Diabetes medications and glucose control

The aim of treatment in T2DM is remission – especially in early disease
The Legacy theory – early, more aggressive treatment has better outcomes in the long term
However… intensive glycaemic control actually causes an increase in risk of all-cause mortality. Probably many of those are hypoglycaemia and related to arrythmias
Rescue therapy for symptomatic hyperglycaemia – consider gliclazide and insulin
Management of chronic hyperglycaemia – think metformin, SGLT2 inhibitors, gliptins / DPP-4 inhibitors
Insulin is not started at a specific HbA1c (it’s very patient dependent). For some, insulin may be considered at an HbA1c of around 70 or 80, in others 100.
In general, the choice of treatment in DM depends on HbA1c, CV risk, patient preference / habits / routine, kidney function
Target CBG target range for most diabetic inpatients should be 6-10 (4-6 is ‘looming hypoglycaemia’ and should be avoided especially if on insulin or gliclazide)

First line in T2DM
Decreases gluconeogenesis and increases peripheral utilisation of glucose
Cheap
Virtually no risk of hypoglycaemia if used alone
Give after food
Dosing
- - Gradually increase over several weeks
  - 500mg OD for 1/52, then 500mg BD for 1/52, then 500mg TDS
  - Max dose 2g daily
  - If using Modified Release prep – increase from 500mg OD to 1g BD
  - Review dose if eGFR <45
  - Can initiate if eGFR >45, but there might be better options
  - Contraindicated if eGFR <30 or there’s an AKI
Monitor renal function once or twice a year whilst on treatment (depending on risk).
Best to avoid in liver failure, ETOH dependence, cardio-respiratory failure, recent MI, shock – all increase risk of lactic acidosis
Withhold if patient is at acute risk of AKI
Side effects
- - B12 deficiency – dose-related, and more common with long treatment duration and Crohn’s. Check levels if anaemic / neuropathic symptoms
  - GI symptoms are common, especially at the start of treatment, and often resolve. Can try Metformin MR if troublesome.
  - Lactic acidosis – metformin exacerbates lactic acidosis by decreasing activity of pyruvate carboxylase
Interactions
- - It is a substrate of both organic cation transporters OCT1 and OCT 2, so care when using with other OCT inducers or inhibitors (eg verapamil, rifampicin, cimetidine, ranolazine, trimethoprim)

If metformin contraindicated / not tolerated, first line options include
- - DPP-4 inhibitor (gliptins)
  - Pioglitazone
  - A sulfonylurea
  - SGLT-2 inhibitor
Add on any of these drugs if monotherapy is ineffective
If dual therapy ineffective
- - Consider triple therapy (But avoid combining dapagliflozin with pioglitazone)
  - Or consider insulin
If triple therapy ineffective
- - Consider switching one drug for a GLP-1 receptor agonist (especially if BMI >35, or insulin would have significant occupational implications)

Eg Dapagliflozin 10mg OD, Empagaglofozin 10mg OD
Often the next add-on treatment with metformin if HF, IHD or high CV risk (start after metformin established)
Cause glycosuria (patients can lose 200 cal/day in sugar)
Side effects
- - UTIs, thrush, Fournier’s gangrene
  - Euglycaemic ketoacidosis (stop if unwell)
Lots of benefits
- - Reduce CV risk, weight and BP
  - Treat HF and CKD
  - Low risk of hypoglycaemia
If acutely unwell – consider stopping it (and explain to patients about sick day rules)
Contraindicated if
- - Previous DKA (relatively contraindicated if at high risk of DKA, eg DM very poorly controlled)
  - If following very low carb / ketogenic diet
  - T1DM
  - Pregnancy / breastfeeding
In CKD
- - For some SGLT-2 inhibitors avoid starting if eGFR <60, and stop if eGFR <45
  - However, Dapagliflozin is licensed in CKD (might avoid if eGFR <15)

eg Gliclazide, glibenclamide, tolbutamide, glipizide, glimerpiride
Promote insulin release from the pancreatic beta cell
Gliclazide dose is 40-80mg OD, up to 160mg OD. If >160mg give BD. Max 320mg daily.
Give before food
Most advise not to be used long term now
Not useful for long standing DM as pancreas stopped working so well by then
Avoid in porphyria, severe liver or kidney disease
Side effects – weight gain, hypoglycaemia, GI symptoms, deranged LFTs, hyponatraemia

Eg sitagliptin 100mg OD, linagliptin 5mg OD
Work by preventing the breakdown of GLP1 and GIP
Low risk of hypos – so good for elderly patients
Reduce dose in renal impairment, but can be used in quite severe CKD
Side effects include GI symptoms, pancreatitis, headache/dizziness/tremor. However – side effects less common than other DM medications
Not generally used if history of pancreatitis
Sitagliptin increases digoxin levels

Eg Dulaglutide (weekly), Semaglutide (weekly), liraglutide (daily), tirzepatide
Also reduce CV risk, weight and BP
Weekly or daily injectables, oral preps also now available
Reduce appetite, increase insulin production, positive effects on heart and liver, reduces rates of gastric emptying
Can cause nausea
Used if triple oral therapy doesn’t work or not tolerated, and BMI >35, or BMI < 35 and can’t take insulin (eg for job)
Only continue if HbA1c falls by 11 and weight falls by 3% in 6 months of treatment
If adding to gliclazide or insulin – consider reducing their dose
Do not add to a DPP-4 inhibitor
Avoid if history of pancreatitis, or in ESRF
More details in obesity section

Dose is 15mg – 45mg OD
May increase risk of HF, especially when combined with insulin. Stop if signs of HF.
May also take a number of weeks to achieve maximal effect
Might increase risk of fractures
Small increase risk of bladder cancer (avoid if at risk – eg family history, cyclophosphamide treatment, radiotherapy to pelvis). Avoid in uninvestigated haematuria
Check LFTs first – contraindicated if ALT > 2.5x ULN
Not used much – causes weight gain and fluid accumulation