Diabetes – Medications

Step 1	Good dietary habits and physical activity
Step 2	Add metformin (use a Sulphonylurea if metformin not tolerated or contraindicated)
Step 3	Add a Sulphonylurea
Step 4	If symptoms of insulin deficiency start insulin                                                             OR
	If only on a sulphonylurea add:     DPP-4 inhibitor       or    SGLT-2 inhibitor        or    Thiazolidinedione                   OR
	If obesity and/or poor dietary habits add a GLP-1 agonist                                    OR
	Pioglitazone or Acarbose can be added to Metformin/Sulphonylurea combination       OR
	DPP-4 inhibitor or SGLT-2 inhibitor can be tried in place of sulphonylurea (with metformin)
Step 5	i. Continue metformin if able ii. If symptoms of insulin deficiency start insulin iii. use an alternate oral agent eg SGLT-2 inhibitor for DPP-4 inhibitor   OR iv. Use triple therapy with Metformin + Sulphonylurea and either Pioglitazone, Acarbose or a GLP-1 agonist
Step 6	Start insulin

METFORMIN

• Med of choice in overweight person w T2DM
• improves cardio outcomes
• no weight gain
• limited risk of hypoglycaemia
• Action
  • reduces hepatic glucose output + insulin resistance
• Side effects
  • GIT sx (N/V, anorexia, diar, abdo cramps)
  • Lac (cease 48hrs before surgery or contrast radiography)

GLP-1 

• is an incretin hormone or gut hormone, which is secreted from the intestinal cells in response to nutrient stimulus, primarily glucose. 
• People with T2D have diminished levels of endogenous GLP-1, which results in:
  • Increased gastric emptying
  • Decreased glucagon suppression that results in increased hepatic gluconeogenesis
  • Glucose mediated insulin secretion
  • Decreased satiety – people with T2D to complain they are always hungry and never feel full after eating.
• Currently, there are 2 approaches to enhancing GLP-1 in an effort to correct the deficiency.  

Oral DDP-4 

inhibitors 

• reduce the degradation of endogenous GLP-1
• thereby providing physiologic concentrations of the GLP-1 hormone.
• Side effects:
  • nasopharyngitis, headache, and upper respiratory infections
• Since, DPP-4 inhibitors do not affect GI motility, they promote a weight neutral effect, which is still beneficial for most people with T2D.

injectable GLP-1 

receptor agonists

• provide exogenous GLP-1 hormone in supraphysiologic concentrations
• slows gastric emptying and increasing satiety
• Since GLP-1 agonists are 6 to 10 times greater than endogenous GLP-1 levels and slow GI motility, nausea and possibly vomiting are the most common side effects; 
• especially if the patient does not change (decrease) their usual food intake. 
• The nausea and vomiting can also be minimized by slow titration of the GLP-1 agonist from starting dose to therapeutic dose. 
• Weight loss is often observed in patients taking GLP-1 agonists. 

• DPP-4 inhibitors primarily target the postprandial plasma glucose (PPG), whereas, GLP-1 receptor agonists target fasting plasma glucose (FPG) as well as PPG. This is the reason a higher A1c lowering effect is observed with GLP-1 agonists, due to the FPG lowering effect.

• Both drug classes have low hypoglycemic risk when used as monotherapy or in combination with non-secretagogues or insulin. Recent studies have demonstrated favorable cardiovascular outcomes; particularly, decreased systolic blood pressure and decreased triglyceride levels in both DPP-4 inhibitors and GLP-1 agonists.

• Clearly both classes are treatment options for people with T2D, however, both are unique in their mechanism of action, adverse drug effect profile, and A1c lowering ability. Therefore, DPP-4 inhibitors should not be referred to as the oral version of GLP-1 agonists.

