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Primary Care Hacks

What Next After Metformin?

Guidelines presents Primary Care Hacks, a series of clinical aide-memoires across a range of topics. Developed by Dr Kevin Fernando, Primary Care Hacks aim to provide a quick and easy resource for primary healthcare professionals and ultimately help improve patients' lives.

Take a Look at Medscape UK's other Primary Care Hacks

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Identifying People at High Risk of Prediabetes

Subclinical Hypothyroidism

Extra-Glycaemic Indications of SGLT2 Inhibitors

Type 2 Diabetes Cardiovascular Renal Metabolic Review Checklist

Diagnosis and Classification of Diabetes

Management of Hyperglycaemia in Type 2 Diabetes and CKD

Comparison of ADA/EASD and NICE Recommendations on Managing Type 2 Diabetes

What Next After Metformin?

This Medscape UK Primary Care Hack is intended to help guide primary healthcare professionals' choice of medication for the management of people living with type 2 diabetes. As always, take an individualised and holistic approach to the care of people living with type 2 diabetes.

Expand the table for full view. Find a downloadable PDF of the table at the end of the article.

 Biguanides (Metformin)SGLT2 Inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin)GLP-1 Receptor Agonists (Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide)DDP-4 Inhibitors or 'Gliptins' (Alogliptin, Linagliptin, Saxagliptin, Sitagliptin, Vildagliptin) Thiazolidinediones (Pioglitazone)Sulfonylureas (Glicazide, Glimepiridse, Glipizide)
Reinforce the importance of 24-hour physical behaviours for T2D. See: Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association and the European Association for the Study of Diabetes
Mode of ActionDecreases hepatic glucose production and reduces IRInsulin-independent; inhibits renal glucose reabsorption by blocking SGLT2 transporterStimulates glucose dependent insulin release from the pancreasIncreases GLP-1 levels by blocking DPP-4 enzyme that inactivates GLP-1Insulin-dependent; reduces hepatic and peripheral IR at a molecular levelStimulates insulin secretion from pancreatic beta-cells
Glycaemic EfficacyModerate/highModerate/highHighLow/moderateModerateHigh
Impact on WeightWeight loss +Weight loss ++Weight loss +++Weight neutralWeight gain +++Weight gain ++
Risk of HypoglycaemiaLowLowLowLowLowHigh
Key AdvantagesWell-established and cost-effective (generic)

Reduces IR

Legacy effect seen with early metformin therapy; early glycaemic control has durable effects on microvascular outcomes, macrovascular outcomes, and mortality

Secondary benefits of weight loss and BP reduction

Average reduction of around 4 mmHg systolic/2 mmHg diastolic seen in ambulatory BP monitoring studies

Certain SGLT2 inhibitors have also demonstrated benefits in ASCVD, HFrEF, HFpEF, and CKD

NICE NG28 (2022)1 now recommends early combination therapy with metformin + SGLT2 inhibitor for those with chronic HF, established ASCVD, or a QRISK2 score of ≥10%

Slows gastric emptying, reduces appetite, and can facilitate significant weight reduction

Predominantly injectable therapies; however, oral semaglutide is now available—needs counselling regarding correct administration to optimise oral absorption

Certain GLP-1 receptor agonists have demonstrated CV benefits in those with established ASCVD and also in the presence of multiple CV risk factors



Safe in CVD

Reassuring adverse effect profile

Can be prescribed in all stages of renal impairment

Well-established and cost-effective (generic)

Reduces IR

Beneficial effects in fatty liver disease

NICE NG49 (2016)2 also recommends consideration of pioglitazone for adults with advanced liver fibrosis with or without T2D (unlicensed indication)

Well-established and cost-effective (generic)

Useful as rescue therapy for symptomatic hyperglycaemia (e.g. polydipsia and polyuria) and steroid-induced hyperglycaemia

