Inevitable trajectory of type 2 diabetes
Antihyperglycaemic therapy in type 2 diabetes
Incretin therapies
SGLT2 inhibitors





Management of diabetes can sometimes be a balancing act between the benefits of treatment versus the risks. On one side we are trying to provide symptomatic relief for our patients, avoid admission into hospital and reduce risk of complications, but we are also trying to avoid hypoglycaemia, medication side effects and weight gain.

A key question is does glycaemic control reduce complications? There have been a number of glycaemic interventions studies looking into this (Figure 1) and all showed a reduction in microvascular complications, but not always cardiovascular complications.

The Diabetes Control and Complications Trial (DCCT), a randomised controlled clinical trial, and the succeeding observational follow-up of the DCCT cohort in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, looked at the effects of intensive treatment on the microvascular complications of type 1 diabetes mellitus.

The DCCT proved that intensive treatment reduced the risks of retinopathy, nephropathy, and neuropathy by 35% to 90% compared with conventional treatment. The absolute risks of retinopathy and nephropathy were proportional to the mean glycosylated hemoglobin (HbA1c) level over the follow-up period preceding each event. Intensive treatment was most effective when begun early, before complications were detectable.

It concluded that intensive treatment should be started as soon as is safely possible after the onset of type 1 diabetes mellitus and maintained thereafter, aiming for a practicable target HbA1c level of 7.0% or less.1

A 2005 update looked at whether the use of intensive therapy as compared with conventional therapy affected the long-term incidence of cardiovascular disease. It found that intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes.2



One of the biggest risks to patients with diabetes is hypoglycaemia, especially in older patients. There are multiple causes and patients with tight control can have symptoms of hypos and be prone to collapse without warning. Family and friends should therefore be trained in the use of treatments such as IM glucagon and glucogel.

There should be a review with the diabetes care team following hypoglycaemia. The morbidity of hypoglycaemia is affected by age and can include neurological effects such as coma, seizures, psychological and cognitive dysfunction. It can also have cardiovascular effects in the form of myocardial ischaemia and cardia arrhythmias. Musculoskeletal effects come in the form of falls and accidents, fractures, dislocations and driving mishaps.


Inevitable trajectory of type 2 diabetes

These is an inevitable trajectory of type 2 diabetes and the typical patterns of progression for glucose levels, insulin resistance, and beta-cell function in patients with type 2 diabetes.3

A characteristic finding in type 2 diabetes is insulin resistance. This is thought to be influenced by genetic and, perhaps, congenital factors and may be augmented by acquired or environmental factors, such as obesity, sedentary lifestyle, and ageing.3

Stages of progression include prediabetes, clinical diagnosis and overt type 2 diabetes. Most studies support that insulin resistance precedes hyperglycaemia and in the early stages of type 2 diabetes, glucose levels remain normal due to increased insulin secretion (hyperinsulinaemia) via compensatory beta cells.3

Over time, beta cells can no longer compensate by maintaining a hyperinsulinaemic state, leading to increased levels of postprandial plasma glucose (PPG) and increased hepatic glucose production.3 Continued decline in beta-cell function and insulin resistance result in overt diabetes, with elevated fasting plasma glucose (FPG) levels above 6.9mmol/l.3



Antihyperglycaemic therapy in type 2 diabetes: general recommendations

In most patients, therapy begins with lifestyle changes and then metformin monotherapy is added at, or soon after, diagnosis (unless there are explicit contraindications). If the HbA1c target is not achieved after three months, then one of five treatment options combined with metformin and sulfonylurea are considered. These are thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide (GLP)-1 receptor agonists, or basal insulin.

Choice is based on patient and drug characteristics, with the over-riding goal of improving glycaemic control while minimising side effects. Shared decisionmaking with the patient may help in the selection of therapeutic options.

In patients intolerant of, or with contraindications for, metformin, select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line therapy, especially when HbA1c is very high (eg. ≥9.0%).

The therapeutic regimen should include some basal insulin before moving to more complex insulin strategies.



Metformin is an old drug and its major effect is to suppress hepatic gluconeogensis, reducing glucose output from liver and it also increases peripheral insulin sensitivity, increasing glucose uptake and utilisation.4,5 Its cardiovascular protective effects cannot be fully explained by glucose lowering and there are various theories proposed as to how it might happen.

The evidence for benefit from metformin is based on the UKPD study in overweight patients. Many guidelines suggest using first line when BMI is not more than 30.6 It has a low hypo risk, weight neutrality and a long history of established safety and clinical use.