SGLT2 inhibitors 

• glucose filtration by the kidney and the role of sodium glucose co-transporter 2 (SGLT2) 
  • glucose is normally filtered in the kidney and is reabsorbed in the proximal tubules
    • glycosuria occurs when the renal threshold of glucose (blood glucose of approximately 10 mmol/l (160-180 mg/dl) has been reached
      • at this threshold the proximal tubule cannot reabsorb all of the filtered glucose, resulting in glycosuria
    • in total, 98% of the urinary glucose is transported across the membrane of the proximal tubule by SGLT2
    • a naturally occurring mutation in the SLC5A2 gene, resulting in a defective SGLT2 protein, produces significant glycosuria
      • individuals who have this mutation have not been seen to have significant problems related to the glycosuria, such as urinary tract infections (UTIs) (1)
      • a therapeutic option in type 2 diabetics is to mimic the effect of the SLC5A2 mutation and prevent the reabsorption of renal-filtered glucose back into the circulation, thereby reducing hyperglycaemia, without the side effects of weight gain or hypoglycaemia
• SGLT2 inhibitor drugs: 
  • SGLT2 inhibitor drugs (dapagliflozin, canagliflozin, empagliflozin, ertugliflozin)
  • SGLT2 inhibitors correct a novel pathophysiological defect, have an insulin-independent action, are efficacious with glycosylated hemoglobin reduction ranging from 0.5% to 1.5%, promote weight loss, have a low incidence of hypoglycemia, complement the action of other antidiabetic agents, and can be used at any stage of diabetes 
  • a systematic review of these dapagliflozin and canagliflozin drugs being used as second or third line drugs has been undertaken
    • Seven trials were reviewed.
      • dapagliflozin 10 mg reduced HbA1c by -0.54% (weighted mean differences (WMD), 95% CI -0.67 to -0.40) compared to placebo, but there was no difference compared to glipizide
      • canagliflozin reduced HbA1c slightly more than sitagliptin (up to -0.21% vs sitagliptin)
      • both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD -1.81 kg (95% CI -2.04 to -1.57), canagliflozin up to -2.3 kg compared to placebo)
    • the study authors concluded that dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed
  • adverse effects:
    • generally well tolerated
    • however, due to side effects, such as repeated urinary tract and genital infections, increased haematocrit, and decreased blood pressure, appropriate patient selection for drug initiation and close monitoring after initiation will be important 
      • genital infections
        • an increase in genital infections in the dapagliflozin groups compared with controls in almost all the studies, with the incidence increasing with higher doses of dapagliflozin
          • reported incidence varied from 3% to 13% versus 0% to 5% in the placebo group
          • when dapagliflozin monotherapy was compared with metformin monotherapy, the incidence of genital infections was 2%-7% versus 2%, respectively
      • UTIs
        • reported urinary tract infection rates were 1%-12.9% in the dapagliflozin groups versus 0%-6.2% in controls and 9% on metformin monotherapy

SGLT2 inhibitors in chronic kidney disease (CKD)

• 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) 

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 inhibitorsinhibit DDP4 which prolongs action of GLP-1 which enhances insulin secretion + inhibits glucagon secretionMainly 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 analoguesincrease 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 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	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	Gastrointestinal symptoms bloating and flatulence that can be difficult to tolerate	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	Worsening of heart failure, increased fracture risk macular oedema cardiac ischaemia bladder cancer	Osteoporosis macular oedema heart failure liver disease

Medicine class	Active ingredient(s)	Brand name(s)
FDC products
DPP 4 inhibitor/metformin	Alogliptin/metformin	Nesina Met
	Linagliptin/metformin	Trajentamet
	Saxagliptin/metformin XR	Kombiglyze XR
	Sitagliptin/metformin	Janumet
	Sitagliptin/metformin XR	Janumet XR
	Vildagliptin/metformin	Galvumet
DPP 4 inhibitor/SGLT2	Linagliptin/empagliflozin	Glyxambi
	Saxagliptin/dapagliflozin	Qtern
	Sitagliptin/ertugliflozin	Steglujan
SGLT2 inhibitor/metformin	Dapagliflozin/metformin XR	Xigduo XR
	Empagliflozin/metformin XR	Jardiamet
	Ertugliflozin/metformin XR	Segluromet