Impact on MACE

See also Primary Care Hacks: Extra-Glycaemic Indications of SGLT2 Inhibitors

Reduced MI and ACM demonstrated in UKPDS3

Reduction in MACE with canagliflozin and empagliflozin

CV mortality benefit with empagliflozin

Reduction in HHF and CV mortality composite with dapagliflozin

Reduction in MACE with dulaglutide, liraglutide, and injectable semaglutideNo reduction seen in MACEReduced recurrent stroke and MI in insulin-resistant individuals demonstrated in IRIS study4

No reduction seen in MACE

The CAROLINA RCT demonstrated that glimepiride was non-inferior to linagliptin with respect to the risk of adverse CV outcomes, i.e., glimepiride use appears to be safe in the context of elevated CV risk5

Impact on HF Outcomes

See also Primary Care Hacks: Extra-Glycaemic Indications of SGLT2 Inhibitors

No reduction seen in hospitalisation or death from HF

Reduction in HHF seen with all SGLT2 inhibitors

Dapagliflozin and empagliflozin have demonstrated significant reductions in HHF and CV mortality composite in HFrEF and are both licensed for HFrEF in people living with and without T2D

Dapagliflozin has demonstrated a CV mortality benefit in HFrEF in people living with and without T2D

Dapagliflozin and empagliflozin have demonstrated significant reductions in HHF and CV mortality composite in HFpEF

Empagliflozin is licensed for HFpEF in people living with and without T2D

No reduction seen in hospitalisation or death from HFNo reduction seen in hospitalisation or death from HF (small increase in HHF seen with saxagliptin)Potential harm due to fluid retention; contraindicated in HFNo reduction seen in hospitalisation or death from HF

Impact on MARE

See also Primary Care Hacks: Extra-Glycaemic Indications of SGLT2 Inhibitors

No reduction seen in MARE

Reduction in MARE seen with canagliflozin, dapagliflozin, and empagliflozin in people living with T2D

Dapagliflozin and empagliflozin have demonstrated a reduction in MARE in people without T2D

Dapagliflozin is licensed for the treatment of CKD in people living with and without T2D

No reduction seen in MARE No reductionNo reduction seen in MARE No reduction seen in MARE No reduction seen in MARE 
Prescribing in CKD

Please refer to the Medscape UK Primary Care Hacks tool, The Pharmacological Management of Hyperglycaemia in People Living with Type 2 Diabetes and Chronic Kidney Disease

Precautions and Adverse EffectsGI side-effects common; ‘start low, go slow’

Long-term usecan lead tovitamin B12deficiency; check FBC annually

Sick day guidance required due to possible association with LA

SAD MANS mnemonic useful clinical aide memoire for which drugs to temporarily pause during any significant intercurrent illness; see the Canadian Diabetes Association's Sick Day Medications List

S: sulfonylureas

A: ACE inhibitors

D: diuretics, direct renin inhibitors

M: metformin

A: angiotensin receptor blockers

N: nonsteroidal anti-inflammatory drugs

S: SGLT2 inhibitors

Mycotic genital infections and UTIs—reinforce good personal hygiene and adequate fluid intake

MHRA (2019)6 warns of rare association between SGLT2 inhibitors and Fournier’s gangrene. Advise patients to seek urgent medical attention if they experience severe pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise

Urinary frequency and possible volume depletion/dehydration

Euglycaemic DKA—if suspected, check ketones even if BG normal. Sick day guidance required— SAD MANS clinical mnemonic for drugs to temporarily pause during significant intercurrent illness. see the Canadian Diabetes Association's Sick Day Medications List

See The Place and Value of Sodium–Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: a Narrative Review for an SGLT2 inhibitor prescribing tool with associated clinical summaries

Counsel about GI side-effects (e.g. nausea, diarrhoea and constipation, early satiety, dyspepsia), but most of these effects generally decrease with time

Eating smaller meals more frequently and stopping eating when starting to feel full can ease these side-effects

Additionally, escalating dosing of GLP-1 receptor agonists over time can improve GI tolerability