Sulphonylureas stimulate endogenous insulin secretion and are glucose independent. They are associated with weight gain and can cause hypos. Particular caution is needed with variable oral intake and chronic kidney disease and gliclazide is the most commonly used drug.

They close potassium channels on beta cells, stimulating release of stored insulin.7 Similar potassium channels are present on cardiac myocyctes.



Thiazolidinediones (TZDs) increase insulin sensitivity by acting as ligands for the nuclear hormone receptor PPARγ, and regulating its transcriptional activity. PPARγ is found predominantly in adipose tissue, but it is also found in pancreatic beta cells, muscle and liver.

TZDs act on PPARγ in adipocytes promoting adipogenesis, predominantly in pre-adipocytes from subcutaneous deposits where the increased transcription of transporters and enzymes involved in fatty acid uptake and lipogenesis increases the deposition of lipid in these adipocytes. This reduces hyperglycaemia by reducing concentrations of nonesterified fatty acids and triglycerides. The consequent effects on the glucose–fatty acid (Randle) cycle is to reduce the availability of fatty acids as an energy source, thereby favouring the utilisation of glucose. Additionally, TZDs increase transcription of GLUT- 4 glucose transporters that directly facilitate glucose uptake.8

Pioglitazone is the only drug in this class left on market. In the PROACTIVE study there was shown to be reduced cardiac events, but this was not a predefined primary endpoint and should be viewed with a degree of caution. Perceived side effects and risks of therapy (and probably the legacy of the rosiglitazone story) has meant that this drug is less commonly prescribed now.9

Pioglitazone improves insulin sensitivity, but fluid retention is a really serious issue. There is also an increased fracture risk in women and possible link with bladder cancer.


Incretin therapies

Incretins are GI hormones and they enhance insulin release (and suppress glucagon) after carbohydrate ingestion so are“glucose dependent”. They delay absorption of digested food leading to a feeling of satiety and are degraded by the enzyme dipeptidylpeptidase-4 (DPP-4).

Oral glucose stimulates the release of the endogenous incretins glucagon-like peptide-1 (GLP-1) and glucosedependent insulin-releasing polypeptide (GIP). These stimulate insulin release and inhibit glucagon release resulting in lower blood glucose. They are rapidly inactivated by dipeptidyl peptidase-4 (DPP-4). The DPP- 4 inhibitors prolong the action of endogenous incretins, enhancing the first-phase insulin response.

There are now five DPP-4 inhibitors on the market. They are all slightly different, but of particular note is that vildagliptin needs LFT monitoring and linagliptin is excreted in bile rather than renally, which may provide an advantage. It needs to be recognised, however, that all these drugs will only give a very modest reduction in HbA1c and are probably going to be less effective in patients who have had diabetes a long time and as a result have established beta-cell dysfunction.

GLP-1 receptor agonist injections also help glycaemic control and weight loss, again with low hypo risk.


SGLT2 inhibitors

The novel mechanism of action may make these drugs useful in a number of circumstances and at any stage in the patient’s history of diabetes (unless they have renal impairment at which point they lose their efficacy). Interestingly these drugs also cause a mild diuresis—resulting in a small reduction in blood pressure. Trials such as CANVASS10 have shown positive cardiovascular and potential mortality benefits.

SGLT2 inhibitors such as dapagliflozin, reduce renal threshold for excreting glucose. They also have glycaemic and blood pressure benefits, but are not insulin dependent. Caution is needed in the elderly due to risk of postural hypotension.



In conclusion, we need to individualise targets and consider treatment benefits and potential side effects. We also need to avoid risk of hypoglycaemia if possible with our expanding field of options.



1. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002; 287(19): 2563–69

2. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353(25): 2643–53

3. Simonson GD, Kendall DM. Diagnosis of insulin resistance and associated syndromes: the spectrum from the metabolic syndrome to type 2 diabetes mellitus. Coron Artery Dis 2005; 16 (8): 465–72

4. Boyle JG, McKay G, Fisher M. Drugs for diabetes: part 1 metformin. Br J Cardiol 2010; 17: 231–4

5. Metformin Summary of Product Characteristics. Available at (accessed October 2014)

6. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854–65

7. Smith CJ, Fisher M, McKay G. Drugs for diabetes: part 2 sulphonylureas Br J Cardiol 2010; 17: 279–82

8. McGrane D, Fisher M, McKay G. Drugs for diabetes: part 3 thiazolidinediones Br J Cardiol 2011; 18: 24–7

9. Dormandy JA, Charbonnel B, Eckland DJ et al. Secondary prevention of macrovascular events in patients with type 2 diabetes. Lancet 2005; 366: 1279–89

10. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377(7): 644–57