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Cardiovascular Disease Risk Reduction

Aug 12, 2017

Earlier initiation of diabetes medications can lead to reduced heart disease risk in type 2 patients.

Type 2 diabetes is accompanied to a large extent by other comorbid conditions of which CVD plays a major role. T2D patients have twofold increased risk for CVD (myocardial infarction, stroke, peripheral vascular disease) and this is the leading cause of mortality in this group of patients. Studies have shown that lowering HbA1c in T2D patients in itself has little or no effect on CVD risk reduction. However, when measures are taken to lower HbA1c levels, this serves as a double-edged sword and leads to a reduction of CVD risk as well. Other cardiac and metabolic risk factors include, obesity, insulin resistance, hypertension, and dyslipidemia. Changes in blood vessels are seen in coronary artery disease, hypertension, T2D and in obese patients.

In an observational cohort study carried out in Denmark between 2000 and 2012, HbA1c levels of T2D patients on metformin were monitored. Baseline HbA1c levels and levels 2-6 months after initiation of metformin were noted and risk of CVD was determined. Seventy-five percent of the patients had HbA1c levels <7% while that of half the patients change by +/-1%. Although an increase in HbA1c resulted in an increase in CVD risk, such increase was not found to be statistically significant.

In another study, 10,484 T2D elderly patients on metformin monotherapy needed escalation and was either switched to or added a sulfonylurea, a DPP4 inhibitor, or a Thiazolidinedione. metformin and DPP-4 inhibitor appeared more beneficial compared to metformin and SU with major adverse cardiac event rates of 39% and 42% respectively. However, a combination of metformin and DPP-4 was costlier compared to that of metformin and SU. Although SU are cheaper compared to other options, they have many side effects and must be used with caution.

Svensson et al. demonstrated in their study that diabetic drugs are more effective in blood glucose control if they are started early when the HbA1c levels are still low. This is especially true for sulfonylureas, metformin/sulfonylurea combination and insulin. Studies show an indirect relationship between HbA1c levels, CVD and mortality. When the baseline HbA1c levels are low, only a small reduction is achieved with treatment, which makes it hard to relate the change with the effect on CVD mortality risk. Diabetes patients with high initial HbA1c percentages have larger reductions in their levels with treatment.

In the CPRD study, DPP-4 inhibitors were compared with placebo and showed no cardiovascular benefit over placebo. The combination of metformin and DPP-4 inhibitor was shown to be both beneficial and cost effective compared to metformin and SU combination.

The LEADER trial showed that glucagon-like peptide 1 (GLP-1) receptor agonists liraglutide have a significant reduction of primary major adverse Cardiac events (MACE) like cardiac death, MI and stroke) at a rate of 13% while the SUSTAIN-6 trial demonstrated a risk reduction of 24% with Semaglutide use. Other trials like EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), IRIS (Insulin Resistance Intervention After Stroke Trial), and PROactive (PROspective pioglitAzone Clinical

Trial In macrovascular Events) had MACE reductions 14%, 24%, and 16% respectively.

In conclusion, the timing and steps taken to reduce HbA1c levels could help decrease CVD risk. Use of combination products of metformin and newer agents would lead to more effective blood glucose control. Newer antidiabetic medications also exert a cardioprotective effect in addition to lowering plasma glucose levels.  This, coupled with correction of traditional CVD risk factors like blood pressure and cholesterol, markedly reduces mortality rate in patients with T2D.

Practice Pearls:

  • Measures taken to lower HbA1c levels serve to reduce CVD risk.
  • Diabetic drugs, especially insulin and metformin, are more effective in blood glucose control if they are started early when the HbA1c levels are still low.
  • Use of combination products of metformin and newer agents would lead to more effective blood glucose control.
  • Correction of traditional CVD risk factors (blood pressure and cholesterol) significantly reduces CVD risk and mortality in patients with T2D.


Abdul-Ghani M. DeFronzo RA. Del Prato S. Chilton R. Singh R. Ryde EJ. Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived? Diabetes Care 2017 Jul; 40(7): 813-820. https://doi.org/10.2337/dc16-2736

Nichols GA. Reducing CV Risk in Diabetes: ‘When’ and ‘How’ Matter. Medscape – Jul 19, 2017.


Josephat Macharia, PharmD candidate, Lecom School of Pharmacy class of 2018