Contraindicated in MEN2 and MTC

Small increase in cholecystitis with liraglutide. Small worsening of pre-existing DR with semaglutide in those with suboptimal glycaemic control at baseline and treated with insulin; monitor for  progression of DR in these individuals. MHRA (2019)6 warns of reports of DKA when concomitant insulin is rapidly reduced or discontinued alongside GLP-1 receptor agonists; any dose reduction of insulin should be done in a stepwise manner with careful SMBG, particularly when GLP-1 receptor agonist therapy is initiated

See Glucagon-Like Peptide 1 Receptor Agonist Usage in Type 2 Diabetes in Primary Care for the UK and Beyond: A Narrative Review for a GLP-1 receptor agonist prescribing tool

GI disturbance. Possible increase in pancreatitis

Rarely, anaphylaxis, urticaria, URTIs, angio-oedema, and arthralgia

Peripheral and central oedema; contraindicated in HF and caution in macular oedema

Increases fracture risk

Possible link with bladder cancer; contraindicated in uninvestigated haematuria and bladder cancer; dipstick urine before starting

All should have access to SMBG, especially

drivers in view of risk of hypoglycaemia

Poor durability of effect

Avoid in frailty; see Diabetes and Frailty: An Expert Consensus Statement on the Management of Older Adults with Type 2 Diabetes for advice on managing diabetes in the older person with frailty

Give driving and hypoglycaemia advice; see Diabetes: Safe Driving and the DVLA


ACM=all-cause mortality; BG=blood glucose; BP=blood pressure; CAROLINA=Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes; CKD=chronic kidney disease; CV=cardiovascular; CVD=cardiovascular disease; DKA=diabetic ketoacidosis; DPP-4=dipeptidyl peptidase-4; DR=diabetic retinopathy; FBC=full blood count; GI=gastrointestinal; GLP-1=glucagon-like peptide-1; HF=heart failure; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction; HHF=hospitalisation for heart failure; IR=insulin resistance; IRIS=Insulin Resistance Intervention after Stroke; LA=lactic acidosis; MACE=major adverse cardiovascular events (composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); MARE=major adverse renal events; MHRA=Medicines and Regulatory products Healthcare Agency; MEN2=multiple endocrine neoplasia type 2; MI=myocardial infarction; MTC=medullary thyroid cancer; NG=NICE Guideline; QRISK2=Cardiovascular Risk Score 2; RCT=randomised controlled trial; SAD MANS=sulfonylureas, angiotensin-converting enzyme inhibitors, diuretics, direct renin inhibitors, metformin, angiotensin receptor blockers, nonsteroidal anti-inflammatory, SGLT2 inhibitors; SGLT2=sodium-glucose co-transporter-2; SMBG=self-monitoring of blood glucose; T2D=type 2 diabetes; UKPDS=UK Prospective Diabetes Study; URTIs=upper respiratory tract infections; UTIs=urinary tract infection

Table based on Summaries of Product Characteristics and the author’s clinical experience and appraisal of the literature.
Click on the link below for a downloadable PDF of the Primary Care Hack.

What Next After Metformin

Primary Care Hacks are developed by Dr Kevin Fernando, GP Partner, North Berwick Health Centre; GP with special interest in CVRM and medical education; Content Advisor for WebMD Medscape Global and UK. This Primary Care Hack is based on the author's interpretation of relevant summaries of product characteristics. Primary Care Hacks are for information for primary healthcare professionals in the UK only. They bring together currently available recommendations and/or prescribing information and indications for therapeutics licensed within Great Britain. Licensed indications and/or prescribing information for Northern Ireland may differ. You are advised to review local licensed indications before prescribing any therapeutic. Primary Care Hacks are reviewed intermittently to ensure the information is up to date at the time of publication. Primary Care Hacks are independently produced by WebMD Medscape UK Ltd (WebMD, LLC) and have not been created in conjunction with any guideline or prescribing body.