Clinical Situations

Clinical situation	Consider an alternative second-line medicine?	Alternative medicine
If adverse effects are unacceptable or intolerable	Yes, if adverse effects cannot be controlled through dose adjustment or diet/lifestyle or using short-acting sulfonylurea	If weight gain is problematic: a DPP-4 inhibitor, SGLT2 inhibitor, or GLP-1 analogue may be appropriate1, If hypoglycaemia is problematic: a DPP-4 inhibitor or SGLT2 inhibitor may be appropriate
During pregnancy and while breastfeeding	Yes. Sulfonylureas are contraindicated4	Insulin is safe to use, but seek specialist advicE
Children under 18 years of age	Yes. Sulfonylureas are not recommended, limited data on the safety and efficacy of sulfonylureas in children	Seek specialist advice
Severe hepatic impairment	Yes. Sulfonylureas are contraindicated	Limited experience but options include sitagliptin,saxagliptin and linagliptin,exenatide or insulin
Severe renal impairment	Yes or reduce sulfonylurea dosage due to increased risk of hypoglycaemia. Short-acting agents are preferred	Options include sitagliptin, alogliptin, saxagliptin and vildagliptin with dose adjustment, and linagliptin without dose adjustment

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.

INSULIN

Nb: T2DM can be managed w single daily dose of intermediate or long acting insulin added to their OHG, quick acting insulin not necc needed.

• Reduces microvascular complications
• Neg: wt gain
• HbA1c:  1.5 – 3.5% w monotherapy

Example:

Glargine (Lantus) – start 10 units at morning or night

Titrate based on finger prick glucose readings every 2-4 days

Fasting Glucose	Algorithm
<4.0mmol/L	Reduce Glargine dose by 2-4 units
4.0 – 7.0mmol/L	Leave Glargine dose unchanged
7.1 – 8.0mmol/L	Add 2 units Glargine
8.1 – 10.0mmol/L	Add 4 units Glargine
10mmol/L or greater	Add 6 units Glargine

+/- Glulisine (Apidra) – 4 units w meal at which 2 hour post prandial glucose levels are most elevated above the target range

Short Acting Insuilin

• Novorapid – fast/rapid acting, onset 1-20min, duration 3-5 hrs, eat immediately after injection. 
• Actrapid (misnomer), short acting, onset 30min, duration 6-8 hrs, eat 30min after injection
• Regimens

For T1 DM: BASAL BOLUS REGIMEN

• BASAL: 40% of daily insulin requirement delivered by daily long-acting insulin glargine (Lantus)
• BOLUS: insulin to correct for carbohydrate intake delivered by rapid-acting insulin aspart (Novorapid)

• Daily insulin is approx. 05-0.8 U/kg/day. 
• Start with 0.3-0.4 U/kg/day divided 40/60 and titrate doses until targets achieved.
• Basal insulin is adjusted to achieve target fasting capillary glucose concentrations.
• Bolus insulin is titrated considering basal glucose, intended carbohydrate intake and physical activity.

2. CONTINUOUS SUBCUT INSULIN INFUSION (CSII)

• CSII uses an external insulin pump programmed to deliver a basal short-acting insulin infusion throughout the day and night, and bolus short-acting insulin doses as required. 

• Requirements:

• motivation, education and supervision by specialist diabetes centre.
• close glucose monitoring, carb counting and careful selection of bolus insulin doses.
• action plan in case of pump malfunction to immediately transition to basal bolus regimen

• Logistics:
• Disposable catheters are used and the site needs to be changed at least every 3 days.

• Complications:

• injection site abscesses
• catheter blockages

• The newest insulin pumps are able to link with subcutaneous continuous glucose monitors, enabling more intensive blood glucose monitoring, alarm systems for hypoglycaemia or hyperglycaemia and automatic cessation of the infusion in the event of hypoglycaemia. 

3. MIXED INSULIN REGIMEN