior to DPP-4 inhibitors
As add on to insulin therapy: -0.5% to -0.8%

Microvascular Outcomes No primary outcome studies.

Macrovascular and
Mortality Outcomes

Empagliflozin therapy was associated with a reduction in all-cause death, cardiovascular-death and hospitalisation
for heart failure in patients with established cardiovascular disease. There has been no signal of adverse
cardiovascular outcomes in systematic meta-analyses for the other SGLT2 inhibitors.

Hypoglycaemia
Hypoglycaemia rates are not different to placebo except when SGLT2 inhibitors are combined with insulin or insulin
secretagogues.

Non-glycaemic benefits
Mean weight loss of 1.6 to 2.5 kg; not different to GLP-1RAs (meta-analysis)
Systolic and diastolic blood pressure reduction (-4.0 and -1.5 mmHg) respectively.

Side effects and
precautions

Mycotic genital infections are common (and more so in women); do not use in patients with a history of recurrent
genital infections.

The risk of urinary tract infections may be increased but can be minimised by advising adequate hydration and
fastidious bathroom hygiene; do not prescribe SGLT2 inhibitors in patients with a history of recurrent UTI.

Dehydration and hypotension can occur particularly in susceptible patients (treated with loop diuretics, have
advanced cardiac disease or older than 65 years). Always ensure and emphasise adequate hydration when
prescribing SGLT2 inhibitors.

eGFR usually declines within the first weeks of initiating therapy and then gradually returns toward baseline.
Monitor eGFR and discontinue SGLT2 inhibitors if the decline is ≥ 30%.

Diabetic ketoacidosis may occur at mildly elevated levels of blood glucose particularly in insulin treated patients.
Warn patients of the symptoms of DKA and advise them to seek medical attention immediately.

The risk of fractures and lower-limb (especially toe) amputations is increased with canagliflozin. Therefore do not
use canagliflozin, and exercise caution with the other drugs in this class, in patients who are at high risk for these
conditions.

Do not prescribe dapagliflozin to patients with bladder cancer or in combination with pioglitazone.

S Afr Fam Pract 2018;60(1):4-1414

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Dosing

eGFR Dapagliflozin Empagliflozin Canagliflozin

≥60 ml/min 5 mg or 10 mg 10 mg or 25 mg 100 mg or 300 mg

45-60 ml/min Contraindicated
Continue 25 mg but do

not initiate therapy
Continue 100 mg but do

not initiate therapy

<45 ml/min Contraindicated Contraindicated Contraindicated

Cost Unknown; not registered in South Africa as at March 2017.

SEMDSA 2017 Recommendations for SGLT2 inhibitors
Do not use SGLT2 inhibitors as initial monotherapy C

Consider a SGLT2 inhibitor as add-on (dual therapy) to metformin (or other initial drug therapy) in selected patients not achieving
or maintaining their glycaemic targets.

Consider a SGLT2 inhibitor as the 3rd glucose lowering drug in selected patients not achieving or maintaining their glycaemic
targets on an existing oral two-drug regimen.

Circumstances where an SGLT2inhibitor may be preferred to other treatment options:
• Overweight and obese patients.
• Weight gain or hypoglycaemia has been, or is likely to be problematic with other treatment options.
• Patients with established cardiovascular disease (empagliflozin benefit); to be managed at specialist care level.

Circumstances where an SGLT2 inhibitor may not be the preferred option:
• Patients with recurrent mycotic genital infections or urinary tract infections.
• Patients at risk for dehydration and hypotension.
• Patients at high risk for stroke, fracture (canagliflozin), amputation (canagliflozin), bladder cancer (dapagliflozin) or ketoacidosis

(refer to drug review).

Do not initiate SGLT2 inhibitors when the eGFR is < 60 ml/min/m2.

Stop all SGLT2 inhibitors when the eGFR is < 45 ml/min/m2.

Do not persist with any chosen treatment if the HbA1C has not decreased by > 0.5% after six months

9.7: Alpha-glucosidase inhibitors (acarbose)

SEMDSA Type 2 Diabetes Guideline Expert Committee

Mechanism of Action
Prevents the conversion of complex carbohydrates into monosaccharides within the intestine thereby
decreasing the ability to absorb monosaccharides.

Glycaemic efficacy and
indications

HbA1C reduction when used as monotherapy of between 0.6 and 0.8%.
A

Microvascular Outcomes Reduction of Microvascular Complications are inferred from the benefit of improved glycaemic control. B

Macrovascular and
Mortality Outcomes

Acarbose significantly reduced the risk of cardiovascular events by 49% in patients with impaired glucose
tolerance. No data for patients with Diabetes.

Hypoglycaemia Hypoglycaemia rates are no different to placebo except when combined with Insulin or Insulin
Secretagogues.

Non glycaemic benefits Weight neutral. B

Side Effects and
Precautions

Transient elevation of hepatic transaminases. B

Gastrointestinal Side Effects (Flatulence and diarrhoea). B

Dosing

eGFR Acarbose

≥30 ml/min
Start with 50 mg once daily with meals, and increase by 50 mg every

two weeks if tolerated.
Maximum dose is 100 mg x3 daily.

<30 ml/min Not recommended

Cost High (R407.00).